Cocaine abuse is a major public health
problem. The drug has a reputation as an
enhancer of sexual drive, performance and
pleasure and is frequently used for these
purposes. The sexualstimulant properties of
cocaine are not surprising, as one of the major
actions of the drug is to block the reuptake of
dopamine (DA) and so increase its synaptic
availability; also the key role of DA in
modulating reward and sexual behaviour is well
documented. However, there are few
properly-controlled studies relating cocaine
effects to human and animal sexual behaviour.
Since animal models have proved to be valid
tools in the evaluation of cocaine activity, our
study was first designed to examine the
influence of cocaine on three different aspects
of male rat sexual behaviour.
We took into account: (1) penile erection
(PE) of sexually-naive animals in the absence of
females in oestrus (2) copulatory performance of
sexually-experienced rats; and (3)
indiscriminate mounting stimulated by the
dopaminergic agonist, lisuride. In order to
investigate the involvement of DA D2 receptors
in the effects of cocaine on sexual behaviour,
some tests were conducted after the pretreatment
of rats with the selective DA D2 antagonist, (-)
eticlopride, which is reported to interfere with
DA agonist-induced PE and stereotyped behaviour
in rats. Further, a series of experiments was
performed to evaluate the stretching-yawning
(SY) response to the challenge of the DA D2
agonist, SND 919, at a low, non-stereotyping
dose in rats subchronically-treated with
cocaine.
The rationale behind this investigation is
that neurochemical alterations at DA ergic
levels brought about by repeated injections of
cocaine might involve the DA D2 autoreceptor
function, and might be reflected in a modified
SY response. This is reputed by many researchers
to be an index of the stimulation of DA D2
autoreceptors. However, others believe that the
DA receptors involved in SY are
post-synaptically located; they would be DA
sensitive as autoreceptors and might correspond
to DA D3 receptors.
[...]
DISCUSSION
The present study confirms the stimulant
properties of acute cocaine on PE in freely
moving rats in the absence of receptive females
and provides new information about the influence
of the drug on the copulatory pattern of male
rats and on some of the behavioural effects
induced by DA agonists. Previous experiments in
our laboratory described cocaine-induced PE at a
dose (15 mg/kg) that is now reported to be
ineffective. The reason for this discrepancy
probably lies in the different methods used
(strain of animals and adaptation period in the
test cages before cocaine injection), with
repercussion on the animals' motor activity,
which seems markedly to inhibit PE. However, the
influence exerted by the DA D2 antagonist (-)
eticlopride on cocaine-induced effects is
confirmed: while (-) eticlopride antagonized
cocaine-induced motor hyperactivity it did not
inhibit PE which, in the case of high cocaine
doses, was actually stimulated. This finding is
in accordance with those of other studies where
the DA D2 antagonist has been found to
counteract behavioural sensitization to
cocaine-induced motor hyperactivity and to
reverse the inhibitory effect of cocaine on PE
observed after repeated injections with the
stimulant.
Acute injection of cocaine at moderate doses
facilitated indiscriminate mounting, typically
elicited by lisuride at doses higher than 0.2
mg/kg . The term "indiscriminate" is justified,
as in preliminary experiments conducted in our
laboratory it was seen that males treated with
lisuride indiscriminately mounted males or
females in oestrus or not, all grouped together,
and that cocaine pretreatment does not affect
sexual preference (data not presented).
Facilitation of the phenomenon was prevented by
pretreatment with (-) eticlopride, as was motor
hyperactivity, thus suggesting that DA D2
mediated mechanisms are crucially involved in
both behaviours but are not those underlying PE.
Moreover, results obtained after (-) eticlopride
are in line with those reporting the antagonism
exerted by classical neuroleptics towards
heightened locomotor activity after cocaine and
suggest that indiscriminate mounting is likely
to be a form of compulsive motor induction
rather than motivated sexual stimulation.
As regards the mating tests, the most
striking effect after acute cocaine injection at
7.5 and 15 mg/kg was the increase in mounts
preceding ejaculation. In human terms, such a
result, along with acute cocaine-induced PE
could suggest an enhancement of sexual
appetitive behaviour and, therefore, an
aphrodisiac-like effect of the drug.
Alternatively, an increase in mounts before
ejaculation could be interpreted as a decrement
in copulatory behaviour, whereby the rats need
more stimulation in order to ejaculate. In the
light of the overall data obtained, it is hardly
likely that cocaine has a consistent and, above
all, long-lasting sexual stimulant effect on
male rats. It is well known that the copulatory
behaviour of these animals comprises a
precopulatory phase, the most common measure of
which is ML, and a consummatory phase, mainly
represented by IF and EL. While ML as well as
PET are considered indexes of rat sexual
appetitive behaviour, IF and EL reflect the
ejaculatory threshold; sex arousal and
ejaculatory mechanisms are distinct, as
demonstrated by the different influence of drugs
on the respective parameters. In our study,
neither acute nor subchronic cocaine at 15 mg/kg
was able to stimulate copulatory behaviour in SI
rats; moreover, cocaine at 7.5 and 15 mg/kg did
not significantly reduce the IL, ML and PET of
SA rats but actually prolonged them dramatically
when administered acutely at 30 mg/kg, when
there was a general abatement of sexual
activity, reflected in all the other test
parameters.
The impairment of copulatory ability was
aggravated by subchronic treatment of cocaine
and was long-lasting, for even after treatment
had been suspended for a week the animals'
performance was still markedly impaired. Despite
the fact that our tests were conducted during
the light phase, it seems improbable that the
effects obtained after cocaine are dependent on
the experimental procedure adopted, for although
rats are nocturnal animals, it has been found
that after appropriate training, copulatory
tests are regularly performed in the light phase
by a high percentage of animals. The increase in
MF produced by acute cocaine at moderate doses
was completely abolished by 7 days of treatment,
thus suggesting that this effect declines
rapidly, as in the case of PE. The mating
pattern observed in rats after subchromc
cocaine, in particular at 15 mg/kg, differed
significantly from that obtained after the first
injection and shows that only ejaculation
mechanisms are affected; moreover, it seems to
reflect a premature ejaculation reminiscent of
that produced by acute systemic DA
agonists.
This similarity between subchronic cocaine-
and DA agonist-induced effects would, therefore,
suggest that the neuronal substrates in the two
cases are quite similar, though different from
those affected by acute cocaine injection. The
role of the specific DA receptors involved in
the facilitation of ejaculation by DA agonists
is questioned. What is more, any hypothesis as
to the mechanisms involved in the various
behavioural effects exerted by such compounds
now seems suspect in view of the proliferation
of DA receptor subtypes and of the yet limited
understanding of specific affinity for them of
the DA agonists and antagonists. (-)
Eticlopride, itself previously described as a
selective DA D2 antagonist, has more recently
been reported as having considerable affinity
for the DA D3 receptor.
However, leaving aside any specific
neurochemical interpretation of the effects of
cocaine on rat sexual behaviour, our findings
support the notion that, although the drug might
heighten sexual potency and urge in the short
term (hence its popular reputation as one of the
best aphrodisiacs), after high doses or repeated
use it may well have an inhibitory effect. In
fact, just as drug-induced hyperactivity
sensitizes , certain sexual stimulant effects
rapidly decline. A functional as well as
neurochemical interdependence of the two
phenomena is possible and would also be
indirectly confirmed by the results obtained on
cocaine-induced PE and motor activity after (-)
eticlopride pretreatment.
There is conflicting evidence regarding DA
D2 autoreceptor function after chronic cocaine
some authors have found a decrease, some an
increase and others no change. The present study
clearly shows a significant enhancement of SND
919-induced SY after 7 days of cocaine
treatment. If it is true that the SY syndrome
reflects the selective stimulation of DA D2
autoreceptors or DA D3 receptors, our
behavioural results would indirectly confirm
that one of these two DA receptor subtypes is
supersensitive, at least in our experimental
conditions. Since a DAergic deficit is the
result of stimulation both of DA D2
autoreceptors, which inhibit DA synthesis and
release, and of DA D3 receptors, our data are in
accordance with those showing DA depletion after
chronic use of cocaine. However, in view of the
fact that cocaine blocks the reuptake of
monoamines in general, clarification of this
issue awaits the result of further biochemical
and behavioural studies.
