RESUMO

The endocannabinoid system (ECS) plays a key neuromodulatory role in the brain. Main features of endocannabinoids (eCBs) are that they are produced on demand, in response to enhanced neuronal activity, act as retrograde messengers, and participate in the induction of brain plasticity processes. Sexual activity is a motivated behavior and therefore, the mesolimbic dopaminergic system (MSL) plays a central role in the control of its appetitive component (drive to engage in copulation). In turn, copulation activates mesolimbic dopamine neurons and repeated copulation produces the continuous activation of the MSL system. Sustained sexual activity leads to the achievement of sexual satiety, which main outcome is the transient transformation of sexually active male rats into sexually inhibited animals. Thus, 24 h after copulation to satiety, the sexually satiated males exhibit a decreased sexual motivation and do not respond to the presence of a sexually receptive female with sexual activity. Interestingly, blockade of cannabinoid receptor 1 (CB1R) during the copulation to satiety process, interferes with both the appearance of the long-lasting sexual inhibition and the decrease in sexual motivation in the sexually satiated males. This effect is reproduced when blocking CB1R at the ventral tegmental area evidencing the involvement of MSL eCBs in the induction of this sexual inhibitory state. Here we review the available evidence regarding the effects of cannabinoids, including exogenously administered eCBs, on male rodent sexual behavior of both sexually competent animals and rat sub populations spontaneously showing copulatory deficits, considered useful to model some human male sexual dysfunctions. We also include the effects of cannabis preparations on human male sexual activity. Finally, we review the role played by the ECS in the control of male sexual behavior expression with the aid of the sexual satiety phenomenon. Sexual satiety appears as a suitable model for the study of the relationship between eCB signaling, MSL synaptic plasticity and the modulation of male sexual motivation under physiological conditions that might be useful for the understanding of MSL functioning, eCB-mediated plasticity and their relationship with motivational processes.

RESUMO

RATIONALE: Exposure of male rats to an inaccessible receptive female and copulation increases dopamine (DA) levels in the nucleus accumbens (NAcc). Males copulating to satiety become sexually inhibited and most of them do not display sexual activity when presented with a sexually receptive female 24 h later. This inhibitory state can be pharmacologically reversed. There are no studies exploring NAcc DA levels during this sexual inhibitory state. OBJECTIVES: To characterize changes in NAcc DA and its metabolites' levels during sexual satiety development, during the well-established sexual inhibitory state 24 h later, and during its pharmacological reversal. METHODS: Changes in NAcc DA and its metabolites were measured in sexually experienced male rats, using in vivo microdialysis, during copulation to satiety, when presented to a new sexually receptive female 24 h later, and during the pharmacological reversal of the sexual inhibition by anandamide. RESULTS: NAcc DA levels remained increased during copulation to satiety. DA basal levels were significantly reduced 24 h after copulation to satiety, as compared to the initial basal levels. Presenting a receptive female behind a barrier 24 h after satiety did not induce the typical NAcc DA elevation in the sexually satiated males but there was a decrease that persisted when they got access to the female, with which they did not copulate. Anandamide injection slightly increased NAcc DA levels coinciding with sexual satiety reversal. CONCLUSIONS: Reduced NAcc DA concentrations coincide with the inhibition of an instinctive, natural rewarding behavior suggesting that there might be a DA concentration threshold needed to be responsive to a rewarding stimulus.

Assuntos

RESUMO

Endocannabinoids modulate mesolimbic (MSL) dopamine (DA) neurons firing at the ventral tegmental area (VTA). These neurons are activated by copulation, increasing DA release in nucleus accumbens (NAcc). Copulation to satiety in male rats implies repeated ejaculation within a short period (around 2.5 h), during which NAcc dopamine concentrations remain elevated, suggesting continuous neuronal activation. During the 72 h that follow copulation to satiety, males exhibit long-lasting changes suggestive of brain plasticity processes. Enhanced DA neuron activity triggers the synthesis and release of endocannabinoids (eCBs) in the VTA, which participate in several long-term synaptic plasticity processes. Blockade of cannabinoid type 1 receptors (CB1Rs) during copulation to satiety interferes with the appearance of the plastic changes. Glutamatergic inputs to the VTA express CB1Rs and contribute to DA neuron burst firing and synaptic plasticity. We hypothesized that eCBs, released during copulation to satiety, would activate VTA CB1Rs and modulate synaptic plasticity processes involving glutamatergic transmission. To test this hypothesis, we determined changes in VTA CB1R density, phosphorylation, and internalization in rats that copulated to satiety 24 h earlier as compared both to animals that ejaculated only once and to sexually experienced unmated males. Changes in glutamate AMPAR and NMDAR densities and subunit composition and in ERK1/2 activation were determined in the VTA of males that copulated to satiety in the presence or absence of AM251, a CB1R antagonist. The CB1R density decreased and the proportion of phosphorylated CB1Rs increased in the animals that copulated compared to control rats. The CB1R internalization was detected only in sexually satiated males. A decrease in α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR) density, blocked by AM251 pretreatment, and an increase in the proportion of GluA2-AMPARs occurred in sexually satiated rats. GluN2A- N-methyl-D-aspartate receptor (NMDAR) expression decreased, and GluN2B-NMDARs increased in these animals, both of which were prevented by AM251 pre-treatment. An increase in phosphorylated ERK1/2 emerged in males copulating to satiety in the presence of AM251. Results demonstrate that during copulation to satiety, eCBs activate CB1Rs in the VTA, producing changes in glutamate receptors compatible with a reduced neuronal activation. These changes could play a role in the induction of the long-lasting physiological changes that characterize sexually satiated rats.

RESUMO

Sexual behavior is a natural reward and the mesolimbic (MSL) system is involved in the processing of its motivational component and reinforcing properties. Endocannabinoids control rewarding behaviors through the modulation of MSL system's activity. The endocannabinoid anandamide (AEA), systemically administered, produces dose-based, biphasic effects on male rat copulation, facilitating its expression at low doses in both, sexually experienced and sexually exhausted male rats. We hypothesized that AEA's sexual facilitative effects might be exerted at the MSL circuit. Therefore, in this work different AEA doses were bilaterally infused into the VTA of sexually experienced or sexually exhausted animals and their copulatory behavior recorded. Results showed that the lowest AEA dose tested lacked an effect, intermediate doses facilitated specific sexual parameters, and the highest dose inhibited copulation of sexually experienced males. In sexually exhausted animals low AEA doses reversed the sexual inhibition that characterizes sexual satiety, but this effect was lost at higher doses. Together, these data show that the VTA is a target for AEA's biphasic sexual effects suggesting a role of the MLS system in the actions of endocannabinoids on male rat sexual behavior.

Assuntos

RESUMO

Male sexual satiety has been associated with a decrease in dopamine levels. Spontaneous recovery of copulatory behavior begins at least 72 h after sexual satiety is reached or in the condition in which a sexually-satiated male is exposed to a new receptive female distinct from the one with which sexual satiety was reached. The aim of the present study was to explore whether dopaminergic activation by bromocriptine (BrCr) can reactivate copulatory behavior with the same sexual mate immediately after sexual satiety is reached. Male rats were divided into three groups exposed to one of the following three conditions: 1) administration of 2 mg/kgs.c. of BrCr and exposure to the same female with whom sexual satiety was previously reached; 2) administration of 0.3 mLs.c. of the vehicle solution with exposure to the same female with whom sexual satiety was reached; and, 3) exposure to a new receptive female after sexual satiety was reached. Results showed that BrCr significantly reactivated copulatory capability in sexually-satiated males with the same receptive female. In contrast, no males in the vehicle group ejaculated with the same female after reaching sexual exhaustion. Copulation was reactivated by BrCr in a way similar to that observed in untreated males exposed to a new receptive female (i.e., the Coolidge effect). The reversal of sexual satiety in the males treated with BrCr could be explained by its action on D2 family receptors, which promotes a reactivation of sexual motivation at a level sufficient to allow renewed copulation with the same female mate.

Assuntos

RESUMO

The mating inhibition after repeated copulation (sexual satiety) and its re-commencement after changing the sexually active partner (Coolidge effect) are well recognized phenomena in males, but their occurrence in females is little explored. These two phenomena were compared in conditions when the female regulates copulation timing (pacing) and under non-paced mating. Female rats selected in proestrus copulated incessantly for 3 h with two different partners (for 90 min each), both of them sexually active and unknown for the female. During the entire test we recorded the hop/dart and ear wiggling frequencies and the lordosis quotient. In the pacing test we also registered the percentage of exits and the return latencies after mounts, intromissions and ejaculation within each copulatory series, the mean time the female spent in the neutral chamber and the number of crossings. In the non-paced mating situation there was a reduction in ear wiggling and hop/darting frequencies after 3 h of constant copulation. In the paced mating condition, also by the end of the test, the female spent more time in the neutral compartment and showed fewer crossings to the male's zone. Only when the female regulated mating, the change of the male provoked an increased hop/darting frequency accompanied by a reduced percentage of exits from the male's chamber after an intromission and in the time in the neutral compartment. These changes were not associated with alterations in receptivity, which was maximal along the test. Data are discussed by comparing the mating conditions and the sex differences in the effect of repeated copulation and partner replacement.

Assuntos