Mating Behavior In Male Rats Research Articles

Cocaine abuse and midbrain circuits: Functional anatomy of hypocretin/orexin transmission and therapeutic prospect

Cocaine abuse remains a pervasive public health problem, and treatments thus far have proven ineffective for long-term abstinence maintenance. Intensive research on the neurobiology underlying drug abuse has led to the consideration of many candidate transmitter systems to target for intervention. Among these, the hypocretin/orexin (hcrt/ox) neuropeptide system holds largely untapped yet clinically viable therapeutic potential. Hcrt/ox originates from the hypothalamus and projects widely across the mammalian central nervous system to produce neuroexcitatory actions via two excitatory G-protein coupled receptor subtypes. Functionally, hcrt/ox promotes arousal/wakefulness and facilitates energy homeostasis. In the early 2000s, hcrt/ox transmission was shown to underlie mating behavior in male rats suggesting a novel role in reward-seeking. Soon thereafter, hcrt/ox neurons were shown to respond to drug-associated stimuli, and hcrt/ox transmission was found to facilitate motivated responding for intravenous cocaine. Notably, blocking hcrt/ox transmission using systemic or site-directed pharmacological antagonists markedly reduced motivated drug-taking as well as drug-seeking in tests of relapse. This review will unfold the current state of knowledge implicating hcrt/ox receptor transmission in the context of cocaine abuse and provide detailed background on animal models and underlying midbrain circuits. Specifically, attention will be paid to the mesoaccumbens, tegmental, habenular, pallidal and preoptic circuits. The review will conclude with discussion of recent preclinical studies assessing utility of suvorexant – the first and only FDA-approved hcrt/ox receptor antagonist – against cocaine-associated behaviors.

Potential effects of yohimbine and sildenafil on erectile dysfunction in rats

In this study the effects of yohimbine and sildenafil on cold stress-induced erectile dysfunction in rats were investigated. Yohimbine hydrochloride (0.2mg/kg, i.p.) and sildenafil citrate (20mg/kg, i.p) were administered to rats 1h before the stress session daily for 14 consecutive days and their effect was assessed. Results of this section revealed that, immersion of rats in cold water significantly decreased sexual arousal and motivation as indicated by increased latencies and intervals. Furthermore decreased copulatory performance and potency as indicated by decreased ejaculation frequency was observed. Decreased copulatory activity was confirmed by decreased testosterone, luteinizing hormone (LH) and follicle-stimulating-hormone (FSH) levels as well as decreased cholesterol content in rat testes. Treatment with yohimbine or sildenafil significantly increased the sexual arousal and potency and corrected the effects induced by stress on the mating behavior of male rats. On the contrary they did not significantly alter testosterone, FSH and LH levels which is reflected by failure of both drugs to alter cholesterol content in rat testes. Regarding the effect of yohimbine and sildenafil on isolated rat corpus cavernosum, their cumulative dose response curves (3×10−7, 3×10−6 and 3×10−5M) were determined in corpus cavernosum strips isolated from normal rats and pre-contracted with phenylephrine (3×10−6M) were also assessed. Results of this part showed that both yohimbine and sildenafil have a relaxant effect on rat corpus cavernosum strips in a dose dependant manner, which is confirmed by the increase in nitric oxide content in rats' penis shown by sildenafil.

Fos expression at the cerebellum following non-contact arousal and mating behavior in male rats

The cerebellum is considered a center underlying fine movements, cognition, memory and sexual responses. The latter feature led us to correlate sexual arousal and copulation in male rats with neural activity at the cerebellar cortex. Two behavioral paradigms were used in this investigation: the stimulation of males by distant receptive females (non-contact sexual stimulation), and the execution of up to three consecutive ejaculations. The vermis area of the cerebellum was removed following behavioral experiments, cut into sagittal sections, and analyzed with Fos immunohistochemistry to determine neuronal activation. At the mid-vermis region (sections from the midline to 0.1 mm laterally), non-contact stimulation significantly increased the activity of granule neurons. The number of activated cells increased in every lobule, but lobules 1 and 6 to 9 showed the greatest increment. In sexual behavior tests, males reaching one ejaculation had a high number of activated neurons similar to those counted after non-contact stimulation. However, two or three consecutive ejaculations showed a smaller number of Fos-ir cells. In contrast to the mid-vermis region, sections farthest from the midline (0.1 to 0.9 mm laterally) revealed that only lobule 7 expressed activated neurons. These data suggest that a well-delineated group of granule neurons have a sexual biphasic response at the cerebellar vermis, and that Fos in them is under an active degradation mechanism. Thus, they participate as a neural substrate for male rat sexual responses with an activation-deactivation process corresponding with the sensory stimulation and motor performance occurring during copulation.

Implants of Estradiol Conjugated to Bovine Serum Albumin in the Male Rat Medial Preoptic Area Promote Copulatory Behavior

The expression of mating behavior in male rats is dependent on estrogen-responsive neurons in the medial preoptic area (MPO). Previous reports showed that mating is attenuated if the aromatization of testosterone to estradiol (E₂) is blocked in the MPO and that mating is maintained by MPO E₂ implants. However, the mechanisms by which E₂ exerts its action are not fully understood. It had been thought that E₂ acted exclusively by binding to nuclear estrogen receptors to exert it effects; however, recent reports suggest that E₂ also binds to membrane-associated receptors activating downstream intracellular cascade responses. In this study, we aimed to determine if an action of E₂ at the cell surface is sufficient to support mating behavior. Therefore, either vehicle, E₂, or E₂ conjugated to bovine serum albumin (BSA-E₂: a complex of E₂ and a large protein that will not cross the plasma membrane, thereby restricting the action of E₂ to cell surface signaling) was chronically administered bilaterally to the MPO of castrated, dihydrotestosterone-treated male rats. Mating behavior was supported by MPO BSA-E₂ implants, suggesting that E₂ operates in the MPO via a cell surface mechanism to facilitate male rat mating behavior.

Effect of corticoliberin fragment CRF4–6 on sexual behavior in male mice

Centrally administered doses of the tripeptide corticoliberin fragment CRF4–6 (Pro-Pro-Ile) suppressed mating behavior in male rats. Doses of 1 and 2 µg of the tripeptide produced dose-dependent increases in the latent periods of mounting, intromission, and ejaculation. Changes in measures of sexual behavior demonstrated that the corticoliberin fragment CRF4–6 suppressed both sexual motivation and sexual performance.

Effects of corticoliberin fragment CRF4–6 on sexual behavior in male mice

Centrally administered doses of the tripeptide corticoliberin fragment CRF(4-6) (Pro-Pro-Ile) suppressed mating behavior in male rats. Doses of 1 and 2 microg of the tripeptide produced dose-dependent increases in the latent periods of mounting, intromission, and ejaculation. Changes in measures of sexual behavior demonstrated that the corticoliberin fragment CRF(4-6) suppressed both sexual motivation and sexual performance.

Social interactions alter proinflammatory cytokine gene expression and behavior following endotoxin administration

Sick animals display a constellation of behaviors, including anhedonia, anorexia, and reduced social interactions. Acute infection eliminates female mating behavior, but fails to attenuate mating behavior in male rats. These results have been attributed to the different reproductive strategies and parental investment of the two sexes. Males putatively suppress the symptoms of infection in order to “deceive” females into mating. We sought to investigate the mechanisms responsible for this suppression. Adult male CD-1 mice were treated with lipopolysaccharide (LPS; a component of bacterial cell walls; 400 μg/kg), then paired 2 h later with a receptive female or juvenile male or remained isolated. Blood samples and brains of the males were collected 3 h post-LPS; hypothalamic interleukin-1 ( IL- 1) and tumor necrosis factor-α ( TNFα) gene expression was measured using RT-PCR. Contrary to our prediction, exposure to a female increased hypothalamic IL- 1 and TNFα gene expression. LPS treatment significantly decreased testosterone and increased corticosterone secretions. Social interactions altered absolute corticosterone concentrations in saline-injected animals only. In order to determine whether increased production of hypothalamic cytokines reflected increased severity of sickness responses, body temperature was monitored in a second group of mice implanted with telemetric transmitters. Body mass, food intake, and consumption of sweetened condensed milk (a highly favored food) were also monitored in these mice for 72 h post-injection. LPS injections reduced milk intake, an effect that was modulated by social interactions; however, fever was unaltered relative to isolated animals. These results suggest that social interactions can adjust behavioral responses to infection although the ultimate cause of this adjustment remains unspecified.

Regional brainstem expression of Fos associated with sexual behavior in male rats

This study utilized Fos expression to map the distribution of activated cells in brainstem areas following masculine sexual behavior. Males displaying both appetitive and consumatory sexual behaviors (Cop) were compared to animals prevented from copulation (NC) and to socially isolated (SI) animals. Following copulation, Fos was preferentially augmented in the caudal ventral medulla (CVM), a region mediating descending inhibition of penile reflexes, and which may be regulated by a forebrain circuit that includes the medial preoptic area (MPOA). Copulation-induced Fos was observed in the medial divisions of both the dorsal cochlear nucleus (DC) and trapezoid bodies (Tz), areas which are part of a circuit processing auditory information. In addition, the medullary linear nucleus (Li) displayed comparable amounts of Fos in Cop and NC as compared to the SI animals. Other regions of the pontomedullary reticular system, which may mediate sleep and arousal, did not exhibit Fos expression associated with consumatory sexual behavior. We suggest that Fos is associated with the inhibition of sexual behavior following ejaculation in the CVM, and that auditory information arising from the DC and Tz is combined with copulation-related sensory information in the subparafasicular nucleus and projected to the hypothalamus. In addition, equal amounts of Fos expression observed in the Li in both the Cop and NC animals suggests that this region is involved in sexual arousal. Overall, the data suggest that processing by brainstem nuclei directly contributes to the regulation of mating behavior in male rats.

The inhibition of sexual behavior in male rats by propranolol is stereoselective

We have previously reported that administration of racemic mixtures of propranolol was associated with a marked inhibition of mating behavior in male rats. To compare the effects of (+)-propranolol, (−)-propranolol, and (±)-propranolol in sexually experienced males, rats ejaculating in four or more mating tests were divided into three groups ( N = 16 per group) such that no differences in parameters of copulatory behavior were evident in preexperimental tests. No major effect of propranolol on parameters of behavior associated with initiation of sexual behavior was evident. In contrast, other measures of behavior were profoundly modified. The ejaculatory threshold, indicated by the number of intromissions preceding ejaculation, was increased after (+)- and (±)-propranolol, but not (−)-propranolol. The number of mounts without intromission preceding ejaculation was increased only after (±)-propranolol. A decrease in copulatory efficacy was evident after (−)- or (±)-propranolol, but not after (+)-propranolol. Increases in ejaculation latency, intercopulatory interval, and postejaculatory interval were observed after (−)- and (±)-proranolol, but not after (+)-propranolol. In summary, the present data indicate that the (−) isomer of propranolol is the active form necessary for the inhibitory effects of propranolol on male sexual function. We suggest that this inhibition is due to specific receptor-mediated mechanisms, involving β-adrenoceptors and 5-HT 1A receptor interactions.

Acute alcohol exposure markedly influences male fertility and fetal outcome in the male rat

Although it is recognized that drugs ingested by pregnant females produce marked cognitive and physiological deficits in their offspring, the possibility that paternal exposure to drugs prior to mating may have adverse effects on fertility and fetal outcome has not received much attention. The purpose of the present studies was to examine whether a single, acute exposure to alcohol influences the subsequent ability of adult male rats to mate and produce healthy and viable litters. Our results showed that a relatively large dose of alcohol 24 hours prior to breeding had little effect on the mating behavior of male rats, but there were markedly fewer pregnancies in females mated with alcohol-exposed male rats than in controls. Of equal importance, we found that, even when conception occurred and live births were produced, there were striking differences in fetal outcome. Alcohol-treated males sired many fewer pups than control males and there was a markedly enhanced mortality rate in their offspring. Collectively, these data suggest that acute paternal alcohol administration 24 hours prior to breeding does not affect mating behavior, but results in a greatly diminished fertility rate and fewer and less viable offspring. These studies suggest that paternal alcohol use may be as important as maternal alcohol abuse as a negative variable in pregnancy and fetal outcome.

Lesions of the nucleus paragigantocellularis: effects on mating behavior in male rats

We evaluated the effects of bilateral radio-frequency lesions of the paragigantocellular (PGi) reticular nucleus in the ventral medulla on male rat copulatory behavior. In Experiment 1, sexually naive male rats with such lesions were more likely than sham-operated controls to copulate to ejaculation during their first exposure to an estrous female. Additionally, among the rats that copulated to ejaculation, those with lesions demonstrated a reduction in mount frequency (MF), intromission frequency (IF), and ejaculation latency (EL), and an increase in copulatory efficiency (CE). In Expt. 2, sexually experienced male rats were allowed to sexual exhaustion. Males with PGi lesions showed an increased latency to sexual exhaustion and an increased number of ejaculations prior to exhaustion. Additionally, rats with PGi lesions displayed reductions in IF, EL, and post-ejaculatory interval (PEI) as they approached sexual exhaustion. Our results provide further evidence that the PGi is a supraspinal locus of descending inhibitory influence on spinal nuclei mediating ejaculatory reflexes in the male rat.

Effects of intrathecal and systemic administration of buspirone on genital reflexes and mating behavior in male rats

Buspirone was studied to determine whether the detailed profile of male sexual behavior observed following treatment with the prototypical 5-HT 1A ligand, 8-OH-DPAT, can be generalized to other 5-HT 1A agonist drugs. Systematic and intrathecal (IT) routes of administration were compared. Like DPAT, significant reduction in intromission frequency followed IT infusion of buspirone (80–160 μg) as did intraperitoneal (IP) injection (1–4 mg/kg). IT doses of 80–160 μg and all IP doses significantly reduced ejaculation latency. Intercopulatory interval significantly decreased following IP buspirone but not after IT infusion although there were trends in that direction. All IP doses and 80 μg IT significantly shortened the postejaculatory interval. Buspirone inhibited erection and/or ejaculation in the ex copula reflex test. A decrease in percentage of rats displaying erections and ejaculation occurred following either route of administration. Ejaculation was significantly inhibited at the low IT dose of 40 μg. We conclude that buspirone affects sexual behavior very much like DPAT or other 5-HT 1A drugs, to the extent known. Sexual effects of buspirone were generally similar regardless of route of administration, but the effective doses were clearly lower with IT treatment.

Effects of intrathecal administration of 8-OH-DPAT on genital reflexes and mating behavior in male rats

Systemic administration of the 5HT 1A receptor agonist, 8-OH-DPAT, consistently decreases the threshold of ejaculatory behavior and enhances some aspects of arousal. Previous findings by others demonstrated the in copula ejaculatory behavior effect using intrathecal (IT) injection at the level of the lumbosacral spinal cord, but the dose used was in the range that produced results systemically. This study aimed at a) a more comprehensive study of the sexual effects of 8-OH-DPAT and b) use of IT doses of 8-OH-DPAT below those effective when administered systemically. The ex copula genital reflex test showed severe inhibition. At doses of 5 μg or more, significant inhibition of the percentage of rats displaying ejaculation occurred, and the two highest doses also significantly reduced the percentage of rats displaying erection. In the in copula mating test, 20 and 80 μg IT 8-OH-DPAT, significantly reduced ejaculation latency, intromission frequency and intercopulatory interval. Copulatory plugs, collected at the highest dose only, showed a trend towards weight reduction. We conclude that the facilitation of ejaculatory behavior and some measure of arousal by 8-OH-DPAT can be mediated directly via the lumbosacral spinal cord. An hypothesis for explaining the inhibitory effect on ejaculation ex copula is presented, but the inhibitory effect on erectile reflexes is without interpretation.

Dissociating antifertility effects of GnRH-antagonist from its adverse effects on mating behavior in male rats.

Antagonist analogues of gonadotropin-releasing hormone (GnRH-A) alone inhibit spermatogenesis in experimental animals, but concomitant decline in serum testosterone leads to abolition of mating behavior. We assessed if the antifertility effects of GnRH-A could be dissociated from its effects on mating behavior by combining it with a small dose of androgen. Seven groups of six adult male Wistar rats were treated for 70 days as follows: I) controls, II) GnRH-A alone (250 micrograms/day), III) GnRH-A + 0.05 mg testosterone enanthate (TE), IV) GnRH-A + 0.15 mg TE, V) GnRH-A + 0.50 mg TE, VI) GnRH-A + 1.50 mg TE, and VII) GnRH-A alone (recovery group). Testes, prostate, and seminal vesicle weights were markedly reduced by GnRH-A treatment alone. Doses of TE required to maintain prostate and seminal vesicle weights were between 0.15 and 0.50 mg. Testis weights were not restored to normal even by the highest dose of TE. Intratesticular sperm counts were markedly decreased by GnRH-A treatment and restored only at the highest dose of TE (1.50 mg). Five out of six animals in group II, six out of six animals in group III, and one out of six in group IV were azoospermic. When mated with normal females, all animals in groups I and VI were fertile, all animals in groups II, III, and IV were infertile, whereas only four out of six animals in group V were fertile. All measures of mating behavior were impaired by GnRH-A treatment and restored by the smallest dose of TE (0.05 mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Medial preoptic connections with the midbrain tegmentum are essential for male sexual behavior

The medial preoptic area appears to play a major role in the control of sexual behavior. Efferents from the medial preoptic area course through the medial forebrain bundle to pass through and/or terminate in the dorsolateral and ventral tegmentum of the midbrain. Bilateral lesions of the dorsolateral tegmentum eliminate mating behavior in male rats, reproducing the effect of bilateral medial preoptic lesions. Sexual behavior is also eliminated when a preoptic lesion on one side of the brain is combined with a lesion of the dorsolateral tegmentum on the other side of the brain. In other words, asymmetric brain damage which bilaterally destroys the preoptic connections with the dorsolateral tegmentum eliminates male sexual behavior, and we conclude that the connections between these two regions are essential for copulation.

Differential effects of bromocriptine treatment on LH release and copulatory behavior in hyperprolactinemic male rats

Hyperprolactinemia (hyperPRL) induced by grafting four pituitary glands under the kidney capsule suppresses copulatory behavior in male rats and sexually naive male mice. In mice sexual experience attenuates the suppressive effects of hyperPRL on mating behavior, thus a comparison of the behavioral consequences of inducing hyperPRL in sexually naive and experienced male rats was undertaken. Hyperprolactinemia had a significant suppressive effect on mating behavior in both groups of animals. Experienced animals showed deficits in all parameters studied except mount frequency and postejaculatory interval, while naive animals differed from respective controls only in mount latency, intromission latency, and intromission frequency. To determine if the inhibition of chronically elevated prolactin (PRL) levels would reverse the suppression of gonadotropin secretion and copulatory behavior in hyperprolactinemic animals, the effects of bromocriptine (CB-154) administration on plasma hormone levels and mating behavior were examined in pituitary-grafted and control rats. Bromocriptine treatment (1 mg/day for 14 days) led to increases in sexual activity in both the sham-operated and grafted animals. In the grafted animals, plasma PRL was reduced and plasma LH significantly increased in the CB-154-treated animals when compared to oil-treated controls. In sham-operated animals, CB-154 produced no significant changes in plasma LH or FSH despite the suppressed PRL levels. These results indicate that (1) hyperPRL induced by pituitary grafts can cause deficits in mating behavior in male rats despite previous sexual experience, and (2) while CB-154 may be acting through other mechanisms to stimulate copulatory behavior, the reduction of chronically elevated PRL levels due to CB-154 treatment is responsible for reversal of the suppressive effects of hyperPRL on LH secretion.

Electrical stimulation of the basal forebrain and mating behavior in male rats.

Male rats were given brain stimulation before, during, and after copulation. Stimulation before mating improved performance while stimulation after mating improved the initiation of the next mating sequence. Stimulation during mating interfered with sexual behavior. It was concluded that stimulation during a mating sequence disrupts copulation, without being aversive, while stimulation outside of the sequence can improve mating in rats.

The effects of parachlorophenylalanine on the mating behavior of male rats

Four studies are presented on the effects of parachlorophenylalanine (PCPA) on the mounting behavior of male rats. The first study found that PCPA alone and in combination with either pargyline or testosterone increased the tendency for male rats to mount other males. The other three studies strongly indicated that PCPA alone can increase the frequency of heterosexual mounting and copulation in male rats.

Testosterone, androstenedione and dihydrotestosterone: Effects on mating behavior of male rats

The relative effectiveness of testosterone, androstenedione, and dihydrotestosterone in maintaining mating behavior following castration of male rats was studied. In Experiment 1 testosterone, but not dihydrotestosterone, was found to maintain mating. In Experiment 2 testosterone and androstenedione were found to be equally effective in maintaining mating. Dihydrotestosterone failed to maintain mating and was no more effective than no treatment at all. Testosterone, androstenedione, and dihydrotestosterone significantly enhanced seminal vesicle and penis weight. In Experiment 3 castrated male rats were administered radiolabeled testosterone, androstenedione, or dihydrotestosterone. Radioactivity was found in hypothalamic and seminal vesicle samples indicating that these steroids can be accumulated by brain as well as peripheral androgen-sensitive tissues. It was concluded that the peripherally active steroid dihydrotestosterone probably plays no role in the maintenance of sexual behavior.

Effects of the Anti-androgen Cyproterone Acetate on Mating Behavior and Seminal Vesicle Tissue in Male Rats

The synthetic steroid cyproterone acetate (6-chloro-17-hydroxy-lα,2α-methylenepregna- 4,6-diene-3,20-dione acetate) exerts strong antiandrogenic properties with respect to the seminal vesicles, but not with respect to androgen dependent mating behavior in male rats. Gonadectomized, sexually experienced male rats were treated with 1) testosterone propionate (TP); 2) TP plus cyproterone acetate, or 3) oil for 3 weeks, and given 3 mating tests at weeklyintervals. The seminal vesicles of all males were removed after 2 weeks of treatment. The intensity of mating behavior declined progressively in the oil treated castrates but not the androgen or androgen plus anti-androgen treated males. The seminal vesicles of the oil treated and androgen plus anti-androgen treated rats regressed in comparison with the seminal vesicles of males treated only with testosterone. (Endocrinology 84:155, 1969)