Download Drug-activation of brain reward pathways

Drug and Alcohol Dependence 51 Ž1998. 13]22
Drug-activation of brain reward pathways
Roy A. Wise
Intramural Research Program, National Institute on Drug Abuse, PO Box 5180, Baltimore, MD 21224, USA
1. Introduction
A wide variety of biologically important stimuli can
serve as rewards and establish adaptive behavior patterns in higher animals. Such stimuli act through
brain mechanisms that evolved long before the human invention of the hypodermic syringe, the human
harnessing of fire, or the human development of
methods for refining and concentrating psychoactive
substances that occur in nature. These brain mechanisms utilize endogenous neurotransmitters that are
blocked or mimicked by a variety of addictive exogenous substances. The brain mechanisms for feeding, for example, have depended on endogenous opioid peptide neurotransmitters from the earliest stages
of our evolutionary history ŽJosefsson and Johansson,
1979; Kavaliers and Hirst, 1987.. A complete understanding of the brain mechanisms of addiction will
require an understanding of the anatomy and normal
functions of brain pathways that evolved because they
served basic adaptive functions.
Our current understanding of the brain circuitry
through which various rewards gain control over behavior has developed from studies of brain stimulation reward ŽOlds and Milner, 1954.. Rewarding brain
stimulation is useful in anatomical localization of
reward-relevant circuit elements because focal electrical stimulation of the brain only activates nerve fibers
passing within a fraction of a millimetre of the electrode tip ŽFouriezos and Wise, 1984.. However, while
stimulation differentially activates fibers of different
sizes, the stimulation is indiscriminate with respect to
the neurotransmitter a given set of fibers carry. Thus
our knowledge of the neurochemical subtypes of reward-relevant neurons derives primarily from pharmacological studies; the rewarding effects of brain
stimulation can be attenuated or augmented by drugs
that are selective for various neurotransmitter systems ŽWise and Rompre,
´ 1989., and neurochemically
selective drugs can be rewarding in their own right
ŽWise, 1978.. Moreover, laboratory animals can be
0376-8716r98r$19.00 Elsevier Science Ireland Ltd.
PII S0376-8716Ž98.00063-5
trained to self-administer drugs injected directly into
the brain ŽBozarth and Wise, 1981.; such injections
are, to a significant degree, both anatomically and
neurochemically selective.
2. Activation of reward circuitry by direct brain
stimulation
Olds and Milner Ž1954. first discovered that direct
electrical stimulation of the brain can be powerfully
rewarding. The initial finding was that rats would
return to places where they received stimulation of
the septal area ŽOlds and Milner, 1954.. Subsequent
mapping studies showed that stimulation of many
other, seemingly disparate ŽPhillips, 1984., brain regions was rewarding ŽOlds and Olds, 1963.; these
included structures with presumed sensory ŽPhillips,
1970., motor ŽVan Der Kooy and Phillips, 1977., and
associational ŽRouttenberg and Sloan, 1972. functions. The most sensitive sites were along the medial
forebrain bundle, particularly at its lateral hypothalamic, posterior hypothalamic, and ventral tegmental
levels ŽFig. 1..
The lateral hypothalamic medial forebrain bundle
has been the most frequently studied brain stimulation reward site, particularly in studies of the effects
of drugs on brain stimulation reward. Olds and Olds
Ž1965. hypothesized that the medial forebrain bundle
was a final common path for reward messages involving a variety of forebrain reward sites. Unfortunately,
over 50 fiber systems pass through this region of the
brain ŽNieuwenhuys et al., 1982., and only a few of
them are likely to contribute to the fact that stimulation of this region is rewarding. The sub-population of
directly activated fibers that play a role in the fact
that the stimulation is rewarding are designated the
reward-rele¨ ant fibers; a similar distinction between
reward-relevant and reward-irrelevant circuitry is also
useful when considering the multiple actions of rewarding drugs.
By administering stimulation in trains of paired
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R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22
Fig. 1. Drug reward circuitry Žapprox. 1998.. Cocaine and amphetamine trigger reward at NAcc Žand perhaps mFCx. where they elevate DA
levels and thereby inhibit medium spiny GABA neurons. Nicotine triggers reward at cholinergic synapses in VTA, where it activates DA
neurons projecting to NAcc. Morphine and heroin reward by disinhibiting the VTA dopamine cells, inhibiting GABA release for neighboring
neurons in SNc and VTA. PCP Žphencyclidine. triggers reward in NAcc, by blocking the excitatory glutamate input to medium spiny neurons,
and in mFCx, by an unknown mechanism. Cannabis and ethanol increase dopaminergic cell firing, but the cellular basis of this effect, and its
contribution to reward are not yet clear.
pulses and varying the interval between the members
of each pair, one can determine the distribution of
refractory periods of the population of directly activated and reward-relevant fibers. The bulk of rewardrelevant fibers in the medial forebrain bundle have
the short refractory periods typical of large myelinated axons ŽYeomans, 1979.. At least two sub-populations appear to be involved; one of these appears to
be cholinergic ŽGratton and Wise, 1985..
Paired-pulse stimulation can also be used to determine when the same reward-relevant fibers conduct reward signals between two identified reward
sites ŽShizgal et al., 1980.. In this case one pulse of
each pulse-pair is delivered through each of two
properly aligned stimulating electrodes, and connectivity is inferred from collision-like effects familiar to
electrophysiologists. Collision tests have established
connectivity between reward sites along much of the
length of the medial forebrain bundle ŽShizgal, 1989..
Conduction velocities of the reward-relevant fibers
can be estimated from such two-electrode studies;
here evidence of collision between the antidromic
action potentials triggered at the more efferent site
and the orthodromic action potentials triggered at the
more afferent site is used to give estimates that are
again consistent with large myelinated fibers ŽBielajew
and Shizgal, 1982..
Dual-electrode studies can also be used to determine the direction of projection of reward-relevant
fibers. Such studies indicate that the large majority of
reward-relevant fibers in the medial forebrain bundle
project in the rostro-caudal direction ŽBielajew and
Shizgal, 1986..
Pharmacological studies first implicated dopamine
as an important neurotransmitter in brain reward
circuitry ŽWise and Rompre,
´ 1989.. However, dopamine-containing fibers project rostrally from the
substantia nigra and ventral tegmental area, have long
refractory periods and slow conduction velocities.
Moreover, dopaminergic fibers have high thresholds
for activation and are not directly depolarized by
stimulation at the parameters traditionally used in
these studies ŽYeomans et al., 1988.. Thus it is presumed that the dopaminergic link in reward circuitry
is trans-synaptically activated by the more sensitive,
caudally projecting, first-stage or directly acti¨ ated
neurons. ŽThe so-called ‘first-stage’ neurons are, of
course, ‘first-stage’ only with respect to brain stimulation reward; they, too, are presumed to be trans-synaptically activated } that is, ‘nth stage’ } when
considered with respect to more natural rewards like
food and sexual contact..
Little is known as to which other reward sites are
‘wired’ in series ŽWise and Bozarth, 1984. with the
medial forebrain bundle elements and which are, on
the other hand, part of independent, parallel ŽPhillips,
1984., reward circuits. Midline mesencephalic reward
sites ŽRompre
´ and Miliaressis, 1985. appear to be part
of the medial forebrain bundle circuit ŽShizgal, 1989..
The rewarding effects of stimulation of this region are
augmented or attenuated: Ži. by the same drugs; Žii. in
much the same way; and Žiii. to much the same extent
R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22
as are the rewarding effects of medial forebrain bundle stimulation ŽMiliaressis et al., 1986; Bauco and
Wise, 1994., and stimulation in this region causes
dopamine release in nucleus accumbens much as does
medial forebrain bundle stimulation ŽBauco et al.,
1994.. Stimulation of the medial or sulcal prefrontal
cortex, on the other hand, causes different behavioral
side effects than } and has rewarding effects that are
different in some ways to the rewarding effects of
medial forebrain bundle stimulation ŽMcGregor et al.,
1992.. Stimulation of such varied structures as the
cerebellum, brainstem, olfactory bulb, and a variety of
limbic structures has been shown to be rewarding but
has not been studied extensively with respect to drug
sensitivity or connectivity with other reward sites.
The initial hypothesis as to the second-stage neurons in MFB brain stimulation reward was that the
descending first-stage fibers projected directly to the
dopaminergic dendrites or cell bodies of the VTA and
substantia nigra ŽWise, 1980.. This hypothesis was
based on the fact that the MFB reward fibers have
the same dorso-ventral and medio]lateral boundaries
as the dopaminergic cell groups ŽCorbett and Wise,
1980; Wise, 1981.. More recently, however, it has
been shown that at least some MFB reward fibers
project caudally beyond the level of the dopaminergic
cell bodies ŽShizgal, 1989., and sites caudal to the
dopaminergic cells themselves have subsequently been
proposed as the direct synaptic targets of the descending first-stage neurons ŽYeomans et al., 1993..
The chemical sub-type of the first stage MFB reward neurons has been surprisingly difficult to determine ŽGallistel et al., 1981.. Cholinergic fibers appear to contribute a minor sub-population to the first
stage ŽGratton and Wise, 1985., but there are no
rostro-caudal projections of the MFB that utilize
acetylcholine as their transmitter. Nonetheless, the
search for cholinergic links in brain stimulation reward circuitry has suggested a cholinergic input to the
VTA that seems likely to innervate the chemical
trigger zone for nicotine’s rewarding actions ŽYeomans et al., 1993.. The cholinergic projection Ža portion of which co-localizes glutamate; Charara et al.,
1996. from the pedunculo-pontine and latero-dorsal
tegmental nuclei ŽPPTg and LDTg, respectively. to
the VTA. Manipulation of PPTg by cholinergic autoreceptor activation or inactivation modulates brain
stimulation reward ŽYeomans et al., 1993.. In addition, muscarinic blockade in the VTA attenuates MFB
brain stimulation reward ŽKofman et al., 1990.. Yeomans et al. have hypothesized that PPTg is the target
of the first-stage MFB reward fibers, and that descending MFB reward signals activate the mesolimbic
dopamine system indirectly by activating the cholinergic projection from PPTg to VTA. Muscarinic receptors are thought to transduce this reward input, as
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nicotinic blockade does not alter the effectiveness of
rewarding MFB stimulation in non-drugged animals.
An attractive but unproven and counter-intuitive
alternative to the Yeomans hypothesis is that the
first-stage cholinergic contribution to MFB self-stimulation involves the rostrally projecting cholinergic
fibers of LDTg and PPTg. These nuclei send multiply
branched long fibers up the medial forebrain bundle
ŽWoolf and Butcher, 1986.. Activation of these fibers
by rewarding brain stimulation triggers not only orthodromic action potentials propagating toward the
forebrain but also antidromic action potentials propagating toward the PPTg and LDTg cell bodies. Antidromic action potentials along the ‘trunk’ of the
axonal ‘tree’ could conceivably invade the collaterals
that branch off between the electrode tip and the cell
body, including the collateral to the VTA. In this
view, the ascending cholinergic fibers could carry a
rostro-caudal Žantidromic. signal to the branch point
and a caudo-rostral Žorthodromic. signal along the
collateral from the branch point to its terminals in the
VTA. Thus PPTg could be activated both antidromically } by the stimulation itself and trans-synaptically } by the non-cholinergic first-stage MFB reward fibers, i.e. cholinergic neurons might make both
first-stage and second-stage contributions to MFB reward.
3. Activation of reward circuitry by drugs of abuse
Most psychoactive drugs act in the central nervous
system ŽFig. 1. as agonists or antagonists at the receptors for endogenous chemical messengers Žneurotransmitters or neuromodulators.. Opiates act at receptors for endogenous opioid neurotransmitters
ŽGoldstein et al., 1971.; nicotine acts at a subclass
Žnicotinic. of acetylcholine receptors ŽMarks et al.,
1986.; cannabis acts at receptors ŽDevane et al., 1988.
for an endogenous cannabanoid ŽDevane et al., 1992.;
phencyclidine acts at the N-methyl-D-aspartate subtype of glutamate receptor ŽMaragos et al., 1988.; and
caffeine acts at adenosine receptors ŽSnyder et al.,
1981.. Some drugs do not act at neurotransmitter
receptors per se, but nonetheless have actions selective for particular transmitter systems. For example,
cocaine blocks reuptake ŽHeikkila et al., 1975a. of
dopamine, norepinephrine, and serotonin by acting at
the various monoamine transporters; amphetamine
blocks reuptake and causes release ŽHeikkila et al.,
1975b. of these monoamines, also by acting at their
transporters; alcohol influences many neurotransmitter systems though its strongest effects are thought to
be on GABA and glycine receptors ŽMihic et al.,
1997..
Just as only a fraction of the fiber systems activated
by medial forebrain bundle electrical stimulation play
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R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22
causal roles in the rewarding effects of such stimulation, so do only a fraction of the systems activated by
drugs play causal roles in the rewarding effects of
those drugs. Just as it is essential for brain stimulation
reward specialists to identify which of the directly
activated medial forebrain bundle neurons is rewardrele¨ ant, so is it important for the drug reward specialist to identify the reward-relevant targets of drugs of
abuse. It is important to realize that most actions of
habit-forming drugs contribute little if anything to the
rewarding action of the drug; this important goal has
only been partially realized, even in the case of the
best characterized of habit-forming drugs.
The neurotransmitter system that has been most
clearly identified with the habit-forming actions of
drugs of abuse is the mesolimbic dopamine system.
Dopamine was first implicated in the rewarding effects of medial forebrain bundle electrical stimulation
ŽLiebman and Butcher, 1973; Fouriezos and Wise,
1976; Mihic et al., 1997. and of the psychomotor
stimulants amphetamine ŽYokel and Wise, 1975. and
cocaine Žde Wit and Wise, 1977. by pharmacological
studies. Amphetamine and cocaine non-selectively elevate synaptic levels of dopamine, noradrenaline, and
also serotonin, but the rewarding effects of these
agents are attenuated by selective dopamine antagonists and not by selective noradrenergic ŽYokel and
Wise, 1975; de Wit and Wise, 1977. or serotonergic
ŽLyness and Moore, 1983; Lacosta and Roberts, 1993.
antagonists.
Dopamine is found in a limited number of systems
in the brain, and it is the mesolimbic and mesocortical
dopamine systems } which project primarily from
the ventral tegmental area to the nucleus accumbens
and frontal cortex, respectively } that appear to be
involved in psychomotor stimulant reward function.
First, lesions of nucleus accumbens block or attenuate
the rewarding effects of intravenous cocaine ŽRoberts
et al., 1977, 1980. and amphetamine ŽLyness et al.,
1979.. Second, rats learn to lever-press for amphetamine microinjections into the nucleus accumbens ŽHoebel et al., 1983.. Third, they learn to approach portions of their environment where they receive such injections ŽCarr and White, 1983.. Rats
also learn to lever-press for nucleus accumbens microinjections of nomifensine Ža selective dopamine
reuptake inhibitor; Carlezon et al., 1995. and for
dopamine itself ŽDworkin et al., 1986., though, perhaps because of side effects ŽCarlezon et al., 1995.
they do not so readily learn to lever-press for cocaine
into this region ŽGoeders and Smith, 1983; Carlezon
et al., 1995..
Rats also learn to lever-press for cocaine injections
into the medial prefrontal cortex ŽGoeders and Smith,
1983.. However, the role of medial prefrontal cortex
in cocaine reward is not yet completely clear. While
rats more readily learn to lever-press for mPFC cocaine than for NAS cocaine ŽGoeders and Smith,
1983; Carlezon et al., 1995., lesions of mPFC do not
affect lever-pressing for intravenous cocaine in trained
animals ŽMartin-Iverson et al., 1986.. Such lesions
appear, paradoxically, to make untrained animals
more rather than less sensitive to the rewarding effects of cocaine ŽSchenk et al., 1991.. Cocaine injections into mPFC increase dopamine turnover in nucleus accumbens, which suggests at least one hypothesis as to why cocaine is rewarding when injected into
this region ŽGoeders and Smith, 1993..
Both NAS and mPFC are implicated in the habitforming effects of phencyclidine. Rats will learn to
lever-press for injections of PCP-as well as for the
more selective NMDA antagonists MK-801 and CPPinto either mPFC or the shell of NAS ŽCarlezon and
Wise, 1996.. Whereas the rewarding effects of
nomifensine in NAS are blocked by co-injections of
the dopamine antagonist sulpiride, the rewarding effects of PCP, MK-801, and CPP are not. Thus it
appears that PCP is habit-forming primarily because
of its action as an NMDA antagonist, and not because
of its ability to block dopamine reuptake ŽPCP blocks
NMDA receptors at an order of magnitude lower
concentrations than are necessary for it to inhibit
dopamine uptake.. It seems most likely that PCP is
habit forming in NAS because it decreases excitatory
input to the medium spiny output neurons of NAS;
decreased output of medium spiny neurons is also
caused by the elevations of NAS dopamine that result
from rewarding cocaine and amphetamine injections.
Thus decreased medium spiny neuron output appears
to be a common consequence of PCP, cocaine, and
amphetamine reward.
Rewarding opiate treatments also share the ability
to inhibit the output of NAS medium spiny neurons.
Opiates appear to have more than one site of rewarding action; proposed sites of rewarding action include
the ventral tegmental area ŽPhillips and LePiane,
1980; Bozarth and Wise, 1981., NAS ŽOlds, 1982.,
lateral hypothalamus ŽOlds, 1979; but see Britt and
Wise, 1981., hippocampus ŽStevens et al., 1991., and
periaqueductal gray Žvan der Kooy et al., 1982; Corrigall and Vaccarino, 1988.. Of these, the VTA and
NAS are the most clearly implicated ŽWise, 1989..
Rewarding opiate injections into the VTA ŽBozarth
and Wise, 1981; Devine and Wise, 1994. elevate NAS
dopamine ŽDevine et al., 1993. by disinhibiting dopaminergic cell firing ŽJohnson and North, 1992..
Ventral tegmental dopaminergic neurons are tonically
inhibited by neighboring GABAergic neighbors that
express m opioid receptors and are inhibited by morphine ŽJohnson and North, 1992.. It is not clear
whether the GABAergic inhibitors of dopaminergic
activity are interneurons ŽGrace and Bunney, 1979.,
R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22
projection neurons with collaterals to their dopaminergic neighbors ŽTepper et al., 1995., or GABAergic
projection neurons that inhibit dopaminergic cell firing simply through local dendritic GABA release. D
opioids are also capable of elevating NAS dopamine
ŽDevine et al., 1993. and are rewarding in proportion
to their ability to do so ŽDevine and Wise, 1994..
Early evidence suggested that VTA GABAergic neurons have m but not d receptors, but more recent
evidence involving hippocampal GABAergic interneurons that are sensitive to both m and d agonists
ŽLupica, 1995. raises the possibility that d opioid
actions on VTA GABAergic neurons should be sought
more closely.
The medium spiny neurons of NAS, like the opiate
target neurons of VTA, are GABAergic. They express
m receptors ŽGracy et al., 1997. and are inhibited by
morphine ŽJiang and North, 1992.. Opioid injections
into NAS are rewarding ŽOlds, 1982; van der Kooy et
al., 1982., and have psychomotor stimulant actions
similar to those associated with VTA morphine injections Žalthough doses an order of magnitude higher
are generally needed in NAS; Bozarth and Wise,
1981; Kalivas et al., 1983.. Thus opiates have at least
two mechanisms through which they can be rewarding
and through which they inhibit NAS medium spiny
neurons. This adds to the evidence suggesting inhibition of medium spiny neurons as a common and
causal consequence of at least a significant subset of
rewarding drug injections.
A fact that would seem to go against the hypothesis
that decreases in medium spiny neuron activation is
rewarding, however, is the fact that rats will work for
direct electrical stimulation of nucleus accumbens
ŽPrado-Alcala and Wise, 1984.. Such stimulation is
presumed, at first glance, to activate medium spiny
neurons. However, the assumption that direct electrical stimulation activates cell bodies near the electrode
tip is called into question by what is known of brain
stimulation reward in the region of the dopaminergic
cell bodies of the ventral tegmental area and substantia nigra. Inasmuch as Ži. dopaminergic antagonists
block brain stimulation reward; and Žii. reward sites
in this region have the same lateral, dorsal, and
ventral ŽCorbett and Wise, 1980; Wise, 1981. boundaries as the region of dopaminergic cell bodies, it
was first assumed ŽRouttenberg and Malsbury, 1969.
that stimulation in this region was rewarding because
it activated the dopaminergic cell bodies directly.
However, the population of first-stage neurons in the
ventral tegmental area has refractory periods that are,
for the most part, considerably faster than those of
dopaminergic neurons ŽYeomans, 1979.. Moreover,
there are similar refractory periods and connectivity
between VTA reward sites and lateral hypothalamic
reward sites ŽShizgal et al., 1980., and the majority of
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fibers common to lateral hypothalamic and ventral
tegmental reward sites have conduction velocities too
fast for dopaminergic fibers ŽBielajew and Shizgal,
1982; Murray and Shizgal, 1994. and project toward
rather than away from the dopaminergic cell bodies
ŽBielajew and Shizgal, 1986.. Finally, the medial forebrain bundle reward fibers are activated by levels of
stimulation approximately three orders of magnitude
lower than what is needed to antidromically activate
dopaminergic fibers ŽYeomans et al., 1988. Žit is difficult to determine the activation threshold of dopaminergic cell bodies from stimulation in the field of
the recording electrode.. Thus, in the case of the
VTA, at least, rewarding stimulation preferentially
activates fibers of passage at levels that do not activate local cells. This may also be true of rewarding
NAS stimulation.
At least some additional habit-forming drugs activate dopaminergic projections to nucleus accumbens
and are likely to decrease the output of medium spiny
neurons as a consequence. For example, nicotine increases dopamine release in nucleus accumbens ŽImperato et al., 1986.. Nicotinic receptors have been
localized to dopaminergic cell bodies ŽClarke and
Pert, 1985. and local nicotine injections increase dopaminergic cell firing ŽClarke et al., 1985.. Nicotine
infused directly into NAS also enhances local dopamine release, presumably by a presynaptic action
on the dopaminergic terminals of this region ŽWestfall et al., 1988.. Alcohol and cannabis also increase
extracellular dopamine concentrations in NAS ŽDi
Chiara and Imperato, 1985; Ng Cheong Ton et al.,
1988.; alcohol does so by increasing dopaminergic cell
firing ŽGessa et al., 1985..
4. Endogenous reward circuitry: current candidates
At the present time, the only firmly identified elements in brain reward circuitry are the mesolimbic
dopamine system, its efferent targets in nucleus accumbens, and its local GABAergic afferents. As mentioned above, the reward-relevant actions of amphetamine and cocaine are in the dopaminergic
synapses of NAS and perhaps mPFC. The lowestthreshold site for rewarding opiate effects involves mand d-opioid actions on GABAergic neurons in the
VTA; a secondary site of opiate rewarding actions
involves m- and d-opioid actions on medium spiny
output neurons of NAS. Thus GABAergic afferents
to the mesolimbic dopamine neurons Žprimary substrate of opiate reward., the mesolimbic dopamine
neurons themselves Žprimary substrate of psychomotor stimulant reward., and GABAergic efferents to
the mesolimbic dopamine neurons Ža secondary site
of opiate reward. form the core of currently characterized drug reward circuitry.
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R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22
While nicotinic blockade does not alter baseline
brain stimulation reward it does block the ability of
nicotine to potentiate brain stimulation reward ŽWise
et al., 1997.. The reward-relevant target of nicotine
appears to be the nicotinic receptor expressed by the
mesolimbic dopamine cells and the cholinergic projections from LDTg and PPTg appear to be the endogenous cholinergic link in reward circuitry. Localization of reward-relevant nicotinic receptors to the
dopaminergic neurons is suggested by four lines of
evidence. First, nicotine is known to activate these
neurons ŽClarke et al., 1985. and to cause dopamine
release in nucleus accumbens ŽImperato et al., 1986..
Second, nicotine self-administration is attenuated by
nicotinic antagonists localized to the ventral tegmental area ŽCorrigall et al., 1994.. Third, the nicotinic
agonist cytisine is rewarding when microinjected into
the VTA ŽMuseo and Wise, 1994.. Fourth, the rewarding ŽCorrigall et al., 1992. and reward-potentiating ŽWise et al., 1997. effects of nicotine, as well as
the effects of nicotine on dopamine-mediated locomotion ŽClarke et al., 1988.. are blocked for a curiously long period by the atypical nicotinic antagonist
chlorisondamine.
Chlorisondamine is an insurmountable nicotinic antagonist that acts for a few days Žpresumably the life
of the receptors it binds. in peripheral autonomic
ganglia but that blocks nicotine’s actions on central
dopaminergic neurons for a much longer period
Žseveral weeks.. This drug is taken up by dopaminergic nerve terminals ŽEl-Bizri et al., 1995. and
transported retrogradely to dopaminergic cell bodies
ŽEl-Bizri et al., 1995. where it blocks dopamine-dependent nicotinic actions for months ŽClarke, 1984..
Chlorisondamine is a nicotinic channel blocker, and it
would appear that once the drug is sequestered and
concentrated in dopaminergic cell bodies it is inserted
into new nicotinic receptors as they are expressed or
as they are inserted into the dopaminergic cell membrane. Whereas the drug is not sequestered by peripheral autonomic neurons and blocks only those
ganglionic nicotinic receptors that are expressed on
the membrane at the time of pharmacological treatment, the centrally sequestered chlorisondamine is
concentrated and stored where it can apparently block
many generations of nicotinic receptors in dopaminergic neurons. Thus chlorisondamine exerts a longterm and insurmountable blockade of nicotinic actions on monoaminergic neurons just as it exerts a
long-term and insurmountable blockade on the rewarding ŽCorrigall et al., 1992. and reward-potentiating ŽWise et al., 1997. actions of nicotine. While
chlorisondamine is taken up by serotonergic and
noradrenergic neurons as well ŽEl-Bizri et al., 1995.,
the fact that nicotine reward is blocked by selective
dopamine antagonists and selective dopaminergic le-
sions ŽCorrigall et al., 1992., taken with the fact that
noradrenergic and serotonergic lesions or blockade
fail to alter other forms of drug reward ŽYokel and
Wise, 1975; de Wit and Wise, 1977; Roberts et al.,
1977; Lacosta and Roberts, 1993., suggests that it is
the nicotinic receptors on dopaminergic cell bodies
Žand perhaps dopaminergic nerve terminals. that are
critical for nicotinic reward. Thus the mesolimbic
dopamine system appears to express the chemical
trigger zones for not only amphetamine and cocaine
reward but for nicotine reward as well.
There is much less basis for speculation regarding
the chemical trigger zones at which other drugs of
abuse initiate their rewarding actions in the brain.
Cannabinoid receptors are strongly concentrated in
the zona reticulata of the substantia nigra ŽHerkenham et al., 1991. and the proximity to the dopaminergic cell bodies and the fact that cannabis increases
dopamine release in NAS ŽNg Cheong Ton et al.,
1988. again suggest an interaction involving GABAergic inputs to dopaminergic cell bodies. Ethanol, too,
increases dopamine release in NAS ŽImperato et al.,
1986., and does so by increasing dopaminergic cell
firing ŽGessa et al., 1985.. The circuitry through which
it does so is not known. Phencyclidine has rewarding
actions in both NAS and mPFC ŽCarlezon and Wise,
1996., and the endogenous transmitter implicated in
these effects is glutamate. The mechanism of rewarding action in NAS seems likely to involve blockade of
NMDA-type glutamate receptors on medium spiny
neurons, but the mechanism in mPFC is unidentified.
Interestingly, there are glutamatergic projections from
mPFC to both NAS and VTA ŽSesack and Pickel,
1992., but the effects of mPFC phencyclidine on these
projections are not known.
Not all habit-forming drugs elevate nucleus accumbens dopamine concentration or depend on dopamine
for their rewarding actions. The rewarding effects of
NAS microinjections of phencyclidine and other
NMDA antagonists are dopamine-independent
ŽCarlezon and Wise, 1996.. Benzodiazepines and barbiturates tend to decrease dopamine release, at least
at high doses ŽWood, 1982; Finlay et al., 1992.. In the
case of phencyclidine, however, it appears that the
rewarding actions involve the GABAergic synaptic
targets of the mesolimbic dopamine projection to
NAS. Opiate effects on those targets also appear to
be rewarding ŽOlds, 1982., and inasmuch as benzodiazepines and barbiturates are known to affect GABA
receptor function it is quite possible that these drugs
also act in GABAergic circuitry that is efferent to the
mesolimbic dopamine system.
5. Synaptic inputs to drug reward circuitry
While not yet identified as links crucial to the
R.A. Wise r Drug and Alcohol Dependence 51 (1998) 13]22
rewarding effects of drugs of abuse, there are several
inputs to the mesolimbic dopamine system that might
modulate drug reward by modulating mesolimbic activation. One source of input is GABAergic feedback
from NAS; NAS medium spiny neurons project not
only to VTA but also to other GABAergic neurons
linked to VTA and NAS ŽAlexander and Crutcher,
1990; Kalivas et al., 1993; Van Bockstaele and Pickel,
1995.. Opiates have rewarding actions in some of
these GABAergic links that form a feedback loop
from regions of dopaminergic terminals to regions of
dopaminergic cell bodies. It is not clear how many of
the GABAergic feedback pathways to the VTA are
targets of rewarding actions of morphine.
Another potentially important source of input to
reward circuitry is glutamatergic afferents to dopaminergic neurons of the VTA. The VTA receives
glutamatergic input from mPFC ŽSesack and Pickel,
1992., amygdala ŽWallace et al., 1992., and PPTg
ŽLavoie and Parent, 1994; Charara et al., 1996. and
NAS receives glutamatergic input from these limbic
sources as well as from hippocampus. Electrical stimulation of regions within each of these structures is
rewarding, and such stimulation may have trans-synaptic importance for the mesolimbic system.
Cholinergic input from PPTg and LDTg has been
mentioned ŽOakman et al., 1995.; this now seems to
be an important link in the circuitry of brain stimulation reward and it may provide endogenous cholinergic activation of nicotinic receptors involved in nicotine reward.
The VTA also receives serotonergic innervation.
Manipulation of serotonergic neuronal activation appears to modulate reward function. Serotonergic lesions appear to make cocaine more rewarding ŽLoh
and Roberts, 1990., suggesting that blockade of serotonin reuptake by cocaine may be a factor limiting the
rewarding effects of cocaine. Drug-free Žbut not
‘primed’. rats show some degree of ambivalence to
cocaine ŽEttenberg and Geist, 1991., and serotonin
may contribute to that ambivalence. Infusion of 8OH-DPAT into the dorsal raphe, where it inhibits cell
firing by acting as an agonist at serotonergic autoreceptors, potentiates the rewarding effects of MFB
simulation ŽFletcher et al., 1995., and is rewarding in
its own right ŽFletcher, 1993.. These reward-relevant
effects of serotonergic inhibition may be mediated
through the serotonergic projection to VTA; another
possibility would involve the serotonergic projection
to NAS.
Finally, there are noradrenergic projections from
locus coeruleus to both VTA and NAS ŽSaleem et al.,
1996. and locus coeruleus has been implicated in
aspects of opiate dependence ŽAghajanian, 1978..
While the noradrenergic nucleus locus coeruleus was
19
once proposed as a source of reward circuitry ŽStein,
1971., this view is no longer held ŽWise, 1978; Wise
and Rompre,
´ 1989.. Nonetheless, it is interesting to
note that clonidine, a noradrenergic agonist with great
potency at the noradrenergic autoreceptor, can serve
as a reward in its own right ŽDavis and Smith, 1977.
and, at higher doses, can strongly degrade the rewarding effects of MFB brain stimulation ŽGallistel and
Freyd, 1987.. Thus noradrenergic function appears to
have some ability to modulate reward function.
These several inputs to the mesolimbic dopamine
system offer potential targets for medication development ŽFig. 1.. Drugs that act in these systems may
prove more subtle in their ability to modulate the
resting tone of the mesolimbic system and also its
responsiveness to drugs of abuse. Drugs that act in
these systems may thus be less likely than direct
dopamine agonists or antagonists to have abuse liability of their own or to be rejected as dysphoric agents,
causing problems of compliance with a medication
regimen.
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