Recovery from sexual exhaustion-induced copulatory inhibition and drug hypersensitivity follow a same time course: two expressions of a same process? (2010)
COMMENTS: Sexual exhaustion is rats is marked by multiple brain changes that take at least 4 days to reverse. At the same time, full recovery of sexual activity (number of copulations and ejaculations) takes 15 days. This researcher believes, as we do, that sexual satiation is a mechanisms to prevent over-stimulation of the reward circuitry.
From study: It could be thought that the long lasting sexual inhibition resulting from copulation to satiation constitutes a protective mechanism against over stimulation of the brain circuits involved in its processing. The mesolimbic system plays a role in the processing of natural rewards including sexual behaviour . Constant stimulation of this circuit by repeated administration of drugs of abuse produces behavioural sensitisation  that resembles the drug hypersensitivity exhibited by sexually exhausted rats after repeated ejaculation in a short period, which would continually stimulate the mesolimbic system
Behav Brain Res. 2011 Mar 1;217(2):253-60. doi: 10.1016/j.bbr.2010.09.014. Epub 2010 Sep 25.
Departamento de Farmacobiología, Cinvestav, IPN-Sede Sur, Calzada de los Tenorios 235, Delegación Tlalpan, México 14330 D.F., Mexico. firstname.lastname@example.org
Male rats allowed copulating without restriction with a single oestrous female ejaculate repeatedly until reaching sexual exhaustion. Twenty-four hours after this process, sexually exhausted males exhibit a series of physiological alterations when compared to non-exhausted males. Among them, the most conspicuous are a long-lasting sexual behaviour inhibition and a generalised hypersensitivity to drug actions. The objective of the present work was to establish if there was a correlation between these two features of sexual satiation in relation to the duration of its expression. To that aim, we characterised the spontaneous sexual behaviour recovery process from sexual satiation, as well as the duration of the drug hypersensitivity phenomenon. The latter was assessed through the appearance of a sign of the serotonergic syndrome: the flat body posture. Results showed that the drug hypersensitivity phenomenon and the sexual inhibition that results from copulation to satiation follow a similar time course of recovery, with a drastic decrease in their expression 96 h after the sexual satiation process. This finding indicates that these phenomena might represent two expressions of a same brain plasticity process, as suggested by the long lasting character of both events, which interestingly appears to be reversible.
Copyright © 2010 Elsevier B.V. All rights reserved.
PORTIONS OF THE FULL STUDY:
Sexual satiation is defined as a long lasting sexual inhibitory period that appears after repeated ejaculation in the course of ad libitum copulation [2,12]. Twenty-four hours after the exhaustion process, male rats behave in two different manners in the presence of a receptive female: two thirds of them do not show any sexual activity and the remaining third is capable of ejaculating once, without resuming sexual activity after that ejaculation . Thus, two populations of sexually exhausted rats can be distinguished 24 h after copulation to satiation, a responsive and a non-responsive one. At this same testing point (24 h), sexually exhausted male rats exhibit a series of physiological alterations when compared to non-exhausted males.
For instance, electrical stimulation of brain regions involved in the control of copulatory behaviour like the medial preoptic area , the ventral tegmental area  and the nucleus accumbens  facilitates sexual behaviour expression in sexually experienced male rats, but lacks of an effect in the same subjects when sexually exhausted.
Another change refers to the anxiolytic-like effect of ejaculation described in sexually experienced male rats . This property of ejaculation appears after one, two or six successive ejaculations, however, 24 h after the satiation process, once sexual exhaustion is established, the ejaculation exhibited by the responsive population of sexually exhausted animals, lacks of an anxiolytic-like effect .
Finally, a consistent finding when administering pharmacological treatments to sexually exhausted rats is the manifestation of drug hypersensitivity.
Thus, in sexually satiated rats the serotonergic 5-HT1A receptor agonist, 8-hydroxy-di-propil amino tetraline (8-OH-DPAT), in addition to reversing the characteristic sexual behaviour inhibition of exhausted males, induces the appearance of symptoms of the serotonergic syndrome (5-HT syndrome) , after a dose not inducing it in non-exhausted animals . Yohimbine, an _2-adrenergic antagonist known to exert a biphasic, dose-based effect on copulatory behaviour of sexually experienced rats , has a narrower window for its facilitative effects in sexually exhausted rats than in non exhausted ones , and a similar effect is seen with the opioids antagonists naloxone and naltrexone . Finally, the dopaminergic antagonist, haloperidol, elicits circling behaviour in sexually exhausted animals at doses that lack such an effect in sexually experienced rats . Together, these data suggest that the hypersensitivity to drug actions is a generalised phenomenon of sexually satiated rats, since it appears after the systemic injection of diverse pharmacological agents acting at different neurotransmitter systems
Thus, after the 24 h postsatiation recording, where almost no one of the sexually exhausted responsive population resumed copulation, a progressive increase in the ejaculatory capacity of sexually exhausted rats was observed.
Hence, 40% of satiated rats exhibited up to 3 successive ejaculations 72 h after the exhaustion procedure. This percentage was statistically significantly higher than the one obtained at 24 h and significantly lower when compared to the performance of sexually experienced rats during the satiation procedure. A maximum of 4 successive ejaculations was achieved by satiated rats 96 h after satiation, and this number rose to 5 after the 7-day period of sexual rest.
The data on the temporal course of sexual behaviour recovery after copulation to satiation show that the spontaneous recovery process is to be followed mainly through three variables: the percentage of satiated rats achieving ejaculation, the proportion of these animals that resume copulation after ejaculation and the ejaculatory capacity exhibited by satiated rats after the different periods of sexual rest. The results show that during the first 48 h following the copulation to exhaustion session, animals are clearly sexually inhibited, with an increase in the ejaculatory capacity (3 successive ejaculations) in a very small proportion of rats.The proportion of males exhibiting this increased ejaculatory capacity augments 72 h after satiation. After a 96 h period of sexual rest, all animals are able to ejaculate and resume copulation after ejaculation. This is a qualitative change, since the criterion used to consider that an experimental manipulation reverses sexual exhaustion is the recovery of the ability of satiated rats to resume copulation after ejaculation . Thus, it can be said that at this point the sexual inhibition that characterises satiation is reversed in all animals, which are all capable of achieving two successive copulatory series. After a 7-day period of sexual rest the ejaculatory capacity of almost all animals increases to 4 successive ejaculations, to 5 after 10 days and to 6 after 15 days of sexual rest.
The mean number of successive ejaculations exhibited by sexually experienced males during the copulation to satiation procedure (seven) is achieved by half of the satiated rats after 15 days of sexual rest. This last proportion is not different from the one obtained during the copulation to satiation session in non-exhausted males.
Beach and Jordan’s original study on sexual exhaustion  reported a period of 15 days for full recovery from sexual exhaustion which was determined by observations at few specific time intervals following satiation. Present data, were obtained using large (more representative) independent groups of rats for each time point of the recovery process, and evaluated the ejaculatory capacity at each of these points applying the satiation criterion (90 min without ejaculating after the last ejaculation). Interestingly, in spite of the different sexual exhaustion paradigms used in both studies and the contrasting methods employed for establishing the duration of the inhibitory period, the same space of time was found to be necessary for full recovery. This coincidence, together with the fact that a mean number of 7 successive ejaculatory series and an exponential increase in the duration of the post-ejaculatory interval have been consistently observed in response to different sexual exhaustion paradigms [3,12,18], suggests that these are all key features of the sexual exhaustion phenomenon that emerge, independently of the paradigm used to induce this inhibitory state.
The characterisation of the progressive recovery of the original ejaculatory capacity here reported are novel data that can be useful for the establishment of the duration of the effects of experimental manipulations facilitating sexual behaviour expression in sexually exhausted rats, as well as to determine the degree of the inhibitory state reversal produced in rats subjected to our particular satiety paradigm.
In relation to the drug hypersensitivity phenomenon, the analysis of the different signs of the 5-HT-syndrome revealed that the FBP is the most consistent sign observed after the i.p. injection of low doses of 8-OH-DPAT in rats. This is also the sign best evidencing the differential sensitivity of male rats with diverse sexual conditions.
As mentioned earlier, FBP together with forepaw treading are the two symptoms that were previously associated to the i.p. injection of 8-OH-DPAT in non-sexually exhausted rats, although at higher dose levels . However, in our experiments, the forepaw treading sign appeared only occasionally in the animals, independently of their sexual condition. The differential result is very likely to rely on the low dose levels of the 5-HT1A agonist used in our experiments. Interestingly, at these low dose levels the hindlimb abduction sign of the 5-HT syndrome, not reported earlier to result from the i.p. injection of 8-OH-DPAT, was expressed in almost all animals of each sexual condition and the reason might be the same, i.e. that it only appears at very low doses, not tested in other works. The expected drug sensitivity difference between sexually experienced and sexually satiated animals was clearly evidenced by the FBP sign, but interestingly, the existence of a differential sensitivity between sexually naïve and sexually experienced rats could also be established.
The difference in drug sensitivity between sexually naïve and sexually exhausted animals reaches one order of magnitude. To our knowledge this is the first work reporting that sexual experience alters the sensitivity of rats to drug actions. These data call our attention to the effects of sexual experience on brain functioning in adult animals. In the last years an increasing number of works have addressed this issue. Thus, we can find works reporting that sexual experience influences steroid hormone secretion [8,29], increases medial preoptic area nitric oxide synthase , modifies mood and affect by reducing anxiety-  and depressive-like behaviours ; increases adult neurogenesis in response to predator odor stress  and promotes changes in gene expression in the dorsal and ventral striatum . According to the results of the present work, an increase in drug sensitivity can be added to the list of long term changes in brain functioning produced by sexual experience.
It is important to point out that the drug hypersensitivity observed in sexually experienced rats compared to sexually naïve animals must be the result of a different process than the one underlying the hypersensitivity observed in sexually exhausted rats. This is so, because the former is not related to recent sexual activity (these rats had their last sexual encounter at least 5 days prior to 8-OH-DPAT injection), while the latter appears to be clearly related to the copulation to satiation experience (vide infra). The differential sensitivity to 8-OH-DPAT of sexually experienced and sexually exhausted animals could also be detected in the facilitative actions of this compoundoncopulatory behaviour. Thus, while 8-OH-DPAT almost lacked of an effect in sexually experienced rats, it facilitated all sexual behaviour parameters of satiated rats by significantly reducing them, at particular doses, and significantly increasing the percentage of exhausted animals that resumed copulation after ejaculation. Although the ability of 8-OH-DPAT to reverse sexual satiation was already established , in the present work this effect was found at much lower doses than those originally used, confirming the hypersensitivity of sexually satiated rats to drug actions. Nevertheless, it should be kept in mind that the sexual inhibitory condition of sexually satiated rats might have played a role amplifying the facilitative effects of 8-OH-DPAT on copulation. Sexual facilitatory effects of experimental manipulations are best seen in animals with a poor sexual performance. In any case, when evaluating copulatory behaviour, it is not possible to distinguish between a drug hypersensitivity phenomenon and an effect due to a distinct basal sexual behaviour condition.
Examination of the duration of the hypersensitivity to 8-OHDPAT as measured by the expression of FBP shows that this phenomenon lasts 72 h following the satiation procedure, and virtually disappears 96 h after copulation to satiation. By contrast, the facilitative actions of 8-OH-DPAT on copulatory behaviour of sexually exhausted males are still present in all specific sexual behavior parameters 96 h after the satiation procedure. Again, the contribution of the sexual inhibitory condition to the facilitative actions of this low dose of 8-OH-DPAT in sexually satiated rats cannot be discarded. In contrast, the FBP sign of the 5-HT syndrome cannot be confounded with the sexual effects of the satiation procedure itself and appears, therefore, as a better feature to establish the characteristics of recovery from the drug hypersensitivity phenomenon.
Analysis of the spontaneous recovery process of the sexual behaviour inhibition resulting from sexual exhaustion and that of the hypersensitivity to 8-OH-DPAT, evaluated through FBP expression, reveals that both phenomena follow a same time course. Thus, after 96 h of sexual rest, the sexual inhibition is reversed in all animals and the proportion of satiated rats showing FBP falls to 25%, in contrast to almost 100% of them exhibiting this 5-HT syndrome sign during the first 72 h following satiation. This similar time course of recovery suggests that these two phenomena might represent different manifestations of a same brain plasticity process. The fact that the hypersensitivity of sexually exhausted rats disappears 4 days after the last sexual experience further supports the idea that the underlying mechanism must be different from the one producing hypersensitivity in sexually experienced rats, which was still present 5 days after their last sexual interaction. Pitchers et al. recently reported that sexual experience induces a behavioural sensitization phenomenon in male rats, in which sexually experienced rats display an increased locomotor response to amphetamine when compared to sexually naïve animals . The similarity of this finding with present data is evident, because behavioural sensitization implies an increased responsiveness/hypersensitivity to drugs of abuse. In line with present data of sexually experienced animals, the reported sensitisation phenomenon was recorded after repeated intermittent mating; a method analogous to the one used in the present work to render rats sexually experienced, and one week after the last mating session; a latency comparable to the 5 day period allowed before testing the 5-HT syndrome in our work.
Interestingly, Pitchers and colleagues also tested the effect of repeated ejaculation on 7 consecutive days on the amphetamine-induced locomotor sensitisation phenomenon and found no difference with the response obtained after intermittent mating . This data contrast with the more pronounced and shorter lasting hypersensitivity to 8-OH-DPAT here reported for sexually exhausted rats when compared to sexually experienced animals. This discrepancy might rely on the fact that in the sexual exhaustion paradigm repeated ejaculation (7 in average) occurs in a relatively short time period (around 2.5 h) and might therefore trigger a distinct process than the one produced by one ejaculation per day on 7 consecutive days. The main difference in the outcome of these two paradigms is observed in the duration of the hypersensitivity phenomenon, which lasted only 3 days in sexually exhausted rats and was maintained at least for 28 days in the rats subjected to repeated mating on 7 consecutive days in Pitchers work.
Together, the data here presented show that copulatory activity in general affects brain functioning of male rats, by altering the threshold for drug actions. Copulation to satiation, in particular, induces both a drug hypersensitivity phenomenon and a sexual inhibitory state that appear to follow a similar time course of recovery, showing a drastic diminution 96 h after sexual satiation. The long lasting character of both events can only be explained by the occurrence of brain plastic changes that, interestingly, disappear gradually in time evidencing a reversible nature. It could be thought that the long lasting sexual inhibition resulting from copulation to satiation constitutes a protective mechanism against over stimulation of the brain circuits involved in its processing. The mesolimbic system plays a role in the processing of natural rewards including sexual behaviour . Constant stimulation of this circuit by repeated administration of drugs of abuse produces behavioural sensitisation  that resembles the drug hypersensitivity exhibited by sexually exhausted rats after repeated ejaculation in a short period, which would continually stimulate the mesolimbic system .
The coincident temporal courses of drug hypersensitivity and sexual inhibition here reported could be interpreted as an evidence for their occurrence at the mesolimbic system. Both events could be different expressions of a common, transient, brain plasticity phenomenon aimed to protect the mesolimbic system from extreme stimulation in the course of copulation to exhaustion.
Future experiments should be conducted directed to study the possible mechanisms involved in such an interesting process: the induction of long lasting changes in brain functioning that appear to be reversible.