Download Dopamine receptors in the ventral tegmental area

Brain Research, 512 (1990) 1-6
Elsevier
BRES 15281
1
Research Reports
Dopamine receptors in the ventral tegmental area modulate male
sexual behavior in rats
Elaine M. Hull, Terence J. Bazzett, Robert K. Warner, Robert C. Eaton and
James T. Thompson
Department of Psychology, State University of New York at Buffalo, Amherst, N Y 14260 (U.S.A.)
(Accepted 8 August 1989)
Key words: Sexual behavior; Dopamine; Apomorphine; c/s-Flupenthixol; Ventral tegmental area; Motivation; Depolarization block
The mesocorticolimbic dopamine tract is considered to be a substrate for motivation and reward as well as for locomotor behavior. The
present experiments assessed the role of dopamine cell bodies in the ventral tegmental area (VTA), the source of this tract, in the copulatory
behavior of male rats. The dopamine agonist apomorphine or the dopamine antagonist c/s-flupenthixol were microinjected into the VTA
immediately before sexual behavior tests with a receptive female. Apomorphine delayed the onset of copulation and slowed its rate, presumably
by stimulating somatodendritic autoreceptors and thereby decreasing the firing rate of VTA neurons. Control injections of apomorphine into
the substantia nigra were without effect, c/s-Flupenthixol, which would have blocked autoreceptors and thereby depolarized VTA neurons,
shortened the latency to begin copulating in those animals that did copulate; however, fewer animals exhibited sexual behavior. One possible
explanation for the apparently contradictory effects of c/s-flupenthixol may be that VTA neurons increased their rate of firing in some animals,
leading to a faster onset of copulation, but that in other animals depolarization block in a substantial number of neurons resulted in a lack
of copulation. These results are consistent with a contribution of the mesocorticolimbic dopamine tract to motivational and/or motor aspects
of male copulatory behavior.
INTRODUCTION
T h e ventral tegmental a r e a ( V T A ) , the source of
d o p a m i n e r g i c projections to various limbic and cortical
structures, is thought to contribute to l o c o m o t o r and
motivational aspects of behavior 5'14'37. Studies manipulating dopamine ( D A ) and/or opiate receptors in the V T A or
the nucleus accumbens, one of its terminal fields, have
suggested that this pathway may enhance feeding 9'16'27,
locomotor activity1°,18,21,24, drug self administration 4,32 and
electrical self stimulation of the brain 6'23'26'3°,33.
The possible role of this system in sexual motivation has
not been adequately assessed. Microinjection of the mu
opiate agonist morphine 2, the D A agonist apomorphine 2°
or the indirect catecholamine agonist amphetamine 12 into
the nucleus accumbens resulted in dose related decreases in
the latency to begin copulating; however, the apomorphine
effect was of borderline statistical significance (P = 0.058).
These findings suggest that sexual motivation, measured as
the inverse of the latency to begin copulating, may be
enhanced by D A and/or opiate activity in this terminal field
of the mesocorticolimbic D A system.
The present experiments investigated whether manipulation of impulse regulating D A autoreceptors, located on cell
bodies and dendrites in the VTA, would affect copulation
of male rats. D A agonists injected systemically or applied
iontophoretically have been reported to decrease the firing
rate of D A neurons in the V T A 1'36. D A antagonists, on the
other hand, have generally increased the firing rates of these
cells8'36. These results are assumed to result from stimulation or blocking, respectively, of D A autoreceptors in the
VTA. We predicted that stimulation of these autoreceptors
with apomorphine microinjections would increase the latency to begin copulating, by decreasing the firing rate of
these neurons and therefore decreasing the release of D A
in limbic terminal fields. O n the other hand, microinjections
of the D A antagonist c/s-flupenthixol into the V T A were
expected to decrease the latency to copulate. Control
injections into the substantia nigra (SN) were expected to
be ineffective.
MATERIALS AND METHODS
Animals
Adult male Long-Evans rats were housed individually in large
plastic cages with food and water available ad libitum. They were
tested for sexual behavior 3 times before surgery; only those that
copulated consistently were chosen. Ovariectomized females of the
same strain were used as stimulus animals and were housed in a
Correspondence: E.M. Hull, Department of Psychology, Park Hall, State University of New York at Buffalo, Amherst, NY 14260, U.S.A.
separate room. Females were brought into behavioral estrus with a
single s.c. injection of estradiol benzoate (20 ktg in oil) 48 h before
behavioral testing.
Surgery and cannulae
The male rats were anesthetized with ketamine hydrochloride (50
mg/kg) and xylazine hydrochloride (4 mg/kg) i.m., and received
bilateral stainless steel guide cannulae ending 1 mm above the VTA
(AP: - 3.0 from bregma, ML: + 1.2, DV: - 8.2, incisor bar: + 5)2'~
or the SN (AP: - 3.0, ML: + 2.7, DV: 7.8, incisor bar: + 5) 2~. The
guide cannulae were constructed of 23 gauge thin wall stainless steel
tubing (o.d. = 0.6 mm; i.d. = 0.4 mm). An obturator constructed
from 27 gauge stainless steel tubing (o.d. = 0.4 mm; i.d. = 0.2 mm)
was cut flush with the end of the guide cannula and remained in the
guide cannula except during microinjections. Injection cannulae
were also constructed from 27 gauge tubing and extended 1 mm
below the end of the guide cannula. Details of surgery and cannula
construction are described in Hull et al. z~.
Drugs
The DA agonist apomorphine (Sigma Chemical) was dissolved in
0.5 #1 of 0.2% ascorbate. The DA antagonist cis-flupenthixol was a
gift of H. Lundbeck A/S, and was dissolved in 1/zl sterile water.
Procedures
Two weeks following surgery, males were given a single postoperative baseline test for sexual behavior. Thereafter, behavioral
tests were given at 1 week intervals. All animals received all doses
in counterbalanced order. Drugs were administered using a Harvard
infusion pump while the animal moved freely in his cage. The rate
of injection was 1.0 #l/min, with the injection cannula being left in
place for 30 s after the injection was completed. The male was then
carried in his home cage to an adjacent testing room, where a
stimulus female was introduced into his cage. Testing began
immediately.
Each test lasted for 30 min following the first intromission, or for
a total of 30 min if the male failed to intromit. The occurrence and
time of each mount, intromission, and ejaculation were recorded by
a program written for the IBM XT microcomputer19. Measures
derived from the data were: number of ejaculations per test,
numbers of mounts and of intromissions preceding each ejaculation,
latencies to the first mount and the first intromission, ejaculation
latency (time from the first intromission of an ejaculatory series to
the subsequent ejaculation), postejaculatory refractory period (time
from the ejaculation to the next intromission), interintromission
interval (the average time between intromissions), and intromission
ratio (the number of intromissions divided by the number of mounts
plus intromissions). Intromissions were distinguished behaviorally
from mounts without intromission by the presence of a deep thrust
followed by a rapid, springing dismount. Ejaculation patterns were
characterized by longer, deeper thrusts, slow dismounts and a
prolonged period of rest following ejaculation.
Statistical analysis
Data were analyzed by one way repeated measures analyses of
variance, followed by Newman-Keuls comparisons among groups.
Ordinal data were analyzed by Cochran's Q-tests, followed by
paired comparisons using McNemar's test. All data are presented as
means +_ S.E.M,
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After all behavioral tests were completed, males were anesthetized and sacrificed by decapitation. Coronal sections of the brain
were cut at 40 k~m, stained with cresylviolet, and examined with a
projection magnifier. Data from animals with one or both cannulae
located more than 0.5 mm from the VTA or SN were excluded from
statistical analysis.
Experiments
In Expt. 1 apomorphine was microinjected bilaterally into the
VTA of 18 animals with accurate cannula placements. Doses were
0.5
2.0
APOMORPHINE (p~g)
Fig. 1. The effects of microinjections of apomorphine into the VTA
on the latency (in sec) to the first intromission in sexual behavior
tests. Values are means + S.E.M. The 2 #g dose significantly
delayed the first intromission, compared to vehicle (*P < 0.05).
0 (vehicle), 0.1, 0.5 or 2.0/xg per cannula. In Expt. 2 apomorphine
was microinjected bilaterally into the SN of 20 animals with accurate
cannula placements. Doses were the same as in Expt. 1. In Expt.
3 cis-flupenthixol was microinjected bilaterally into the VTA of 14
animals with accurate placements. Doses were 0, 2, 5, and 10 #g per
cannula. In Expt. 4 c/s-flupenthixol was microinjected bilaterally
into the VTA of 14 animals with accurate placements. Doses were
0.0, 0.02, 0.2, and 2.0 #g per cannula.
RESULTS
Expt. 1: effects of apomorphine in the VTA
As predicted, apomorphine microinjected into the
VTA increased the latency to begin copulating (F3,sl =
3.14, P < 0.05; see Fig. 1). Apomorphine also reduced
the number of ejaculations (F3,sl = 4.75, P < 0.01; see
Fig. 2). This reduction reflected a slowed rate of
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Fig. 2. The effects of microinjections of apomorphine into the VTA
on the number of ejaculations during sexual behavior tests, which
lasted for 30 min from the first intromission (30 min total, if no
intromission occurred). The two highest doses (0.5 and 2.0 #g)
significantly decreased the number of ejaculations, compared to
vehicle (**P < 0.01).
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Fig. 4. The effects of microinjections of high doses of c/sflupenthixol into the VTA on the number of ejaculations during
sexual behavior tests, which lasted 30 min from the first intromission
(30 min total, if no intromission occurred). The highest dose (10/~g)
significantly decreased the number of ejaculations, compared to
vehicle (**P < 0.01). This decrease reflected a decrease in the
number of animals copulating (see text).
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2.0
APOMORPHINE (p,g)
Fig. 3. Top: the effects of microinjections of apomorphine on the
mean interval (in sec, + S.E.) between intromissions in sexual
behavior tests. The two highest doses (0.5 and 2.0/~g) significantly
slowed the rate of intromitting, compared to vehicle (**P < 0.01).
Bottom: the effects of microinjections of apomorphine into the VTA
on the mean latency (in sec, + S.E.) from the first intromission to
the first ejaculation. The two highest doses (0.5 and 2.0 /~g)
significantly slowed the occurrence of the first ejaculation, compared to vehicle (**P < 0.01).
copulation, rather than a decrease in the number of
animals copulating. Specifically, the interval between
intromissions was lengthened (F3,sl = 10.83, P < 0.001;
see Fig. 3 top), resulting in an increased ejaculation
latency (F3,51 = 6.22, P < 0.005; see Fig. 3 bottom).
Measures that were not affected included intromission
ratio, number of intromissions preceding ejaculation,
postejaculatory latency to resume copulation, and number of animals copulating.
the number of ejaculations during the test period (F3,39 =
6.61; P < 0.001; see Fig. 4). This decrease reflected a
reduction in the number of animals copulating (Vehicle:14/14; 2 ag:14/14; 5/~g:12/14; 10/~g:8/14; Q(3) = 13.09;
P < 0.005), since there was no drug related decline
among animals that copulated consistently. There was no
gross impairment of motor behavior by the doses used in
this experiment; however, animals that did not copulate
appeared generally less active. A higher dose (20/zg) in
a pilot study did result in marked sedation. No other
measures were significantly affected by cis-flupenthixol,
although there was a nonsignificant trend towards decreased intromission latency among those animals that
did copulate (0.05 < P < 0.1). This trend provided the
rationale for testing lower doses in Expt. 4.
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No measure was affected by any dose of apomorphine
in the SN.
Expt. 3: effects of high doses of cis-flupenthixol in the
VTA
ct~-Flupenthixol produced a dose related decrease in
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Expt. 2: effects of apomorphine in the SN
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Fig. 5. Effects of microinjections of low doses of c/s-flupenthixol
into the VTA on the mean latency (in sec, + S.E.) to the first
intromission in sexual behavior tests. The highest dose (2 /~g)
hastened the occurrence of the first intromission, compared to
vehicle (*P < 0.05).
Expt. 4: effects of low doses of cis-flupenthixol in the VTA
The 2/*g dose of cis-flupenthixol decreased the number
of animals copulating (Vehicle: 13/14; 0.02/~g: 14/14; 0.2
~g:13/14; 2/~g:9/14; Q(3) = 8.6, P < 0.05). However, the
decrease in number of animals copulating was offset by
a nonsignificant increase in number of ejaculations in
those animals that did copulate, resulting in no overall
change in the number of ejaculations of the entire group.
The 2 ~g dose also decreased the latency to intromit of
those animals that did copulate (F3,36 = 3.02; P < 0.05;
see Fig. 5). No other measures were affected. (The
reason for the ineffectiveness of the 2/,g dose in Expt. 3
is not known. Failure to copulate after cis-flupenthixol
did not appear to be correlated with cannula placement
or with temporal order of testing.)
DISCUSSION
Stimulation of impulse regulating somatodendritic
autoreceptors in the VTA with apomorphine increased
the latency to begin copulating, suggesting that sexual
motivation may have been impaired. This effect is
consistent with the proposal that activation of the
mesocorticolimbic D A tract enhances motivation and/or
reward. However, other rate measures were lengthened
as well, implying that motor behavior may have been
generally slowed, although the animals did not appear to
be sedated and all animals did copulate. Thus, the
increased latency to begin copulating may have reflected
a slight motor retardation, as well as, or instead of, a
motivational reduction. A recently completed experiment designed to dissociate motor from motivational
effects of these treatments suggests that locomotor
slowing was the primary deficit 34. In that experiment
apomorphine injections into the VTA slowed the rate of
running to all arms of an X maze, but did not affect the
percentage of trials on which the male chose the goal arm
containing a receptive female.
These effects of apomorphine appear to be relatively
specific to the VTA. Previous studies have shown that
apomorphine in the medial preoptic area increased the
efficiency of copulation without affecting the latency to
intromit 3,2°,2s, whereas when injected into the nucleus
accumbens, it somewhat decreased the latency to the first
intromission z~j. Apomorphine injections into several
other structures (caudate nucleus, lateral septum, paraventricular nucleus) did not affect copulation (20, unpublished observations). In the present experiments
apomorphine microinjected into the SN was likewise
without effect. Cannulae in Expt. 2 were located in the
lateral half of the SN, an area that probably projected to
the caudate-putamen and/or amygdala 13. The coordinates
were chosen to maximize the distance from the VTA, so
as to decrease the probability of drug diffusion to that
structure. We cannot exclude the possibility that injections through cannulae situated more medially in the SN
may have affected copulation. However, this does not
seem likely, since the drug probably diffused throughout
a substantial volume of the SN, including both zona
compacta and zona reticulata, and yet did not produce
even a trend toward a behavioral effect. (We have
previously found that similar microinjections of dye
diffused in a volume no more than 1 mm ~ surrounding the
tip of the cannula, and extending up the cannula track.)
The DA antagonist cis-flupenthixol was expected to
enhance sexual motivation and/or motor performance by
blocking impulse regulating autoreceptors in the VTA
and thereby increasing the firing of mesocorticolimbic
DA neurons. In support of this hypothesis, cis-flupenthixol did decrease the latency to begin in those animals
that did copulate, (this effect was statistically significant
only in Expt. 4). However, the higher doses of cisflupenthixot (5 and 10/~g in Expt. 3, and 2/~g in Expt.
4) decreased the number of animals copulating, an
unexpected effect. The apparent decrease in sexual
motivation and/or motor performance in those animals
that failed to copulate, coupled with an apparent increase
among those that did copulate, appears paradoxical.
One possible explanation for these results is a reduction in the number of spontaneously firing neurons, due
to induction of depolarization block, in some VTA
neurons and a simple excitation of others. Thus, removal
of inhibition normally exerted by autoreceptors would be
expected to result in a net depolarization of VTA
neurons 36. In some neurons this would be reflected in an
increased firing rate and a shift to a bursting pattern of
firing that may result in a greater release of DA from the
axon terminal 15. In other neurons the depolarization
would be great enough to silence the firing as a result of
depolarization block 817. According to this hypothesis,
animals that began copulating with a shorter latency
would be those whose VTA neurons primarily increased
their firing rates; those that failed to copulate would be
those whose VTA neurons were primarily blocked. No
direct evidence for or against this explanation was
obtained in these experiments.
One factor mitigating against this explanation is the
finding that acute treatment with neuroleptics is usually
incapable of inducing depolarization block (reviewed in
refs. 7,11). Typically, chronic treatment over a period of
2-3 weeks has been required ~35. However, these electrophysiological recording experiments have utilized
anesthetized preparations. Decreased excitability of neurons resulting from the anesthesia may have reduced the
incidence of depolarization block 22"25. In addition, the
electrophysiological recording studies have generally
employed either systemic drug injections or microiontophoresis. However, greater concentrations of drug at the
active site may be produced by local microinjections than
by systemic administration, and a larger portion of the
neuron may be affected by microinjection than by
microiontophoresis. Thus, our use of localized microinjections in unanesthetized animals may possibly have
increased the likelihood of depolarization block in our
animals. A recent report of depolarization block after
acute neuroleptic treatment confirms that higher doses of
neuroleptic drugs can sometimes induce such inactivation, even in anesthetized animals a7.
Another behavioral example of apparent depolarization block was recently reported by Rompr6 and Wise 3a.
Briefly, systemically administered pimozide elevated the
threshold for electrical self stimulation of the brain,
presumably by blocking postsynaptic D A receptors in
limbic terminal areas. Low doses of morphine microinjected into the VTA reversed this desensitization, restoring self stimulation to normal. However, higher doses of
morphine frequently resulted in a complete absence of
self stimulation. Finally, the G A B A agonist muscimol,
which normally inhibits neurons by hyperpolarization,
was able paradoxically to restore self stimulation.
Rompr6 and Wise suggested that the ability of high doses
of morphine to block self stimulation resulted from
depolarization block of VTA D A neurons, and that the
hyperpolarizing influence of muscimol was able to restore
the neurons to normal. While Rompr6 and Wise's
regimen differs considerably from ours, their results are
consistent with the ability of acute treatments to induce
depolarization block in VTA neurons and with the
detrimental effects of such inactivation on motivated
behavior.
An alternative explanation for the decrease in the
number of animals copulating is that cis-flupenthixol may
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