Lucille A. Lumley

Hormone-neurotransmitter interactions in the control of sexual behavior

The stimuli from a receptive female and/or copulation itself leads to the release of dopamine (DA) in at least three integrative hubs. The nigrostriatal system promotes somatomotor activity; the mesolimbic system subserves numerous types of motivation; and the medial preoptic area (MPOA) focuses the motivation onto specifically sexual targets, increases copulatory rate and efficiency, and coordinates genital reflexes. The previous (but not necessarily concurrent) presence of testosterone is permissive for DA release in the MPOA, both during basal conditions and in response to a female. One means by which testosterone may increase DA release is by upregulating nitric oxide synthase, which produces nitric oxide, which in turn increases DA release. Hormonal priming in females may also increase DA release in the MPOA, and copulatory activity may further increase DA levels in females. One of the intracellular effects of stimulation of DA D1 receptors in the MPOA of male rats may be increased expression of the immediate-early gene c-fos, which may mediate longer term responses to copulation. Furthermore, increased sexual experience led to increased immunoreactivity to Fos, the protein product of c-fos, following copulation to one ejaculation. Another intracellular mediator of DAs effects, particularly in castrates, may be the phosphorylation of steroid receptors. Finally, while DA is facilitative to copulation, 5-HT is generally inhibitory. 5-HT is released in the LHA, but not in the MPOA, at the time of ejaculation. Increasing 5-HT in the LHA by microinjection of a selective serotonin reuptake inhibitor (SSRI) increased the latency to begin copulating and also the latency to the first ejaculation, measured from the time the male first intromitted. These data may at least partially explain the decrease in libido and the anorgasmia of people taking SSRI antidepressants. One means by which LHA 5-HT decreases sexual motivation (i.e. increases the latency to begin copulating) may be by decreasing DA release in the NAcc, a major terminal of the mesolimbic system. Thus, reciprocal changes in DA and 5-HT release in different areas of the brain may promote copulation and sexual satiety, respectively.

Acute social defeat reduces neurotrophin expression in brain cortical and subcortical areas in mice.

Acute social defeat in mice activates the hypothalamic-pituitary-adrenal axis (HPA) and induces long-term behavioral changes, including exaggerated fear responses and inhibition of territorial behavior. Stress-induced hormonal and neurotransmitter release may contribute to disruption of expression of genes important for cell survival, neuronal plasticity, and neuronal remodeling. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor associated with structural cellular changes that occur during nervous system development and contributes to neural plasticity in the adult brain. In rats, acute (1-2 h) restraint stress transiently reduces BDNF mRNA expression in the hippocampus, a region important in the memory and in HPA regulation; restraint stress also decreases BDNF expression in the basolateral amygdala (BLA), a region important for fear consolidation and emotional memory. We hypothesized that a brief (10 min) exposure to intense social stress, a more naturalistic stressor than restraint stress, would also reduce BDNF mRNA in the hippocampus and BLA of mice. In the present study, we examined the time course of expression of BDNF mRNA expression in the hippocampus and amygdala, as well as other subcortical and cortical brain regions, following acute social stress. In situ hybridization analysis for BDNF mRNA expression showed that there was a significant decrease in BDNF mRNA expression in all regions studied in mice 24 h after social defeat when compared to control (naive) mice (P<0.05). These findings support our hypothesis that BDNF mRNA levels are reduced by social stress, and may have implications for brain plasticity and behavioral changes following social stress.

Opposite influence of medial preoptic D1 and D2 receptors on genital reflexes: Implications for copulation

Dopamine D1 and D2 receptors may synergize with or oppose each others effects. We suggest that stimulation of D1 and D2 receptors in the medial preoptic area (MPOA) of male rats have opposing effects on genital reflexes. In Experiment 1 a D1 agonist injected into the MPOA increased the number of ex copula erections but decreased the number of seminal emissions. In Experiment 2 a D1 antagonist had the opposite effects (decreased erections and increased seminal emissions), as had a D2 agonist previously. We also suggest that D1 and D2 mechanisms in the MPOA have different thresholds of activation. In Experiment 3 a low dose of the mixed D1/D2 agonist apomorphine increased erections and anteroflexions, an effect blocked by the D1 antagonist. In Experiments 3 and 4 a high dose of apomorphine increased seminal emissions, an effect blocked by the D2 antagonist. Thus, low levels of dopaminergic stimulation may facilitate erections and anteroflexions (controlled by the parasympathetic system and striated muscles) via D1 receptors; higher or more prolonged stimulation may shift to seminal emission (controlled by the sympathetic system) via D2 receptors. This may explain the progression from erectile to ejaculatory mechanisms during copulation.

Possible acceleration of age effects on cognition following menopause

Many cognitive functions have been shown to deteriorate with age. Because of the importance of the menopause as a milestone in the life cycles of women, we examined whether the aging-over-time process in some cognitive functions differs between women of reproductive age and postmenopausal women. It is demonstrated here that in some cognitive tests, including driving simulation, reaction time and some visuospatial tests, there is a significant acceleration in deterioration of functioning following menopause. It is suggested that this acceleration might be associated with the lack of gonadal hormones or other reproduction-related factors which may play a protective role against age-related deterioration in some cognitive functions in women.

The roles of nitric oxide in sexual function of male rats

Nitric oxide (NO) may mediate penile erection by inhibiting smooth muscle of the corpora cavernosa, thereby allowing vasodilation of the corpora. In order to test the role of NO in the sexual function of intact male rats, either the precursor of NO (L-arginine, L-Arg) or an inhibitor of its synthesis (NG-nitro-L-arginine methyl ester, NAME) was administered systemically before tests of copulation, ex copula genital reflexes, or sexual motivation/motor activity. NAME impaired copulation in a dose dependent manner. It also decreased the number of ex copula erections, but it increased the number of ex copula seminal emissions and decreased the latency to the first seminal emission. L-Arg marginally increased the number of penile reflexes, but had no other effects. NAME had no effect on sexual motivation or motor activity. The results indicate that nitric oxide promotes erection in intact male rats, probably by mediating filling of the corpora cavernosa. The data also suggest that NO inhibits seminal emission, probably by decreasing sympathetic nervous system activity; this may help prevent premature ejaculation.

The multiple interactional biological processes that might lead to depression and gender differences in its appearance

Several neurotransmitter systems have been implicated in the pathophysiology of depression. Gender differences have been demonstrated in some functions that involve these systems, mostly norepinephrine, serotonin, dopamine and acetylcholine. Several hormonal systems have been shown to be altered in depression and gender differences were demonstrated in their activity as well, notably in thyroid hormones and the hypothalamic-pituitary-adrenal system. Most gender differences in brain systems and their hormonal modulators might be attributed to developmental and state influences of gonadal hormones. It is suggested that gender differences in mechanisms that might underlie formation of depressive symptoms might be related mostly to interactional processes and destabilization of balance among multiple factors or circuitry in the central nervous system. Indeed, gender differences in specific neurotransmitters and hormonal systems can be demonstrated as well.

A D1 agonist in the MPOA facilitates copulation in male rats

The classic dopamine agonist apomorphine, microinjected into the medial preoptic area (MPOA), enhances the copulatory behavior of male rats, while pharmacological blockade of endogenous dopamine inhibits sexual behavior. We now report that MPOA injections of 10 micrograms of the selective D1 agonist dihydroxyphenyl-tetrahydrothienopyridine (THP) significantly increased the number of ejaculations, while decreasing the latency to ejaculate in a 30-min test. These effects were not observed following coadministration of the selective D1 antagonist SCH-23390 with 10 micrograms THP. This enhancement may be related to a D1-stimulated facilitation of penile erections.

Dopamine receptors in the ventral tegmental area affect motor, but not motivational or reflexive, components of copulation in male rats.

Microinjection of apomorphine into the ventral tegmental area (VTA) of male rats was previously shown to delay the onset of copulation and slow its rate, presumably by stimulating impulse-regulating autoreceptors on cell bodies of the A10 mesocorticolimbic dopamine tract. Such stimulation would be expected to slow the firing rate of these neurons and, thereby, to impair locomotion and/or motivational processes. The present experiments tested whether the delayed onset and slowed rate of copulation were related to deficits in motor performance, sexual motivation, and/or genital reflexes. In X-maze tests the speed of running to all 4 goal boxes was slowed; however, the percentage of trials on which the male chose the females goal box was not decreased. Examination of videotaped copulation tests revealed that the male showed fewer complete copulatory behaviors (mounts, intromissions, and ejaculations), but more misdirected or incomplete copulatory attempts after apomorphine in the VTA. There were also fewer scores of active, as opposed to inactive, behaviors, and the onset and rate of copulation were slowed. The total number of female directed behaviors was not different in apomorphine tests, compared to vehicle. Finally, tests of ex copula genital reflexes revealed no significant effects of apomorphine in the VTA on erections, penile movements, or seminal emissions. These data suggest a role of the VTA in the motor aspects and/or sensorimotor integration of copulation. Sexual motivation and ex copula genital reflexes appeared to be unaffected by apomorphine in the VTA.

Effects of a D1 antagonist and of sexual experience on copulation-induced Fos-like immunoreactivity in the medial preoptic nucleus.

The medial preoptic nucleus (MPN) of the medial preoptic area (MPOA) and the medial amygdala are two brain regions in which male rat sexual behavior increased Fos-like immunoreactivity (Fos-Li). Dopamine is released in the MPOA during male rat sexual behavior and facilitates copulation. Psychostimulants, which increase dopamine levels, induce Fos-Li in the striatum through D1 receptors. We examined whether copulation-induced Fos-Li in the MPN was also mediated through D1 receptors. In Experiment 1, sexually inexperienced male rats that received the D1 antagonist Schering 39166 prior to their first sexual experience had fewer Fos-Li cells in the MPN than did those that received vehicle. In Experiment 2, no significant effect of the D1 antagonist was observed on copulation-induced Fos-Li in male rats that had received repeated sexual experiences prior to the drug test day. Sexual experience increases copulatory efficiency; the mechanisms by which this improvement occurs are unclear. In Experiment 3, copulation by highly experienced male rats led to greater Fos-Li in the MPN than did copulation by sexually naive males. Although there were no differences between groups in amygdala Fos-Li in these studies, in several groups Fos-Li in the medial amygdala was positively correlated with the post-ejaculatory interval. These experiments indicate that (1) stimulation of D1 receptors may contribute to the transient copulation-induced increase in Fos-Li in the MPN, and (2) repeated sexual experiences enhanced copulation-induced Fos-Li in the MPN, which may represent a marker of altered responsiveness of neurons in the MPN to sexual or conditioned stimuli.

D2 Receptors in the Paraventricular Nucleus Regulate Genital Responses and Copulation in Male Rats

The D2 dopamine receptor agonist quinelorane (LY-163502), microinjected into the paraventricular nucleus (PVN), affected genital response of restrained supine male rats in a biphasic dose-dependent fashion. A moderate dose (1 microgram) facilitated penile responses (intense erections and penile movements), and decreased the latency to the first response. A high dose of quinelorane (10 micrograms) facilitated seminal emission while inhibiting penile responses. The addition of the D1 antagonist SCH-23390 to the 1 microgram dose of quinelorane potentiated quineloranes increase in seminal emission. We suggest that D1 receptors in the PVN may be antagonistic to D2 receptor-mediated seminal emission, and possibly also penile responses. In copulation tests 1 microgram quinelorane decreased mount latency, whereas 10 micrograms quinelorane increased mount and intromission latencies and slowed copulatory rate. Both 1 and 10 micrograms quinelorane, and also 1 and 10 micrograms of the mixed D1 and D2 agonist apomorphine, decreased the number of intromissions preceding ejaculation.