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Review article 329
Elicited hippocampal theta rhythm: a screen for anxiolytic
and procognitive drugs through changes in hippocampal
function?
Neil McNaughtona, Bernat Kocsisb and Mihaly Hajósc
Hippocampal damage produces cognitive deficits similar
to dementia and changes in emotional and motivated
reactions similar to anxiolytic drugs. The gross electrical
activity of the hippocampus contains a marked ‘theta
rhythm’. This is a relatively high voltage sinusoidal
waveform, resulting from synchronous phasic firing of
cells, variation in which correlates with behavioural state.
Like the hippocampus, theta has been linked to both
cognitive and emotional functions. Critically, it has recently
been shown that restoration of theta-like rhythmicity can
restore lost cognitive function. We review the effects of
systemic administration of drugs on hippocampal theta
elicited by stimulation of the reticular formation. We
conclude that reductions in the frequency of reticularelicited theta provide what is currently the best in-vivo
means of detecting antianxiety drugs. We also suggest that
increases in the power of reticular-elicited theta could
detect drugs useful in the treatment of disorders, such as
dementia, that involve memory loss. We argue that these
Introduction
In this paper, we review the effects of systemically
administered drugs on hippocampal ‘theta rhythm’ that
has been elicited by high-frequency, nonphasic, stimulation of systems afferent to the hippocampus. We focus in
particular on drugs that can affect anxiety and cognition
and will argue that their action on the ascending systems
that elicit and control theta makes a significant contribution to their behavioural and clinical profile. From this, we
suggest that reticular-elicited theta can be used to detect
both anxiolytic and, perhaps also, procognitive drugs.
The hippocampus is well known for its involvement,
together with other temporal lobe structures, in learning
and the acquisition and recall of memories (O’Keefe and
Nadel, 1978; Cohen and Eichenbaum, 1993). From this, it
seems likely that treatments that enhance hippocampal
function could have at least some procognitive effects,
reversing at least some of the symptoms of dementia.
The hippocampus, however, has also been linked with the
control of emotion (Papez, 1937; MacLean, 1949, 1990).
In particular, a very strong qualitative parallel has been
drawn between the effects of anxiolytic drugs and
hippocampal lesions (Gray and McNaughton, 2000). This
suggests that treatments that degrade hippocampal
function could have at least some anxiolytic effects.
functionally distinct effects should be seen as indirect and
that each results from a change in a single form of
cognitive–emotional processing that particularly involves
the hippocampus. Behavioural Pharmacology 18:329–346
c 2007 Lippincott Williams & Wilkins.
Behavioural Pharmacology 2007, 18:329–346
Keywords: anxiety, drug effects, frequency, hippocampus, memory, power,
theta rhythm
a
Department of Psychology, University of Otago, Dunedin, New Zealand,
Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, Massachusetts and cDepartment of Neuroscience,
Pfizer Global Research and Development, Eastern Point Road, Groton,
Connecticut, USA
b
Correspondence to Professor Neil McNaughton, PhD, Department Psychology,
University of Otago, POB56, Dunedin 9054, New Zealand
E-mail: [email protected]
Received 9 April 2007 Accepted as revised 16 June 2007
The parallel between hippocampal lesions and anxiolytic
drug action extends to tests that are often viewed as
assessing purely cognitive processes. Novel [acting via
serotonin (5-hydroxytryptamine; 5-HT) neurotransmission] and classical [acting via g-aminobutyric acid
(GABA) neurotransmission] anxiolytic drugs act through
quite different primary neural mechanisms and have
quite different side effects both in animal tests and in the
clinic. Nonetheless, they have a common action on
the Morris Water Maze Test (McNaughton and Morris,
1987, 1992). This is the most common current test of
hippocampal-mediated cognitive function and yet also
appears to be a test of anxiolytic action, and is one of the
few behavioural tests to have a linear dose–response
curve with novel anxiolytic drugs (McNaughton and
Morris, 1992). This suggests that hippocampal function
can range along a continuum between procognitive/
proanxiety and anticognitive/antianxiety actions. We will
argue below that its functional position on this continuum can adjusted by the level (in terms of frequency
or power) of the hippocampal theta rhythm; and that
alteration of the ascending control of theta is the basis for
some of the behavioural effects and clinical properties of
the drugs we will review. We, however, will also argue, at
the end of this paper, that procognitive and anxiolytic
actions may be partially separable and, therefore, that
c 2007 Lippincott Williams & Wilkins
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330
Behavioural Pharmacology 2007, Vol 18 Nos 5 & 6
obtaining one effect may not necessarily mean obtaining
the other.
to have major functional implications and potential
therapeutic applications.
Hippocampal theta rhythm (theta activity) is an approximately sinusoidal electroencephalogram (EEG) activity
that can be recorded at amplitudes as great as 1000 mV
through gross electrodes placed almost anywhere in and
around the hippocampal formation and entorhinal cortex.
[The name ‘theta rhythm’ derives from early experiments
with anaesthetized or unmoving rabbits, cats and dogs
in whom the frequency is in the human EEG theta band
(4–7 Hz)]. Hippocampal theta, however, can range from
4 to even 14 Hz (Vanderwolf et al., 1975). Human frontal
theta rhythm is substantially different from hippocampal
theta (Burgess and Gruzelier, 1997), despite some
superficial parallels. Frontal or occipital theta may sometimes be linked to hippocampal theta. It has highly
consistent behavioural correlates in rats (Vanderwolf,
1969) and its apparent simplicity and ease of recording
have resulted in a voluminous literature (Bland, 1986;
Winson, 1990; O’Keefe, 1993; Kirk, 1997; Vertes
and Kocsis, 1997; Sainsbury, 1998; O’Keefe and Burgess,
1999; Buzsáki, 2002, 2005; Burgess and O’Keefe, 2005;
Hasselmo, 2005; Lisman, 2005; Vertes, 2005).
Theta rhythm is easily recorded in rats, rabbits, cats, dogs
and other small mammals. Its existence in primates has
been controversial. As with the rat data reviewed in the
remainder of this paper, theta, however, can also be
elicited in the human hippocampus by hypothalamic
stimulation (Sano et al., 1970) and clear theta activity,
with a pharmacological resemblance to rodent theta, has
been demonstrated in urethane-anaesthetized monkeys
(Stewart and Fox, 1991). A number of recent studies have
reported theta from human hippocampus in analogues of
tasks in which rats produce theta (O’Keefe and Burgess,
1999; Tesche and Karhu, 2000; Cantero et al., 2003;
Ekstrom et al., 2005). The data obtained in rodents that
we review below, therefore, are likely to reflect neural
changes that have functional implications for human
clinical conditions.
Theta has been suggested to be involved in sensorimotor
integration (Bland and Oddie, 2002) but can also occur in
the absence of movement when the animal is aroused
(Sainsbury, 1998). Many theories have postulated a
contribution of theta activity to cognitive processing by
the hippocampus (O’Keefe and Nadel, 1978; Fox and
Ranck, 1979; Gray, 1982; Miller, 1991; Worden, 1992;
Carpenter and Grossberg, 1993; Cohen and Eichenbaum,
1993; Gray and McNaughton, 2000); and, in particular, to
the shared behavioural effects of anxiolytic drugs, septal
lesions and hippocampal lesions (Gray, 1982; Gray and
McNaughton, 2000).
It has recently been shown that restoring theta-like
rhythmicity, using an electrical circuit to bypass blocked
inputs to the hippocampus, can restore learning in the
Morris Water Maze Test (McNaughton et al., 2006). This
is one case where a procognitive effect of increased theta
has been demonstrated – and gives some hope that
elicitation of theta can provide a simple test of potential
procognitive action. Equally, an anxiolytic benzodiazepine
injected directly into the supramammillary nucleus, one
of the nuclei that controls theta frequency (Kirk and
McNaughton, 1991, 1993; Vertes and Kocsis, 1994;
Kocsis and Vertes, 1997; Kocsis and Kaminski, 2006),
has similar effects on both theta frequency and behaviour
to those it has when injected systemically (Woodnorth
and McNaughton, 2002). This suggests that elicitation of
theta can provide a simple test of potential anxiolytic
action. A good reason exists, then, to see the capacity of a
drug to increase or decrease theta rhythm as being likely
Elicitation of theta
It has been known for some time that high frequency
trains of stimulation of the midbrain reticular formation
can elicit hippocampal theta rhythm (Green and Arduini,
1954; Sailer and Stumpf, 1957; Stumpf, 1965). Increasing
levels of stimulation produce a linear increase in the
frequency of theta both in anaesthetized (Sailer and
Stumpf, 1957) and in free-moving rats (Fig. 1).
It is important to note that, unless the stimulation
activates an adjacent motor pathway, elicited theta is not
normally accompanied by movement, with reticular
placements. Movement can affect results with drugs that
interact with the cholinergic system (see below) and, for
that reason, can produce apparent differences between
free-moving and anaesthetized preparations. Pharmacologically speaking, there appear to be two main ‘types’ of
theta in unanaesthetized animals. The theta accompanying movement is insensitive to muscarinic antagonists,
whereas theta occurring during immobility (spontaneous
or drug-induced) is blocked by them (Vanderwolf, 1988).
Serotonin depletion by itself does not have obvious
effects on movement-related theta. The combination of
5-HT depletion and muscarinic antagonists, however,
results in a total abolition of theta whether the animal is
moving or not (Vanderwolf and Baker, 1986; Vanderwolf,
1987). This was interpreted by Vanderwolf as showing
that movement-related theta has a combination of
underlying cholinergic and serotonergic components,
either of which permits theta to occur. Later studies
have failed to demonstrate a role for 5-HT in the active
promotion of theta. Averaging techniques and spectral
analysis, however, have confirmed the presence of a weak
atropine-resistant theta even under urethane anaesthesia
elicited by high intensity brainstem stimulation (Kocsis
and Li, 2004; Li et al., 2007). This shows that
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Elicited hippocampal theta rhythm McNaughton et al. 331
Fig. 1
(a)
(b)
11
160 µA
Theta frequency (Hz)
10
120 µA
80 µA
9
8
7
6
40 µA
5
20 40 60 80 100 120
Stimulation strength (µA)
Stimulation
0
1
s
2
Effects of reticular stimulation on hippocampal theta rhythm in a single unanaesthetized rat. Increasing intensities of stimulation produce theta at
increasing frequency and amplitude. (a) Examples of theta production at high intensities, stimulation produces movement and theta that outlasts the
stimulation (see 160 mA 2). (b) In the absence of movement frequency is linearly related to intensity (McNaughton and Sedgwick, 1978).
nonmovement theta has at least some underlying
noncholinergic component. Cholinergic-supported and
serotonergic-supported theta can, therefore, occur either
separately or concurrently depending on the state of the
animal (Leung, 1985).
The entire range of frequencies of theta can be elicited,
unchanged, in the presence of anticholinergic drugs
(McNaughton and Sedgwick, 1978); but at all frequencies the occurrence or not of theta appeared to depend on
whether, at the time of stimulation, the animal was
moving, however slightly (McNaughton, unpublished
observations). Similarly, in a figure reporting the effects
of atropine on theta in freely moving animals (Vanderwolf,
1975, Fig. 5), such theta as occurs after atropine is
essentially identical to that which occurs before atropine
but, in the absence of movement, theta is not elicited.
Some have linked nonmovement (cholinergic) theta with
lower frequencies and movement theta with higher
frequencies. This, however, is due to the behavioural
conditions under which such theta is typically obtained in
the laboratory. With appropriate stimuli, nonmovement
theta can reach frequencies as high as 12 Hz (Sainsbury
RS, personal communication, Fig. 1 in Sainsbury and
Montoya, 1984).
These results have been interpreted (Gray and
McNaughton, 2000) as evidence for multiple ‘gates’ that
permit theta to occur but do not affect its frequency.
Different gates can permit (release) theta, separately or
jointly. Which specific gates are operative would
depend on the behavioural state of the animal. The
presence of these gating systems is important for our
understanding of the different effects that can
be obtained with elicitation of theta from different
ascending systems.
Stimulation of ascending cholinergic systems can elicit
clear theta; but increasing levels of stimulation have a
very modest effect on its frequency (Kirk, 1993).
Injections of local anaesthetic into a pathway that arises
in the pedunculopontine tegmentum do not alter
frequency of theta at all – producing a simple on/off
effect of the injections (McNaughton et al., 1997). By
contrast, similar injections into the ascending reticular
pathway produce major changes in frequency (Kirk, 1993;
Kirk and McNaughton, 1993). This suggests that
stimulation of the pedunculopontine tegmentum activates two separate pathways: a presumed cholinergic one
which has a permissive effect on the production of theta;
and a noncholinergic one, which travels by some different
route and produces a modest activation of a frequency–
control system, gated by the cholinergic system.
Likewise, electrical stimulation within the median raphe
(Graeff et al., 1980; Peck and Vanderwolf, 1991) elicits
both immobility and a theta rhythm which shows only a
moderate increase with stimulus intensity. This elicitation of theta is unaffected by the administration of
serotonergic drugs, and is blocked by anticholinergic
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
332 Behavioural Pharmacology
2007, Vol 18 Nos 5 & 6
drugs. It is therefore likely to involve cholinergic
neurones (Lewis and Shute, 1967) rather than the
serotonergic (Dahlström and Fuxe, 1965) cells. In fact,
recent findings indicate that some brainstem 5-HT
neurons exert a tonic inhibitory regulation of hippocampal theta activity. Thus, in anaesthetized rats, inhibition
of activity of median raphe neurons evokes theta
oscillation of septal neurons and hippocampal EEG
(Kinney et al., 1995; Varga et al., 2002); and inhibition of
5-HT neurons by the selective 5-HT1A receptor agonist
8-hydroxy-2-dipropylaminotetralin induces hippocampal
theta activity not only in anaesthetized rats (Vertes et al.,
1994; Kinney et al., 1996) but also in freely moving cats, as
well (Marrosu et al., 1996). Furthermore, 5-HT2c receptor
agonists inhibit, whereas 5-HT2c receptor antagonists
induce or augment, septal and hippocampal theta
oscillation in anaesthetized (Hajos et al., 2003b) and
freely moving rat (Kantor et al., 2005; Kocsis and Hajos,
unpublished). In line with these observations, enhanced
hippocampal norepinephrine, but not 5-HT neurotransmission, induces theta (and gamma) oscillatory activity of
the septohippocampal system in anaesthetized rats
(Hajos et al., 2003a).
The key point to note, in relation to the data that we will
review below, is that if clear drug effects are to be
obtained on theta frequency, care must be taken to
stimulate the pathways that normally elicit theta with a
strong relationship between stimulation intensity and
theta frequency; and to avoid pathways that can modulate
or gate theta but that do not normally contribute to
frequency. The focus of the review is on elicited theta,
also, because with spontaneously occurring theta, apparent effects of drugs on theta could be indirect effects of
the drugs on behaviour rather than an effect on theta
generating mechanisms themselves.
The effects of drugs on the elicitation of theta have been
tested both in nonanaesthetized and anaesthetized
animals. The anaesthetic most commonly used in these
cases is urethane. Barbiturates (see below) have very
strong effects on theta frequency and essentially
eliminate theta at anaesthetic doses. They have not,
therefore, been used as anaesthetics in the study of the
effects of drugs on elicited theta.
Urethane and ether both appear to generally produce
(relative to the nonanaesthetized state) a reduction in
the frequency of theta elicited with hypothalamic or
midbrain reticular stimulation (Kramis et al., 1975a).
Theta, however, is unchanged at some stimulation sites.
Overall, this means that we must be prepared for
significant differences in the effects of other drugs when
these are tested in awake as opposed to anaesthetized
animals.
Theta frequency reduction and anxiolysis
In this section, we review the effects of drugs that have a
primary use as anxiolytics in the clinic. We distinguish
anxiolytic action, in this sense, from antipanic, antiphobic, antiobsessive/compulsive actions. These actions are
neurally distinct (see below) but the symptoms affected
tend to co-occur in the different disorders (panic
disorder, simple phobia, obsessive-compulsive disorder,
social anxiety disorder etc.) that are conflated as ‘anxiety
disorders’ by Diagnostic and statistical manual of mental
disorders. We argue that all currently known anxiolytic
drugs, defined in this narrow way, reduce the frequency of
reticular-elicited theta; and that they achieve this
common effect through quite distinct pharmacological,
and proximal neural, mechanisms. Both theoretically
(Gray and McNaughton, 2000) and given the apparently
Table 1 Relative effectiveness of drugs in treating different aspects of defensive disorder and their relation to reticular-elicited theta
frequency
Antianxiety
Specific phobia
Generalized anxiety
Social anxiety
Unipolar depression
Atypical depression
Panic attacks
Obsessions/compulsions
Abuse potential
Elicited theta frequency
Antidepressant
BDZ1
BUS
BDZ2
TRI
CMI
MAOI
SSRI
0
–
–
0
0
0
0
+
–
?
–
(–)
–
?
0
(–)
0
–
?
–
(–)
–
?
–
0
+
–
0
–
0
–
(–)
–
(–)
0
–
?
–
(–)
–
?
—
—
0
?
(–)
?
–
–
–
–
(–)
0
(–)
(–)
–
–
–
?
–
—
0
–
Stein et al., 1992, 2004; Westenberg, 1999; Gray and McNaughton, 2000; McNaughton, 2002; Rickels and Rynn, 2002; Stevens and Pollack, 2005. Different patterns
of response in the table can be attributed to the variation in receptor occupancy or interaction of particular drugs in different parts of the brain. No drug or drug class
produces a specific limited effect (despite the omission of side effects from the table) but the variation in relative effectiveness across the different aspects of disorders of
fear and anxiety argues for distinct neural control of each effect.
0, no effect; – , reduction; —, extensive reduction; + , increase; ( ), small or discrepant effects.
BDZ1: early benzodiazepines, for example, chlordiazepoxide (Librium) and diazepam (Valium) administered at typical antianxiety doses. Other sedative antianxiety drugs
(barbiturates, meprobamate) have similar effects; BDZ2, later high potency benzodiazepines, for example alprazolam (Xanax). The antipanic effect is achieved at higher
doses and this has also been reported with equivalent high doses for BDZ1 (Noyes et al., 1996); BUS, buspirone (BuSpar) and related 5-HT1A agonists; CMI,
clomipramine (Anafranil); MAOI, monoamine oxidase inhibitors, for example phenelzine (Nardil); SSRI, selective serotonin reuptake inhibitors, for example fluoxetine
(Prozac); TRI, imipramine and related tricyclic antidepressants, but excluding clomipramine.
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Elicited hippocampal theta rhythm McNaughton et al. 333
indirect and delayed clinical action of these drugs, it
should be possible to find anxiolytic drugs with a quite
different mode of action – we will return to this issue in
our conclusions.
What is an anxiolytic drug?
The term ‘anxiety’ is often used clinically to include a
wide spectrum of disorders of defensive reactions. A good
reason exists to distinguish fear and anxiety functionally
(Blanchard and Blanchard, 1990a, b), pharmacologically
(Gray, 1977; Blanchard et al., 1997) and neurally (Gray and
McNaughton, 2000). By contrast, the term ‘anxiolytic’,
when used as a clinical class identifier (when contrasted
with, e.g. antidepressant, antipanic and antiobsessive
agents), is used in a fairly restricted fashion. It applies to
two main classes of drug that can treat a group of anxiety
disorders, particularly generalized anxiety, but are not
generally effective in treating specific phobia, panic,
obsession or depression and the like (Table 1). Anxiolytic
action is obtained, in addition to other actions, by various
other classes of drug (e.g. antidepressants, Table 1). A key
issue to be addressed below is how far specific anxiolytic
action, across many different classes of compound, can be
linked to the capacity to change hippocampal theta.
The two main classes of anxiolytic drugs are ‘classical
anxiolytics’ that act at GABAA receptors (see below), and
novel anxiolytics that act through 5-HT1A receptors (see
below). Buspirone was the first novel anxiolytic to be
marketed. It is a partial agonist at 5-HT1A receptors and,
although it has antidepressant action, does not affect
panic and has been used mainly to treat anxiety.
Tricyclic drugs and specific 5-HT reuptake inhibitors
block reuptake of 5-HT and so increase its levels in the
synaptic cleft. They are normally termed ‘antidepressant’
drugs, but have similar actions to buspirone on anxiety
and, in addition, are effective in treating panic. An
important point (as all of the novel, serotonergic,
anxiolytics have some antidepressant action) is that the
anxiolytic action of these drugs appears to be independent of their antidepressant action (Kahn et al., 1986;
Nemeroff, 2003).
Monoamine oxidase inhibitors are like tricyclic drugs in
that they increase levels of 5-HT (and noradrenaline) in
the synaptic cleft and in that they are classed as
antidepressants. As the name implies, they, however,
block the breakdown of these monoamines by monoamine oxidase and do not affect reuptake. They may, as a
result, have a somewhat different clinical profile from
tricyclic drugs. Phenelzine has been reported to be
particularly effective in the treatment of atypical depression, which presents with concurrent anxiety symptoms,
panic attacks or phobia, and in the treatment of the
symptomatically similar ‘endogenous anxiety’ (Sheehan
et al., 1981; Liebowitz et al., 1984; Quitkin et al., 1988,
1990). This appears to be different from conventional
anxiolytic action as, in the case of Sheehan’s study,
essentially all the patients had been treated for years with
conventional anxiolytic drugs without obtaining relief
(Sheehan et al., 1981). Thus, although they do reduce
anxious symptoms in what appears to be a specialized
form of depression, monoamine oxidase inhibitors
appear to have a different type of anxiolytic action
to that seen with the novel and classical anxiolytics –
and have not been reported to be useful in treating
generalized anxiety.
Clonidine is an a-adrenoceptor agonist which has been
prescribed for the relief of anxiety associated with panic
disorders or with morphine withdrawal (Gold et al., 1978;
Hoehn-Saric et al., 1981; Redmond, 1981; Charney et al.,
1983). It also has anxiolytic effects in animal models of
anxiety (Insel et al., 1984) and so can potentially be
classified as an anxiolytic.
Baclofen is a GABAB-agonist that has been reported to
reduce clinical ratings of anxiety and the incidence of
panic attacks (Breslow et al., 1989).
All classes of anxiolytic reduce theta frequency
All known classes of drugs that are clinically effective in
treating generalized anxiety disorder (barbiturates,
benzodiazepines, 5-HT1A receptor agonists, selective
serotonin reuptake inhibitors) decrease the frequency
of reticular-elicited theta. Critically, drugs that are
antipsychotic or sedative but not anxiolytic (haloperidol,
chlorpromazine) do not have this effect.
Imipramine, is particularly interesting in this context.
It is effective in treating generalized anxiety disorder
and does so independently of its antidepressant action
(Kahn et al., 1986). It appears to increase 5-HT levels
particularly effectively at sites with 5-HT1A receptors
given its substitution capacity in drug discrimination
studies (Barrett and Zhang, 1991). The fact that a
significant part of its 5-HT transmission facilitation is via
5-HT1A receptors has been argued to be the basis of its
clinical anxiolytic action (Gardner, 1988). As discussed
later, the effect of 5-HT1A-acting drugs on reticular
elicited theta is blocked by a 5-HT1A receptor blocker
but not by a benzodiazepine receptor blocker; and vice
versa for the effects of benzodiazepines. This double
dissociation means that these different classes of
anxiolytic are acting on quite distinct proximal neural
pathways that then converge on the hippocampal
production of theta as a final common neural path that
generates their common effects.
Phenelzine is a monoamine oxidase inhibitor and so, like
imipramine, has the capacity to increase the level of
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334
Behavioural Pharmacology 2007, Vol 18 Nos 5 & 6
5-HT in the postsynaptic cleft – but through a quite
different mechanism and so, potentially, a quite different
balance in the types of 5-HT receptors affected. It has
not been reported to be effective in generalized anxiety
disorder and, as noted above, is effective in anxious
depression that is refractory to conventional anxiolytic
drugs. It has no immediate action on reticular-elicited
theta (see below) but does have an effect if administered
chronically. Its effects on reticular-elicited theta, therefore, predict a capacity to affect anxiety in the same way
as conventional anxiolytics, but at a longer delay. Its
effects on anxious (atypical) depression, however, clearly
operate via a different mechanism and it is not clear
whether this action is technically anxiolytic or whether
the change in symptoms of anxiety is secondary to a
change in depression.
The acute effects of the monoamine oxidase inhibitor and
antidepressant, phenelzine and the effects of antipsychotic
drugs are totally unlike those of conventional anxiolytics
(McNaughton et al., 1986; Zhu and McNaughton, 1994a).
The immediate effects of the anxiolytics on theta
frequency are more likely, then, to be related to effects
on generalized anxiety than on schizophrenia, endogenous depression or atypical depression.
There are three drugs that are not commonly used as
anxiolytics that do reduce the frequency of reticularelicited theta: baclofen, clonidine and ethanol. In the
case of baclofen and clonidine, as we noted above, it can
be argued that there is evidence for some clinical anxiolytic action – even if this is not the primary action of the
drug and may be masked by other (e.g. antipanic) actions.
Ethanol is in a sense the oldest anxiolytic drug. As we will
see below it acts, like other classical anxiolytic drugs, via
the GABAA receptors, but of course has a variety of
additional actions.
The extent to which the reticular-elicitation test lacks
false positives and false negatives is in strong contrast to
the bulk of current animal models used in anxiolytic
detection. It seems likely that it involves a critical neural
pathway for the action of the drugs. A number of features
of the pharmacology of anxiolytic effects on reticularelicited theta, however, are present that are important for
interpreting this correlation with clinical action.
First is the fact that the effects of both classical and novel
anxiolytics on reticular elicited theta are immediate, and
long term administration does not change these effects
greatly (Zhu and McNaughton, 1991a, b). All classes of
anxiolytic drugs, however, require at least a week’s
administration to achieve their full clinical effect and
show similar temporal changes when assessed with
clinical anxiety scales (Wheatley, 1990). (The muscle
relaxant side effects of the classical anxiolytics and the
negative hedonic effects of buspirone, both of which
show tolerance, tend to mask the similar temporal trends
in their core anxiolytic action on the central nervous
system.) The effects of the drugs on the hippocampus,
then, are not directly on anxiety itself but (like the much
broader effects of hippocampal damage) are more akin to
an anterograde amnesia for threats – blocking the
formation of new anxious cognitions but, for a while,
leaving those that were formed earlier intact. Here, we
see anxiolytic action as, to some extent, the inverse of the
procognitive action discussed below.
Second is the role of corticosteroids in the neural and
behavioural effects of anxiolytic drugs. As we note below,
buspirone appears slightly different from classical anxiolytics in that it does not change the slope of the function
relating stimulation intensity to frequency. Buspirone is
known to release corticosterone (de Boer et al., 1990).
This is in contrast to classical anxiolytics, which block
the release of corticosterone. When chlordiazepoxide
is administered together with corticosterone, similar
effects on theta to those of buspirone are produced
(McNaughton and Coop, 1991).
It is probably this release of corticosterone which gives
buspirone its U-shaped dose–response curve in many
acute-administration animal tests, and probably also in
the clinic. This release of corticosterone can be presumed
to have an anxiolytic blocking or anxiogenic effect
(Johnston and File, 1988). The development of tolerance
in the capacity to release corticosterone explains in part
both the superficially slower onset of buspirone’s clinical
effects compared with benzodiazepines and the withdrawal syndrome produced by the latter (Zhu and
McNaughton, 1995b; McNaughton et al., 1996).
Final evidence for a specific link between reduced theta
frequency and anxiolytic action comes from the fact that
the GABAA drugs and 5-HT1A drugs such as buspirone,
imipramine and fluoxetine have nothing in common in
the clinic other than anxiolytic action. The serotonergic
drugs are not anticonvulsant, hypnotic, muscle relaxant or
addictive (Riblet et al., 1982) – indeed, to some extent,
they have the opposite effects. The common effect of all
these anxiolytic drugs on theta frequency, and their linear
dose–response curves, contrasts with the general failure
of animal behaviour models to detect all classes of
clinically effective anxiolytic.
Classical anxiolytics and the gamma-aminobutyric acid
receptor
As we noted briefly above, classical anxiolytics all act via a
GABAA receptor – but they do so via different binding
sites. This is important both for the identification of the
GABAA receptor as their common target and for
important variations in their clinical action. The role of
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Elicited hippocampal theta rhythm McNaughton et al. 335
this receptor in the control of reticular-elicited theta has
received some analysis that we will review below.
Compounds acting on the benzodiazepine-binding site
can enhance GABA-mediated Cl – current (positive
allosteric modulators, such as anxiolytic benzodiazepines), reduce the effect of GABA (negative allosteric
modulators, also called inverse agonists, such as FG7142), or have no effect on the actions of GABA. In this
latter case, they act to prevent other ligands from binding
at the benzodiazepine-binding site. Drugs such as Ro 151788 (flumazenil) are thus benzodiazepine, but not
GABA, antagonists (for reviews see Haefely et al., 1993;
Sieghart, 2006). Opposite effects of positive and negative
allosteric modulators of GABAA receptors on hippocampal
theta have been demonstrated in anaesthetized rats
(Hajos et al., 2004a; Ujfalussy et al., 2007).
The gamma-aminobutyric acid type A receptor allosteric
modulators and theta
Activity of GABAA receptors can be modulated by
endogenous neurosteroids (Hosie et al., 2006), as well as
drugs acting at different allosteric sites of the pentameric
receptors (Rudolph and Mohler, 2004). As pure GABAA
receptor-positive allosteric modulators do not directly
affect the ion channel, but rather augment or diminish
any ongoing GABAergic neurotransmission, they are the
most desirable targets for pharmacotherapy. Known
positive allosteric modulators include the benzodiazepines, barbiturates, ethanol, halothane and enflurane – of
which only the benzodiazepines have essentially pure
allosteric action. The different classes of drug act at a
number of distinct binding locations at GABAA receptors.
Barbiturates, ethanol, halothane and enflurane all have
the capacity, at higher doses to directly open the chloride
channel in the absence of GABA – rendering them
dangerous at doses much above the normal clinical range.
The benzodiazepines, however, act only by allosteric
modulation of the interaction of GABA with its binding
site and therefore have much less action at high doses,
making them much less toxic. Owing to this, they
have immense clinical importance and their binding
site and mode of action have been studied most
intensively (Sieghart, 2006). Most of the benzodiazepines
currently in clinical practice are nonselective at different
a-subunit-containing GABAA receptors, although there
is a significant effort in drug discovery to identify
subunit-specific modulators of GABAA receptors (Atack,
2005).
The frequency of reticular-elicited theta rhythm is
decreased, and the slope of the intensity–frequency
function (Fig. 1) is decreased, by all drugs that are
positive allosteric modulators of GABAA receptors,
including ethanol (Coop et al., 1990), barbiturates such
as hexobarbitone (Stumpf, 1965), amylobarbitone
(McNaughton and Sedgwick, 1978; McNaughton et al.,
1986; Coop et al., 1992), pentobarbitone (Kramis et al.,
1975b) and benzodiazepines such as chlordiazepoxide
(McNaughton et al., 1986; McNaughton and Coop, 1991;
Zhu and McNaughton, 1991a, b; Coop et al., 1992),
diazepam (McNaughton et al., 1986; Siok and Hajos,
unpublished observations) and alprazolam (McNaughton
et al., 1986). Chlordiazepoxide has a linear dose–response
curve in the range 0.1–20 mg/kg, intraperitoneally
(McNaughton and Coop, 1991), and ethanol has a linear
dose–response curve in the range 1.7–3.1 g/kg, intraperitoneally (Coop et al., 1990). This is consistent with the
doses of both drugs required to affect anxiety-related
behaviour in rats (Gray, 1977).
The effect of chlordiazepoxide is retained even when
administered three times/day for 45 days. This links its
reticular effect to anxiolytic action rather than muscle
relaxant, euphoriant and other side effects which show
tolerance. Its effect is also potentiated rather than
blocked by the nonspecific 5-HT1A antagonist, pindolol
(Zhu and McNaughton, 1991a) as is the effect of the
barbiturate, amylobarbitone (Coop et al., 1992). (Pindolol
blocks the effects of serotonergic drugs, see below.) The
effect of chlordiazepoxide is not blocked by administration of the 5-HT synthesis inhibitor p-chloro-phenylalanine, nor by b-blockers (Zhu and McNaughton,
1994b). This implies that anxiolytic drugs that act via
GABA neurotransmission affect theta frequency through
quite different mechanisms than those that act via 5-HT
neurotransmission. The effects of chlordiazepoxide are,
as expected, blocked by the benzodiazepine binding site
antagonist, Ro 15-1788 (Bonetti et al., 1988; Coop et al.,
1992).
The effects of ethanol have been challenged with the
partial benzodiazepine inverse agonist Ro 15-4513 which
appears to be a selective ethanol antagonist (Suzdak et al.,
1986). Interestingly, this antagonized the effect of
ethanol on the overall frequency of reticular-elicited
theta but did not antagonize its effects on the slope of
the function relating stimulation to frequency (Fig. 1).
This is consistent with the separation of these variables
by the 5-HT1A partial agonist, buspirone (see Novel
anxiolytics and serotonergic mechanisms) and by
administration of corticosterone (see Theta modulation
by anxiolytics).
Direct agonists and antagonists at gamma-aminobutyric
acid type A and gamma-aminobutyric acid type B
receptors
Both GABAA and GABAB direct receptor agonists have
been tested with reticular elicitation of theta. The
GABAA agonist, muscimol, produced effects that were
surprising in two ways. First, at very low doses it produced
an increase in the frequency of theta. This is the opposite
effect to that of the GABAA-positive allosteric modulators
and other drugs that increase chloride flux. As we saw in
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
336
Behavioural Pharmacology 2007, Vol 18 Nos 5 & 6
the previous section, these consistently decrease the
frequency of theta. Second, muscimol had an inverted
U-shaped dose–response curve (over a very wide range of
doses, 0.00001–1.0 mg/kg, intraperitoneally), so that at
the highest dose tested it had essentially no effect (Coop
et al., 1991).
At present, there is no evidence that muscimol has a
clinical anxiolytic action. In animal tests of anxiolytic
action, it produces mixed results (Rodgers and Dalvi,
1997) but appears to have a narrow window of anxiolyticlike action in the range 1–3 mg/kg with a general
disruption of behaviour occurring at 3 mg/kg and above
(Dalvi and Rodgers, 1996; Rodgers and Dalvi, 1997). This
possible anxiolytic action would be consistent with the
frequency-decreasing trend in the data on reticularelicited theta if the observed dose–response curve were
extrapolated beyond 1 mg/kg. On this view, low doses of
muscimol would bind to high-affinity GABAA receptors
that lacked benzodiazepine sites and could act to increase
the frequency of theta. At higher doses, muscimol would
also bind to a low-affinity receptor containing benzodiazepine sites and so produce a countervailing reduction in
frequency and the observed inverted U dose–response
curve.
As we noted earlier, 5-HT depletion, by itself, does not
have obvious effects on the occurrence of theta. The
frequency of theta elicited by reticular stimulation is also
unaffected by blockade of 5-HT synthesis with p-chlorophenyl-alanine (McNaughton and Sedgwick, 1978; Zhu
and McNaughton, 1994b). If 5-HT depletion, however, is
combined with a muscarinic antagonist, this eliminates
theta (Vanderwolf and Baker, 1986; Vanderwolf, 1987).
Serotonin may thus provide a subsidiary ‘gating’ mechanism to acetylcholine. Stimulation of the median raphe 5HT system, however, replaces theta with desynchrony
(Macadar et al., 1974; Vertes, 1981; Peck and Vanderwolf,
1991), although blockade of this system produces an
increase in immobility-related, atropine-sensitive theta
activity (Maru et al., 1979; Kinney et al., 1995; Vertes and
Kocsis, 1997, p. 913; see also Vinogradova, 1995, p. 564).
In cats, where serotonergically gated theta is not
commonly observed, systemic administration of 5-HT1A
agonists releases theta through an action on autoreceptors, presumably in the median raphe (Marrosu et al.,
1996). Critically, the 5-HT1A receptors on which buspirone and related drugs act to alter the frequency of theta
(see below) cannot be on the targets of any tonically
active serotonergic cells (autoreceptors or otherwise) as
serotonergic depletion does not affect theta frequency.
The GABAB agonist, baclofen, produced no effect at
1 mg/kg, and a dose-related decrease in frequency (and of
the slope of the stimulation-frequency function) at 3 and
9 mg/kg – which are high, essentially sedative, doses
(Coop et al., 1991) and are, interestingly, also the doses
required to produce impairments in hippocampal-dependent spatial learning (McNamara and Skelton, 1996). At
27 mg/kg, baclofen eliminated theta (Coop et al., 1991).
The mechanisms underlying the effects of baclofen on
hippocampal activity are unclear, but it is known that
GABAB receptors are located at axon terminals capable of
modulating release of various neurotransmitters (Bettler
and Tiao, 2006). The effect of baclofen was blocked by
the nonspecific 5-HT1A antagonist, pindolol (Coop et al.,
1992), and so may be mediated, secondarily, by the
systems on which the serotonergic drugs act, as discussed
below.
The overall frequency of elicited theta but, unlike with
GABAergic drugs, not the slope of the stimulationfrequency function, is reduced by administration of the 5HT1A partial agonist, buspirone, which has a threshold
dose of approximately 0.5 mg/kg, intraperitoneally, and a
dose-related effect up to at least 40 mg/kg (McNaughton
and Coop, 1991). Frequency is also reduced (Coop et al.,
1992) by the 5-HT1A full agonist 8-hydroxy-di-n-propylamino tetralin. The effect of buspirone on frequency is
unchanged after administration, three times per day for
45 days (Zhu and McNaughton, 1991a). The lack of
effect of buspirone on the slope of the function is
consistent with the separation of these variables that we
discussed in relation to ethanol (see above) and, with the
effects of long-term administration (see ‘The Gammaaminobutyric acid type A receptor allosteric modulators
and theta’).
Novel anxiolytics and serotonergic mechanisms
Consistent with the effect of buspirone, imipramine
(which blocks reuptake of both 5-HT and noradrenaline)
produces a decrease in reticular-elicited theta frequency
when administered acutely, with a threshold in the region
of 3 mg/kg, intraperitoneally and dose-related effects up
to 30 mg/kg (Zhu and McNaughton, 1991b). As with
buspirone this acute effect does not change with
repeated administration but there is an increase in the
baseline frequency of theta over repeated testing on
which the acute decrease is superimposed (Zhu and
McNaughton, 1991b). The acute effect of imipramine
has been replicated with the specific 5-HT reuptake
inhibitor, fluxoetine, at doses between 5 and 20 mg/kg,
Distinct, dorsal and median raphe, serotonergic systems
are present in the brain, with potentially different
functions. The serotonergic drugs with clear anxiolytic
actions, and with effects on theta, appear to act via
5-HT1A receptors (see below) and these receptors can
either directly affect other neurons (with agonists acting
like 5-HT) or can act directly on autoreceptors (with
agonists suppressing the firing of serotonergic neurons
and so, for nonserotonergic neurons, effectively acting as
serotonergic antagonists). Before considering the role of
the 5-HT1A drugs in elicited theta, we will first,
therefore, consider the role of 5-HT itself.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Elicited hippocampal theta rhythm McNaughton et al. 337
intraperitoneally (Munn and McNaughton, submitted for
publication).
The effects of buspirone, 8-hydroxy-di-n-propylamino
tetralin and imipramine were all blocked by the
nonselective 5-HT1A receptor antagonist pindolol (Coop
and McNaughton, 1991; Coop et al., 1992; Zhu and
McNaughton, 1994b). In the case of buspirone, this
effect was shown not to depend on the separate action
that pindolol has on adrenergic b-receptors. The effect of
imipramine, but not buspirone, was blocked by the 5-HT
synthesis inhibitor p-chloro-phenyl-alanine (Zhu and
McNaughton, 1994b). Thus imipramine appears to act
by increasing the levels of 5-HT at sites containing 5HT1A receptors.
Clonidine is an a-adrenoceptor agonist. This also reduced
frequency and the effect was blocked by pindolol,
suggesting a secondary action on 5-HT1A-mediated
systems (Coop et al., 1992).
The effects of buspirone are not blocked by administration of the benzodiazepine antagonist Ro 15-1788 (Coop
et al., 1992), even after long-term administration (Zhu
and McNaughton, 1991a). These results suggest that a
wide range of drugs reduce theta frequency by acting
directly, or indirectly, on 5-HT1A presynaptic or postsynaptic receptors that are not autoreceptors – and do so
independently of benzodiazepine receptors. (As we noted
above, the effects of benzodiazepines are not blocked by
pindolol.)
Neither the 5-HT2 antagonist methysergide, nor the
5-HT3 antagonist GR38032F (ondansetron) affected
reticular-elicited theta and, more significantly, neither
they, nor the D2 antagonist haloperidol, blocked the
effects of buspirone (Coop and McNaughton, 1991).
In partial contrast to the effects of imipramine, phenelzine (0.6–18.0 mg/kg, intraperitoneal), a monoamine
oxidase inhibitor that reduces the break down of
dopamine, noradrenaline and 5-HT, had no effect on
reticular-elicited theta administered acutely. It, however, eventually reduced theta frequency when administered every day for 35 days at 2 mg/kg/day (Zhu and
McNaughton, 1995a). In the long-term case, it also
produced the increase in baseline frequency seen with
long-term administration of imipramine.
Adrenergic mechanisms
The frequency of theta elicited by reticular stimulation is
unaffected by the blockade of noradrenaline and dopamine
synthesis with a-methly-p-tyrosine (McNaughton and
Sedgwick, 1978). Consistent with this, haloperidol and
chlorpromazine, drugs with dopamine antagonist action,
were also without effect (McNaughton et al., 1986).
As noted when considering serotonergic drugs, acute
imipramine (which blocks reuptake of both 5-HT and
noradrenaline) produces a decrease in reticular-elicited
theta frequency (Zhu and McNaughton, 1991b). The
acute effect of imipramine could involve noradrenaline.
Its effect, however, is blocked by the 5-HT1A antagonist
pindolol and the 5-HT synthesis inhibitor p-chlorophenyl-alanine (Zhu and McNaughton, 1994b); and its
effect has been replicated with the specific 5-HT
reuptake inhibitor, fluoxetine (Munn and McNaughton,
submitted for publication). This suggests a role for a
serotonergic mechanism in this action of imipramine. On
the other hand, we have recently demonstrated that
reboxetine, a selective reuptake inhibitor of norepine
phrine (Hajos et al., 2004b) also reduced brainstem
stimulation-induced hippocampal theta oscillation
(Li, Kocsis and Hajos, unpublished observation, Fig. 2).
Interestingly, reboxetine also reduced the threshold
necessary to induce theta oscillation, in line with previous
findings demonstrating its theta-inducing effects (Hajos
et al., 2003a) and unanaesthetized rats (Kocsis et al.,
2007). It is possible, then, that 5-HT and noradrenaline
can have similar, and perhaps synergistic, effects on
reticular-elicited theta.
Blockade of monoamine oxidase has no acute effects but
produces a decrease in frequency with longer-term
administration (Zhu and McNaughton, 1995a), most
likely through the same neural systems as imipramine.
The D2 agonist apomorphine is the only drug so far to
have had an effect on the slope of the stimulation–
frequency function (Fig. 1) without also reducing
frequency (Coop and McNaughton, 1991). Together with
buspirone it shows a double dissociation of these two
parameters.
Enhanced theta power: a sign of procognitive
action?
In the previous section we made a substantial case that a
reduction in the frequency of elicited-theta rhythm
predicts anxiolytic action. As we noted at the beginning
of the paper, injection of anxiolytic drugs into the medial
supramammillary area reduce theta and anxiolytic-sensitive behaviour concurrently and to the same extent, in
both cases, as systemic injections (Woodnorth and
McNaughton, 2002). Furthermore, the behavioural profile of anxiolytic drugs can be viewed as being like that of
diffuse, or in some other way moderate, hippocampal
damage (Gray, 1977; Gray and McNaughton, 1983, 2000).
These data are all then evidence for some degree of
hippocampal involvement in the control of anxiety.
The hippocampus, however, is generally seen as being
more involved in cognitive functions than in anxiety –
and in this section we ask how far elicited theta may
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
338
Behavioural Pharmacology 2007, Vol 18 Nos 5 & 6
provide a test bed for procognitive drugs. That is, we ask
whether increases in theta can predict improvement in
memory function, in contrast to decrease in theta
predicting anxiolytic action. This apposition is not
unreasonable as high doses of anxiolytic drugs produce
some degree of retrograde amnesia (Coull et al., 1999) and
both classical and novel anxiolytic drugs impair acquisition in the Morris Water Maze Test (McNaughton and
Morris, 1987, 1992). Indeed the Water Maze is one of the
few behavioural tests that has a linear dose–response
curve with buspirone (McNaughton and Morris, 1992). It
should, however, be noted that the apposition is not
unidimensional. Anxiolytics reduce theta frequency with
only minor changes in power; drugs that manipulate
memory affect power with little or no change in
frequency.
Neuronal network oscillations, reflecting neuronal synchronization have been positively linked to various cognitive processes, including memory formation (Buzsaki
and Draguhn, 2004; Axmacher et al., 2006). Hippocampal
theta rhythm has also been associated with learning and
memory for over three decades (Berry and Thompson,
1978; Winson, 1978; Berry and Seager, 2001); and a
correlation between learning and hippocampal theta has
been demonstrated in experimental animals (Buzsaki,
2002, 2005; Jones and Wilson, 2005) and humans (Caplan
et al., 2003; Sammer et al., 2006). Hippocampal theta has
been suggested to be a ‘neutral tetanizer’ contributing to
long-term synaptic modulations, such as long-term
potentiation (LTP) in vivo (Winson, 1990; Vertes, 2005).
Critically, a direct functional contribution of theta
frequency oscillation has been shown in rats in which
theta had been blocked: restoration of theta rhythmicity
also restored learning (McNaughton et al., 2006).
Kramis and Vanderwolf, 1980). When theta is elicited by
stimulation of the subnucleus compactus of the pedunculopontine tegmental area this, however, appears
resistant to atropine even in the absence of voluntary
movement (Robinson and Vanderwolf, 1978). As we noted
in the section on theta induction, if the animal is
engaging in any movement during stimulation then the
elicitation of theta is not blocked by anticholinergic drugs
and, indeed, seems completely unaffected in either
frequency or amplitude (McNaughton and Sedgwick,
1978).
Involvement of muscarinic receptors in hippocampal
theta generation can also be demonstrated clearly by
recording brainstem stimulation-induced hippocampal
theta oscillation in anaesthetized rats. Thus, amplitude
of elicited theta oscillation can be greatly reduced
(up to 70–80%) by the muscarinic receptor antagonists
atropine or scopolamine, whereas lower frequency theta
oscillations are abolished by these antagonists (Kinney
et al., 1999; Kocsis and Li, 2004; Siok et al., 2006; Li
et al., 2007).
N-methyl-D-aspartate receptor antagonists
NMDA receptors mediate LTP – a likely basis of longterm learning and memory (Abraham, 2003). Alteration in
their function impacts various cognitive mechanisms,
including LTP-dependent memory formation (Castellano
et al., 2001). For example, the NMDA receptor antagonist,
dizocilpine (MK-801), impairs performance in a hippocampal-dependent spatial learning task (Butelman,
1989). Furthermore, blockade of NMDA receptors
decreases both the frequency and power of hippocampal
theta activity in freely moving rats (Pitkänen et al., 1995);
and, in particular, dizocilpine reduces elicited theta at the
same dose as it produces a deficit in cognitive performance (Kinney et al., 1999). This suggests that elicited
theta could be increased by procognitive drugs acting via
the NMDA receptor, but none appear to have been
tested so far.
Thus a reason exists to suppose that drugs that improve
theta could improve cognitive function and we will
consider, below, the small amount of evidence for
increases in theta being produced by procognitive drugs
of different classes of drugs: mainly cholinergic and
histaminergic. Before doing so, we will consider the
evidence for the converse: that anticholinergic drugs
block elicited theta. This is important because, not only
are anticholinergic drugs amnestic, but disruption of the
cholinergic system is one important feature of dementing
disorders. We will briefly note similar data for the
involvement of N-methyl-D-aspartate (NMDA) receptors
in both memory and the control of theta.
It should be noted, here, that in animal tests, blockade of
NMDA receptors has been linked to anxiolytic-like action
(Dunn et al., 1989; Guimaraes et al., 1991; Xie and
Commissaris, 1992; Anthony and Nevins, 1993; Xie et al.,
1995; Sajdyk and Shekhar, 1997; Adamec et al., 1998;
Gatch et al., 1999). This is consistent with the changes in
theta frequency observed with NMDA receptor blockade
in freely-moving rats (Pitkänen et al., 1995).
Cholinergic antagonists
Cholinergic agonists
In freely moving rats, provided they are immobile at the
time of stimulation, injections of muscarinic antagonists
have the same effects as in anaesthetized rats, eliminating theta when this is elicited from a wide variety of sites
(Kramis et al., 1975a; Robinson and Vanderwolf, 1978;
As would be expected from the theta-blocking effects of
the amnestic anticholinergic drugs, the acetylcholinesterase inhibitor, donepezil, a clinically proven memory
improving drug, significantly enhances the amplitude
of reticular elicited theta oscillations, and can reverse the
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Elicited hippocampal theta rhythm McNaughton et al. 339
In addition to acetylcholinesterase inhibitors and agonists
of muscarinic receptors (Power et al., 2003; Hasselmo,
2006), agonists of nicotinic cholinergic receptors have
been considered as procognitive drugs (Buccafusco et al.,
2005; Levin et al., 2006; Mansvelder et al., 2006). For
example, cognitive enhancing actions of a7 nAChR
agonists have been observed both preclinically in various
animal models (Levin et al., 2006; Wishka et al., 2006;
Pichat et al., 2007) and in clinical studies (Kitagawa et al.,
2003; Olincy et al., 2006).
The contribution of nicotinic acetylcholine receptors to
brainstem stimulation-induced theta has not been
extensively explored. In the septohippocampal formation,
a7 nicotinic receptors (a7 nAChRs), however, are
expressed by neurons well positioned to modulate
hippocampal theta oscillation, such as GABAergic interneurons in the hippocampus, by both GABAergic and
cholinergic septal neurons (Ji and Dani, 2000; Henderson
et al., 2005; Thinschmidt et al., 2005). Consistent with
this, the recently developed selective a7 nAChR agonist
PNU-282987 significantly enhances the power of hippocampal theta elicited by brainstem reticular formation
stimulation (Siok et al., 2006). In addition, amphetamineinduced hippocampal theta oscillation is enhanced by
PNU-282987 in rats (Hajos et al., 2005a).
Potential modulation of elicited hippocampal theta by
other subtype-specific nicotinic receptors has not been
evaluated. Mutation of a4 nicotinic receptors in mice,
however, has been shown to result in hypersensitivity to
nicotine, and to nicotine-induced hippocampal theta
oscillation (Fonck et al., 2005). It would, therefore, be
of particular interest to determine whether a4 nicotinic
receptors modulate physiological or stimulation-induced
theta oscillations in the hippocampus.
One final point to note is that PNU-282987 can augment
elicited theta frequency above 6.5 Hz (Figs 2 and 3, from
Siok et al., 2005). Thus, although endogenous muscarinic
systems appear to promote the power but not the
frequency of theta (see above), exogenous (and possibly
endogenous) nicotinic systems may play some role in the
control of frequency.
Fig. 2
Theta frequency (Hz)
6.5
6.0
5.5
% Expt.
(a)
100
80
60
40
20
0
0.0
Saline
Reboxetine
0.2
0.4
5.0
4.5
Saline
4.0
3.5
−0.2 0.0
Reboxetine
0.2
0.4 0.6 0.8 1.0 1.2
Stimulation intensity (mA)
1.4
1.6
1.4
1.6
(b)
Theta power (mV2)
theta-disruptive effects of scopolamine (Kinney et al.,
1999; Siok and Hajos, unpublished observations).
Increase in power of stimulation-induced hippocampal
theta has also been observed with other preclinically
identified procognitive compounds such as piracetam and
apamin. Interestingly, the theta-enhancing effects of
donepezil, as well as piracetam and apamin are attenuated by scopolamine, therefore a common cholinergic
mechanism by which these drugs enhance theta activity
and improve cognition has been suggested (Kinney et al.,
1999).
3000
2800
2600
2400
2200
2000
1800
1600
1400
1200
−0.2 0.0
P = 0.025
0.2
0.4 0.6 0.8 1.0 1.2
Stimulation intensity (mA)
The selective norepinephrine reuptake inhibitor reboxetine (15 mg/kg,
subcutaneous, n = 6) significantly reduces the frequency of brainstem
stimulation-induced hippocampal theta but, at higher intensities,
increases the power of theta. (a) Effects on frequency. Reboxetine
reduced frequency compared with its vehicle [drug, F(1,60) = 16.5,
P < 0.001]. At the same time, however, reboxetine lowered the
threshold of induction of theta oscillation, as five out of six rats showed
induced theta activity at the lowest stimulating current, in contrast to
two out of six rats after vehicle treatment (insert). (b) Effects on power.
At stimulus intensities above 0.6 mA reboxetine increased power [drug,
F(1,60) = 5.3, P < 0.025).
Histaminergic mechanisms
Despite considerable effort to identify procognitive
mechanisms and compounds, only a few drugs have been
proven clinically effective until now. One of the potential
targets in mnemonic drug discovery is the histamine
system. Direct or indirect activation of the histamine
pathway has been proposed to impact cognitive functions
positively (Bacciottini et al., 2001), including antagonists
or inverse agonists at histamine3 (H3) receptors (Passani
et al., 2004; Esbenshade et al., 2006).
Histaminergic neurons project to the medial septum/diagonal band of Broca (MS/DB) and presumably innervate
both cholinergic and GABAergic septal neurons (Panula
et al., 1989). Although, in the rat brain-slice preparation, it
has been shown that histamine excites septal GABAergic
and cholinergic neurons (Xu et al., 2004), the role of
histamine and various histamine receptors in hippocampal function or hippocampal network oscillations has
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
340 Behavioural Pharmacology 2007, Vol 18 Nos 5 & 6
Fig. 3
PNU-282987
8.0
∗
7.5
Frequency (Hz)
Vehicle
8.0
∗
7.5
7.0
7.0
6.5
6.5
6.0
6.0
5.5
5.5
5.0
5.0
4.5
0.00
0.05
0.10
0.15
0.20
4.5
0.00
0.05
Frequency (Hz)
∗
∗
∗ = Significant at P > 0.05
compared with control
0.10
0.12 0.14 0.16 0.18
Stimulus intensity (mA)
0.15
0.20
Control
Vehicle
Control
PNU-282987
8.0
7.8
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
5.8
5.6
0.10
8.0
7.8
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
5.8
5.6
0.10
0.12 0.14 0.16 0.18
Stimulus intensity (mA)
The effect of increasing stimulation intensity on theta frequency after administration of the selective a7 nicotinic receptor agonist PNU-282987
(1 mg/kg, intravenous, n = 5, left panels), and its vehicle (n = 5; right panels). PNU-282987 caused a subtle, but significant (P < 0.05) increase in
frequency (bottom left panel) only at frequencies greater than 6.5 Hz (from Siok et al., 2005).
not been fully investigated. In-vivo recordings from
the hippocampal CA1 region of freely moving rats
have revealed that high-frequency oscillations (200-Hz
ripples) are markedly enhanced after injection of the H1antagonists, indicating a tonic regulation of hippocampal
activity by the histaminergic system (Knoche et al., 2003).
In addition, systemic administration of H3 receptor
antagonists enhances spontaneously occurring theta
power in chloral hydrate anaesthetized rats (Hajos et al.,
2005b).
Involvement of H3 receptors in reticular-induced theta
has been recently demonstrated. Systemic administration
of H3 antagonists (ciproxifen and thioperamide) enhanced power without influencing theta frequency
(Hajos et al., 2005b). In contrast, application of H3
antagonists directly to the MS/DB via microdialysis does
not modulate stimulated theta activity, indicating that
the theta-modulating effects of H3 antagonists are not
mediated directly via MS/DB neurons. These results are
in line with preclinical behavioural studies indicating
cognitive enhancing effects of H3 receptor antagonists
(Passani et al., 2004), and suggest that the procognitive
effects of H3 antagonists could be mediated, at least in
part, by modulation of hippocampal oscillatory activity.
Conclusion
The role of theta in anxiety and memory
The data we have reviewed make a strong case for seeing
reductions in the frequency of reticular-elicited theta as
providing a good in-vivo means of detecting antianxiety
drugs, independent of their mode of action. We also have
indications that increases in the power of reticularelicited theta could detect drugs useful in the treatment
of disorders, such as dementia, that involve memory loss.
At first blush, it might seem we are suggesting that
increases and decreases in theta have qualitatively
distinct actions from each other. We might also be seen
to be suggesting that the occurrence of theta represents
anxiety and memory formation. Here we argue against
both of these apparent implications.
First, let us make clear that the presence of theta does
not mean that it is fulfilling a function. In rats, the
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Elicited hippocampal theta rhythm McNaughton et al. 341
strongest correlate of hippocampal theta frequency is
speed of movement. Yet elimination of theta, or even
complete removal of the hippocampus, has no obvious
effect on simple movement, per se. Theta must then be
seen as providing an input to the hippocampus which is
only critical if the hippocampus is, at that point in time,
required to perform a function. Consistent with this, the
relation of theta to movement is not strong in other
species and, as we go from rabbit to rat to cat to monkey
to human the overall occurrence of theta appears to drop.
Theta rhythm has been observed to occur clearly but
briefly in monkeys as a result of an unprogrammed failure
of delivery of reward, when criterion performance is
reached on no-go trials of a go/no-go problem (Crowne
et al., 1972). It has been suggested that ‘in the monkey . . .
the theta rhythm (is) virtually impossible to see,
excepting under conditions likely to produce extreme
emotional reactions’ (Green, 1960 cited by Crowne et al.,
1972) and we would argue that, in more encephalized
species, the occurrence of theta in the hippocampus,
relative to rodents, has been largely restricted to those
situations where it is important for function. Even in
rodents, the cholinergic ‘gating’ of theta (see ‘Elicitation
of theta’) shows that the nuclei controlling theta
continue to encode reticular system activation as theta
frequency even when production of theta activity is
prevented in the hippocampus itself.
Second, let us consider the relation of theta, and drug
action, to arousal. Theta is modulated by noradrenaline,
5-HT and histamine (systems involved in arousal and
motor activation); and is elicited by stimulation of what
used to be called the ascending reticular activating
system. Indeed, it has in the past been referred to as the
arousal reaction of the hippocampus (Brucke et al., 1959).
The data we have reviewed are consistent with a more
general involvement of theta in the effects of arousal.
High arousal is a problem for those with anxiety; although
low arousal can be a problem in cognitive tasks. To date,
there has, however, been no evidence linking theta to
functions that are not mediated by the hippocampus –
and the latter is certainly not involved, generally, in
arousal. Similarly, there is good reason to see anxiolytic
action as a combination of changes in behavioural
inhibition (mediated by the hippocampus and so
influenced by theta) and autonomic arousal mediated
by the amygdala (Gray and McNaughton, 2000). Thus,
although anxiolytic drugs and procognitive drugs may
produce opposite shifts along a continuum of hippocampal-mediated function they have additional quite distinct
effects in other parts of the nervous system that may
contribute selectively to anxiolytic and procognitive
action, respectively.
Third, let us make clear that the hippocampal function
(or functions) that we presume requires theta is neither
directly related to anxiety nor directly related to memory.
When considering the effects of antianxiety drugs we
noted that their effect on theta was immediate and
unchanging with repeated administration; whereas their
clinical effect is cumulative and delayed – when assessed
by clinical anxiety scales (Wheatley, 1990). We argued
that this clinical action can be viewed somewhat like
the anterograde amnesia associated with hippocampal
dysfunction. Equally, that same anterograde amnesia,
so-called, is neither a loss of memory (as older memories
are intact after hippocampal lesion) nor a loss of the
capacity to form memories (as there are clear cases where
certain classes of item can be learned and it is their
unlearning that shows a deficit). Rather, hippocampal
dysfunction appears to be the result of a failure
to suppress incorrect alternatives (McNaughton and
Wickens, 2003), both in memorial and nonmemorial
tasks under conditions where there is a high level of
competition (see below).
It is clear that decreases and increases in theta can alter
hippocampal function in an essentially anxiolytic and an
essentially procognitive direction, respectively. This
suggests that, on average, the presence or absence of
theta is not necessarily a good or a bad thing. Changes in
theta can adjust the system to a requirement for greater
or lesser hippocampal output depending on the circumstances. If this were not the case, theta would be
continuous and unchanging; the elaborate machinery for
its control would not have evolved (and would not have
been progressively more restricted in more encephalized
species); and endogenous compounds that can alter its
frequency and amplitude (as evidenced by the presence
of multiple types of receptors for this) would also not
have evolved.
The role of theta in hippocampal function
We have said that, in our view, the hippocampal
processing controlled by theta activity is neither directly
related to anxiety nor directly related to memory but
impacts on both. How can two such apparently disparate
classes of process be impacted by a single function
executed by the hippocampus? One explanation is
provided by the theory that the hippocampal formation
is a key node of a behavioural inhibition system (for an
extensive exposition of the ideas summarized below, see
Gray and McNaughton, 2000 and its appendices available
on the Oxford University Press website).
The core of the theory is that when two or more goal
representations in the brain are approximately equally
activated, the motor system is faced with a conflict that it
cannot easily resolve: it cannot achieve both goals at once;
and it cannot easily choose one over the other as they are
equally activated. This conflict is detected by the
hippocampus, which then produces output that inhibits
the production of the competing behaviours (hence
‘behavioural inhibition system’); and, critically, sends
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
342
Behavioural Pharmacology 2007, Vol 18 Nos 5 & 6
output back to the conflicting goal representations that
increases the valence of affectively negative aspects of
their memory representations. As detailed by Gray and
McNaughton, this affectively negative feedback is
increased progressively by a recursive process that
repeatedly circulates information between the goal
representations and the hippocampus. Theta activity
quantizes this recursive processing to reduce the
possibility of information from one cycle of processing
interfering with the next cycle. The frequency of theta is,
for this reason, tuned to the round trip time between the
hippocampus and at least its cortical targets (Miller,
1991). On this view, theta is necessary but not sufficient
for a high level of hippocampal output and that output
affects cognitive processing in an affectively negative
way: increasing negative bias and so suppressing alternatives that have negative valence.
Thus, with a high level of hippocampal output there will
be higher gain in affectively negative associations leading
to suppression of the goal with the greater negative
associations (and so, in memory tasks, reduced interference) and with a low level there will be low gain in
affectively negative associations leading to release of
suppression (and so, in approach–avoidance conflicts
ultimately reduced anxiety). Thus, although theta can
be viewed as having a critical effect on cognitive
processing (and so both action and memory), it does so
via primarily affective means. It is concerned, then, with
cognitive–emotional interaction (Pan and McNaughton,
2004).
So far we have argued for an essentially unitary function
of the hippocampus and so of alterations in theta. We
need to add two caveats.
First, the older ‘emotion’ and newer ‘memory’ theories of
hippocampal function have been essentially amalgamated, recently, in the suggestion that the hippocampus
may be divided into distinct septal and temporal parts,
associated with memorial and emotional/motivational
processing, respectively (Moser et al., 1993; Moser and
Moser, 1998; Bannerman et al., 2004; Trivedi and Coover,
2004; Cenquizca and Swanson, 2006). Thus theta (and
the repetitive ‘slices’ of which the hippocampus is made)
would perform essentially the same computational
operations throughout – but the operations performed
would focus more on cognitive differences between goals
(food to the left versus food to the right) or more on
motivational differences (approach food versus avoid
shock) depending on whether they were occurring in
the septal or temporal portions of the hippocampus. The
anxiolytic and procognitive drugs might, then, have
distinct actions by acting primarily at different hippocampal locations. The clear anticognitive effects of high
doses of the anxiolytic drugs suggest that such a
separation is far from total, if it exists at all.
Second, anxiolytics reduce theta frequency but, by and
large, procognitive drugs alter theta power – most likely
via changes in the extent to which the occurrence of
theta is ‘gated in’. Part of the functional difference in
their actions, then, could be due to the qualitatively
different ways in which (or the different task phases
during which) they alter theta. In particular, cholinergic
activation would be expected to have its greatest effects
when the animal is stationary while frequency reduction
would be expected to have its greatest effects when the
animal is moving. Certainly, an anxiolytic and an anticholinergic drug, at doses that produce equivalent
disruption in the rate of water maze learning, disrupt
learning through substantially different patterns of dysfunctional behaviour (McNaughton and Morris, 1987).
Thus, anxiolytic and anticognitive drugs may appear to
produce a similar level of cognitive disruption through
somewhat different cognitive mechanisms.
Can anxiolytic and anticognitive actions be separated?
As we have already discussed, muscarinic receptor
antagonists and GABAA receptor-positive allosteric modulator benzodiazepines have a similar capacity to reduce
hippocampal theta activity and cognitive functions. But,
although benzodiazepines are anxiolytic, muscarinic
receptor antagonists are not. Therefore, it can be argued
that either different neural circuits or distinct changes in
cellular activities within the same circuits are involved in
the actions of the different classes of drug and so have
different effects on functions associated with hippocampal theta. In particular, we argued above that the drugs
might affect behaviour through different task phases. It is
not clear that anxiolytic action can be separated from
anticognitive action. A strong possibility, however, exists
that procognitive effects indicated by increases in theta
activity can be produced in the absence of concurrent
anxiety as a side effect.
A very important point, here, is that both theoretically
(Gray and McNaughton, 2000) and practically there
should be anxiolytic drugs that have a quite distinct mode
of action from those currently used. Even conventional
anxiolytic drugs (i.e. those without antidepressant action)
act directly on the amygdala and indirectly (via theta) on
the hippocampus to have their effects. Changes in theta,
then, cannot be the whole story. From the practical point
of view, both GABA and 5-HT anxiolytics have a delayed
clinical effect on anxiety proper (Wheatley, 1990) – with
the delay masked for the GABA drugs by initial muscle
relaxant and euphoriant effects that show rapid tolerance.
It follows that there could be drugs that can have
immediate effects on anxiety proper. Two possible
reasons exist, why at present, reticular elicitation of theta
has no clear false-negative compounds. First, anxiety may
be so cognitively mediated that time will always be
required for new learning to alter cognitions. Second, it is
possible that direct drug effects on, say, central arousal
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Elicited hippocampal theta rhythm McNaughton et al. 343
systems normally show tolerance and so have not given
rise to drugs that are therapeutically useful with longer
treatment durations.
Overall, then, we believe the data we have reviewed
suggest that reticular-elicited theta is an excellent screen
for anxiolytic action – capable of detecting drugs with
novel modes of action – and a potential screen for
procognitive action. The contribution of changes in theta
to these end effects should, however, be seen as indirect.
It appears to occur through a change in cognitive–
emotional processing that particularly involves the
hippocampus and then impacts later on other structures
that directly involve anxiety and memory.
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