Experience In Male Rats Research Articles

Sexual experience induces a preponderance of mushroom spines in the medial prefrontal cortex and nucleus accumbens of male rats

Sexual experience improves copulatory performance in male rats. Copulatory performance has been associated with dendritic spines density in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), structures involved in the processing of sexual stimuli and the manifestation of sexual behavior. Dendritic spines modulate excitatory synaptic contacts, and their morphology is associated with the ability to learn from experience. This study was designed to determine the effect of sexual experience on the density of different types or shapes of dendritic spines in the mPFC and NAcc of male rats. A total of 16 male rats were used, half of them were sexually experienced while the other half were sexually inexperienced. After three sessions of sexual interaction to ejaculation, the sexually-experienced males presented shorter mount, intromission, and ejaculation latencies. Those rats presented a higher total dendritic density in the mPFC, and a higher numerical density of thin, mushroom, stubby, and wide spines. Sexual experience also increased the numerical density of mushroom spines in the NAcc. In both the mPFC and NAcc of the sexually experienced rats, there was a lower proportional density of thin spines and a higher proportional density of mushroom spines. Results show that the improvement in copulatory efficiency resulting from prior sexual experience in male rats is associated with changes in the proportional density of thin and mushroom dendritic spines in the mPFC and NAcc. This could represent the consolidation of afferent synaptic information in these brain regions, derived from the stimulus-sexual reward association.

Sexual activity modulates neuroinflammatory responses in male rats

Immune activity influences reproduction, however, the extent to which mating experience may inversely alter immune pathways is poorly understood. A few studies in humans suggest that mating triggers a circulating immune and hypothalamic-pituitary-adrenal axis response. In male rats, mating experience enhances neuroplasticity and improves cognitive function and affective-like behavior, independent of the physical activity component. Yet, the extent to which mating experience may influence immune responses in the brain remain unexplored. Here, we hypothesized that recent mating experience in male rats increases neuroinflammatory signaling (via lipopolysaccharide [LPS] stimulation, i.p.) and associated sickness behaviors (i.e., food intake, weight loss) relative to sexually-naïve controls. Virgin male rats were exposed to a sexually non-receptive (control) or sexually-receptive female for 30 min for six consecutive days. Immediately following the last mating experience, rats were administered a saline or LPS injection and euthanized four hours later. Mating increased Tnfα responses to LPS in the brain, which positively correlated with LPS-induced weight loss. Mating also increased peripheral corticosterone among saline-treated rats, but this corticosterone response was attenuated in the most proficient copulators (e.g., shortest latencies). Thus, recent mating experience may be a unique modulator of select stimulated inflammatory signals that are relevant to adaptive neuroimmune responses and behavior.

Remodeling of the number and structure of dendritic spines in the medial amygdala: From prepubertal sexual dimorphism to puberty and effect of sexual experience in male rats.

The posterodorsal medial amygdala (MePD) is a sexually dimorphic area and plays a central role in the social behavior network of rats. Dendritic spines modulate synaptic processing and plasticity. Here, we compared the number and structure of dendritic spines in the MePD of prepubertal males and females and postpubertal males with and without sexual experience. Spines were classified and measured after three-dimensional image reconstruction using DiI fluorescent labeling and confocal microscopy. Significantly differences are as follows: (a) Prepubertal males have more proximal spines, stubby/wide spines with long length and large head diameter and thin and mushroom spines with wide neck and head diameters than prepubertal females, whereas (b) prepubertal females have more mushroom spines with long neck length than age-matched males. (c) In males, the number of thin spines reduces after puberty and, compared to sexually experienced counterparts, (d) naive males have short stubby/wide spines as well as mushroom spines with reduced neck diameter. In addition, (e) sexually experienced males have an increase in the number of mushroom spines, the length of stubby/wide spines, the head diameter of thin and stubby/wide spines and the neck diameter of thin and mushroom spines. These data indicate that a sexual dimorphism in the MePD dendritic spines is evident before adulthood and a spine-specific remodeling of number and shape can be brought about by both puberty and sexual experience. These fine-tuned ontogenetic, hormonally and experience-dependent changes in the MePD are relevant for plastic synaptic processing and the reproductive behavior of adult rats.

An animal model of compulsive sexual behavior induced by morphine

It is well recognized that psychoactive drugs impact sexual function, performance, and arousal. Chronic use of drugs in general leads to compulsive sexual behavior (CSB) in substance abusers and causes high rates of sexually transmitted diseases, including HIV, although different drugs are associated with variable degrees of sexual risk behavior. Existing research has consistently demonstrated high rates of cooccurrence between CSBs and substance use disorders, with comorbidity rates ranging from 40% to 60%. Morphine is one of the most abusive illicit drugs in the world. Similar to effects of psychostimulants, morphine abuse is commonly associated with loss of sexual inhibition and subsequent compulsive sexual behavior, including heightened sexual desire, numerous sexual partners, and lack of protection. Previous research has focused almost exclusively on the effects of drugs of abuse on sexual motivation and performance. Although such effects are indeed reported in humans as well, the human studies have indicated that one of the largest and most problematic effects of drugs on sex behavior is the increase in risk-taking behaviors related to sexual activity. Yet, few animal studies have attempted to investigate this phenomenon, in part probably due to a lack of an established paradigm to study CSB in rodents. This study aims to develop an animal model of CSB in morphine pretreated (total 330 mg/kg; i.p. 5 d) male rats by a sexual aversion conditioning paradigm, in which increasing intensity foot-shock is paired with sexual contact to assess the compultive motivation. Following 7 d morphine withdrawal, a sexually receptive female rat is placed in the stimuluscage, the male rat can contact with the female rat by going through an electric rods. The current value of the electric rods was increased after each trial according to the following: 0.2, 0.3, 0.4, 0.6, 0.8, 1, 1.4, 1.8 mA. To avoid foot damage, the cut-off of 2 mA was introduced. The results show that morphine pretreated group expresses a persistent preference toward the sexually receptive female despite the foot-shock, as indicated by a significant increase in the current value compared to saline pretreated group. Moreover, the compulsive motivation to approach a sexually receptive female rat is no difference betweent saline pretreated rats and morphine pretreated but sexually naive rats, thereby suggesting that sexual experience in male rats is a critical influence factor for CSB. We think the model has a higher face and predictive validity compared to previous models and the model will help further examine the neurobiological underpinnings of CSB as well as providing a tool to study the influence factors on CSB in detail.

Increased expression of carbon monoxide-producing enzymes in the MPOA after sexual experience in male rats

The hypothalamus contains numerous nuclei involved in the regulation of reproductive, stress, circadian, and homeostatic behaviors, with many of these nuclei concentrated within the preoptic and anterior regions. The gaseous neurotransmitter, nitric oxide (NO), has already been shown to have an important regulatory role within the medial preoptic area (MPOA) of the anterior hypothalamus, where it facilitates sexual behaviors. However, little is known about the role of other gaseous neurotransmitters in this area. Here, we report that the carbon monoxide (CO) producing enzymes HO-1 and HO-2 are present in the MPOA and are differentially influenced by sexual experience in a manner similar to that previously reported for NO enzymes. Immunohistochemical staining of brains collected after 0, 1, or 7 sexual experiences reveals that HO-1 is expressed transiently after the first sexual experience, while HO-2 increases only with repeated experience. This increase appears to be specific to the MPOA, as nearby brain areas do not exhibit this degree or pattern of expression. We observed a transient increase in HO-2 colocalization with neuronal nitric oxide synthase (nNOS) after a single sexual experience, but these cells appear to be otherwise disparate, despite the fact that both express within the central nucleus of the MPOA. Together, these findings suggest that endogenous CO may be behaviorally relevant within the MPOA and that CO and NO may be differentially regulated there.

Maladaptive Sexual Behavior Following Concurrent Methamphetamine and Sexual Experience in Male Rats is Associated with Altered Neural Activity in Frontal Cortex.

The use of psychostimulants is often associated with hypersexuality, and psychostimulant users have identified the effects of drug on sexual behavior as a reason for further use. It was previously demonstrated in male rats that methamphetamine (Meth), when administered concurrently with sexual behavior results in impairment of inhibition of sexual behavior in a conditioned sex aversion (CSA) paradigm where mating is paired with illness. This is indicative of maladaptive sex behavior following Meth and sex experience. The present study examined the neural pathways activated during inhibition of sexual behavior in male rats and the effects of concurrent Meth and sexual behavior on neural activity, using ERK phosphorylation (pERK). First, exposure to conditioned aversive stimuli in males trained to inhibit sexual behavior in the CSA paradigm increased pERK expression in medial prefrontal (mPFC), orbitofrontal cortex (OFC) and areas in striatum and amygdala. Second, effects of concurrent Meth and sex experience were tested in males that were exposed to four daily sessions of concurrent Meth (1 mg/kg) or saline and mating and subsequently exposed to CSA one week after last treatment. Meth and mating-treated males showed significant impairment of inhibition of mating, higher pERK expression under baseline conditions, and disrupted pERK induction by exposure to the conditioned aversive stimuli in mPFC and OFC. These alterations of pERK occurred in CaMKII-expressing neurons, suggesting changes in efferent projections of these areas. Altogether, these data show that concurrent Meth and mating experience causes maladapative sexual behavior that is associated with alterations in neural activation in mPFC and OFC.

MGluR5 activation in the nucleus accumbens is not essential for sexual behavior or cross-sensitization of amphetamine responses by sexual experience

Natural rewards and psychostimulants cause similar neural plasticity in the nucleus accumbens (NAc). In addition, sexual experience in male rats causes increased locomotor activity and conditioned place preference (CPP) induced by d-Amphetamine (amph). The latter is dependent on a period of abstinence from sexual reward. In this study, the role of mGluR5 activation in the NAc for expression of mating and the cross-sensitizing effects of sexual experience was tested. First, intra-NAc infusions of mGluR5 antagonists MPEP (1 or 10 μg/μL) or MTEP (1 μg/μL) 15 min prior to mating during 4 daily sessions had no effect on male rat sexual behavior. Subsequently, these sexually experienced males were tested for amph-induced locomotor activity and CPP after one week of abstinence from sexual reward. In addition, sexually naïve males that received MPEP, MTEP or vehicle infusions prior to 4 daily handling sessions were included. Cross-sensitization of locomotion or CPP was not prevented by NAc mGluR5 antagonism during acquisition of sexual experience. Instead, sexually naive animals that received NAc mGluR5 antagonists without mating demonstrated sensitized amph-induced locomotor responses and enhanced CPP on par with sexually experienced males. Finally, we showed that sexual experience caused prolonged down-regulation of mGluR5 protein in the NAc, dependent on abstinence from sexual behavior. Together, these findings suggest that mGluR5 activation in the NAc is not essential for the expression of mating, but that experience-induced reduction in mGluR5 protein may contribute to the cross-sensitization of amph responses by sexual experience and abstinence.

Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats

Sexual experience in male rats followed by a period of abstinence causes sensitization to d-Amphetamine (Amph) reward, evidenced by an increased conditioned place preference (CPP) for low doses of Amph. Moreover, sexual experience induces neural plasticity within the nucleus accumbens (NAc), including induction of deltaFosB, which plays a key role in Amph reward cross-sensitization. The NMDA receptor subunit NR1 is also upregulated by mating, but the functional relevance of NMDA receptors in sex experience-induced effects is unknown. Here, we examined the influence of intra-NAc MK 801 infusions on sex experience-induced NAc deltaFosB and cFos expression, as well as mating- and Amph-induced CPP in adult male rats. In experiment 1, males received MK 801 or saline into the NAc during each of 4 consecutive days of mating or handling and were tested for Amph CPP and experience-induced deltaFosB 10 days later. Intra-NAc MK 801 during sexual behavior prevented experience-induced increases in Amph CPP and NAc deltaFosB expression without affecting sexual behavior. In experiment 2, the effects of intra-NAc MK 801 on mating-induced CPP were examined by intra-NAc infusion of MK 801 or saline prior to mating on conditioning days. Intra-NAc MK 801 did not affect mating-induced CPP. Next, effects of intra-NAc MK 801 on mating-induced cFos immunoreactivity were examined. MK 801 prevented mating-induced cFos expression in NAc shell and core. Together, these results provide evidence that NAc NMDA receptor activation during sexual behavior plays a key role in mating-induced cFos and deltaFosB expression and subsequent experience-induced cross-sensitization to Amph reward.

Pretreatment with curcumin attenuates anxiety while strengthens memory performance after one short stress experience in male rats.

It is observed that memories are more strengthened in a stressful condition. Studies have also demonstrated an association between stressful events and the onset of depression and anxiety. Considering the nootropic, anxiolytic and antidepressant-like properties of curcumin in various experimental approaches, we appraised the beneficial effects of this herb on acute immobilization stress-induced behavioral and neurochemical alterations. Rats in test group were administrated with curcumin (200mg/kg/day), dissolved in neutral oil, for 1 week. Both control and curcumin-treated rats were divided into unstressed and stressed groups. Rats in the stressed group were subjected to immobilization stress for 2h. After stress, the animals were subjected to behavioral tests. Immobilization stress induced an anxiogenic behavior in rats subjected to elevated plus maze test (EPM). Locomotor activity was also significantly increased following the acute immobilization stress. Pre-administration of curcumin prevented the stress-induced behavioral deficits. Highest memory performance was observed in stressed rats that were pre-treated with curcumin in Morris water maze (MWM). Brain malondialdehyde (MDA) levels, catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and acetylcholinesterase (AChE) activities were also estimated. Present study suggests a role of antioxidant enzymes in the attenuation of acute stress induced anxiety by curcumin. The findings therefore suggest that supplementation of curcumin may be beneficial in the treatment of acute stress induced anxiety and enhancement of memory function.

Natural and Drug Rewards Act on Common Neural Plasticity Mechanisms with ΔFosB as a Key Mediator

Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. Recent evidence suggests that natural rewards may cause similar changes in the NAc, suggesting that drugs may activate mechanisms of plasticity shared with natural rewards, and allowing for unique interplay between natural and drug rewards. In this study, we demonstrate that sexual experience in male rats when followed by short or prolonged periods of loss of sex reward causes enhanced amphetamine reward, indicated by sensitized conditioned place preference for low-dose (0.5 mg/kg) amphetamine. Moreover, the onset, but not the longer-term expression, of enhanced amphetamine reward was correlated with a transient increase in dendritic spines in the NAc. Next, a critical role for the transcription factor ΔFosB in sex experience-induced enhanced amphetamine reward and associated increases in dendritic spines on NAc neurons was established using viral vector gene transfer of the dominant-negative binding partner ΔJunD. Moreover, it was demonstrated that sexual experience-induced enhanced drug reward, ΔFosB, and spinogenesis are dependent on mating-induced dopamine D1 receptor activation in the NAc. Pharmacological blockade of D1 receptor, but not D2 receptor, in the NAc during sexual behavior attenuated ΔFosB induction and prevented increased spinogenesis and sensitized amphetamine reward. Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets.

Natural Reward Experience Alters AMPA and NMDA Receptor Distribution and Function in the Nucleus Accumbens

Natural reward and drugs of abuse converge upon the mesolimbic system which mediates motivation and reward behaviors. Drugs induce neural adaptations in this system, including transcriptional, morphological, and synaptic changes, which contribute to the development and expression of drug-related memories and addiction. Previously, it has been reported that sexual experience in male rats, a natural reward behavior, induces similar neuroplasticity in the mesolimbic system and affects natural reward and drug-related behavior. The current study determined whether sexual experience causes long-lasting changes in mating, or ionotropic glutamate receptor trafficking or function in the nucleus accumbens (NAc), following 3 different reward abstinence periods: 1 day, 1 week, or 1 month after final mating session. Male Sprague Dawley rats mated during 5 consecutive days (sexual experience) or remained sexually naïve to serve as controls. Sexually experienced males displayed facilitation of initiation and performance of mating at each time point. Next, intracellular and membrane surface expression of N-methyl-D-aspartate (NMDA: NR1 subunit) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA: GluA1, GluA2 subunits) receptors in the NAc was determined using a bis(sulfosuccinimidyl)suberate (BS3) protein cross-linking assay followed by Western Blot analysis. NR1 expression was increased at 1 day abstinence both at surface and intracellular, but decreased at surface at 1 week of abstinence. GluA2 was increased intracellularly at 1 week and increased at the surface after 1 month of abstinence. Finally, whole-cell patch clamp electrophysiological recordings determined reduced AMPA/NMDA ratio of synaptic currents in NAc shell neurons following stimulation of cortical afferents in sexually experienced males after all reward abstinence periods. Together, these data show that sexual experience causes long-term alterations in glutamate receptor expression and function in the NAc. Although not identical, this sex experience-induced neuroplasticity has similarities to that caused by psychostimulants, suggesting common mechanisms for reinforcement of natural and drug reward.

Decrease in spine number of the sexually dimorphic nucleus of the preoptic area (SDN-POA) with sexual experience in male rats

Decrease in spine number of the sexually dimorphic nucleus of the preoptic area (SDN-POA) with sexual experience in male rats

Neuroplasticity in the Mesolimbic System Induced by Natural Reward and Subsequent Reward Abstinence

Natural reward and drugs of abuse converge on the mesolimbic system, where drugs of abuse induce neuronal alterations. Here, we tested plasticity in this system after natural reward and the subsequent impact on drug responses. Effects of sexual experience in male rats on behavioral sensitization and conditioned place preference associated with d-amphetamine (AMPH) and Golgi-impregnated dendrites and spines of nucleus accumbens (NAc) cells were determined. Moreover, the impact of abstinence from sexual behavior in experienced males on these parameters was tested. First, repeated sexual behavior induced a sensitized locomotor response to AMPH compared with sexually naive control subjects observed 1, 7, and 28 days after last mating session. Second, sexually experienced animals formed a conditioned place preference for lower doses of AMPH than sexually naive males, indicative of enhanced reward value of AMPH. Finally, Golgi-Cox analysis demonstrated increased numbers of dendrites and spines in the NAc core and shell with sexual experience. The latter two alterations were dependent on a period of abstinence of 7-10 days. Sexual experience induces functional and morphological alterations in the mesolimbic system similar to repeated exposure to psychostimulants. Moreover, abstinence from sexual behavior after repeated mating was essential for increased reward for drugs and dendritic arbors of NAc neurons, suggesting that the loss of sexual reward might also contribute to neuroplasticity of the mesolimbic system. These results suggest that some alterations in the mesolimbic system are common for natural and drug reward and might play a role in general reinforcement.

D1 receptors involved in the acquisition of sexual experience in male rats

As we found previously, changes in ultrasonic vocalizations in the 50-kHz band emitted before a female is introduced into a copulatory chamber (precontact vocalizations—PVs) and shortening of ejaculation latency (EL) in subsequent copulatory sessions are correlated and reflected acquisition of sexual experience in male rats. In the present experiments, we investigate the role of the D1 receptor in this phenomenon. First, the effects of a D1 antagonist and D1 agonists injected subcutaneously during the first sexual contacts were analyzed. The antagonist (SCH-23390) inhibited changes in PVs and EL as well as rearing (R) and mount latency (ML). Both agonists (SKF-38393 and selective SKF-82957) inhibited PVs also at doses where no effects on EL and ML were observed. Repeated injections of five agonists, with or without socio-sexual contacts, had an effect on later PVs and R (long-term effect) but not on copulatory performance during the subsequent four sessions. In the last experiment, a D1 agonist (SKF-82957, 0.5μg) was injected bilaterally into nucleus accumbens (N.Acc) before each of the first five sessions. The D1 agonist in N.Acc facilitated initiation of copulation in treatment-naïve rats. Repeated administration of the D1 agonist into the brain had long-lasting effects on PVs, R and ML, probably as a result of long-term changes in neuronal structures involved in acquisition of sexual experience, in this part of the nucleus accumbens. Repeated D1 agonist administration probably inhibits/reverses sensitization processes in dopamine structures. The results indicate a role of D1 receptors in acquisition of socio-sexual experience and suggest independent neuronal pathways for changes in PVs and EL.

Effects of pair-housing after social defeat experience on elevated plus-maze behavior in rats

Social defeat experience in male rats causes an increase in anxiety-like behavior in the elevated plus-maze. Some researchers have suggested that housing rats socially following social defeat attenuates and/or prevents an increase in anxiety-like behavior. However, many other studies have shown that individual housing per se enhances anxiety-like behavior even in the absence of social defeat. In the present study, we assessed the relative contributions of the experience of social defeat and housing conditions on animals' performance in the elevated plus-maze. Rats were assigned to one of the following four groups: defeat/individual housing, defeat/pair-housing, non-defeat/individual housing, and non-defeat/pair-housing. The elevated plus-maze test was conducted 2 weeks after the defeat experience. Our results demonstrated that the defeat/individual housing group spent less time than the other groups in the open arms: moreover, there were no differences between the other three groups. These results confirm the claim that the group-housing of rats prevents an increase in anxiety-like behavior caused by defeat.

Effects of anxiolytic and antidepressant drugs on long-lasting behavioural deficits resulting from one short stress experience in male rats.

Exposure of male Wistar rats to one single session of ten inescapable footshocks induces changes in the behavioural responses to environmental stimuli as measured in the "noise test" 14 days later. Shocked (S) rats showed decreased locomotion and rearing during the first 3 min of exposure to a novel environment compared to control (C) rats. When the 85 dB background noise was switched off a marked immobility response emerged in S rats, concomitant with a further decrease in locomotion and rearing. In response to noise off, C rats showed hardly any immobility and a much smaller reduction in locomotion and rearing compared to S rats. These long-lasting changes in behaviour were not reversed by acute treatment with the antidepressants fluvoxamine (3.0-30.0 mg/kg) and desmethylimipramine (DMI, 2.5-10.0 mg/kg) injected IP 30 min before the noise test on day 14 following the shock session. Chronic treatment (day 1 to day 14) with fluvoxamine or DMI did not reverse the behavioural deficits induced by shock exposure. Diazepam (0.6-5.0 mg/kg) administered acutely only reversed the effects of shock on locomotion during the first 3 min of the noise test. Chronic treatment with diazepam normalized the shock-induced decrease in locomotion and attenuated the rearing decrease during the first 3 min of the test, and partially restored shock-induced changes in behavioural response to switching off the noise. The most potent drug in this study was the 5-HT1A receptor agonist flesinoxan (0.3-3.0 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)