Hormone-neurotransmitter interactions in the control of sexual behavior

doi:10.1016/S0166-4328(99)00086-8

Behavioural Brain Research

Volume 105, Issue 1, 1 November 1999, Pages 105-116

https://doi.org/10.1016/S0166-4328(99)00086-8 Get rights and content

Abstract

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 DA’s 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.

Section snippets

Model of central control of male sexual behavior

Sexually relevant stimuli elicit a complex cascade of genital and somatomotor patterns. Steroid hormones facilitate this process by biasing sensorimotor integration, so that a sexually relevant stimulus is more likely to elicit a sexual response. One step in the translation of long term steroid effects into rapid behavioral events is probably a change in the release or effectiveness of one or more neurotransmitters. One candidate for a central role is dopamine (DA), since dopaminergic drugs

Activation of dopamine release in the medial preoptic area

We have observed a consistent relationship between MPOA DA release during a precopulatory period, with a receptive female behind a perforated barrier, and the subsequent ability of a male to copulate [36] (Fig. 3). An increase in DA release, measured in microdialysate, was not elicited by the presence of another male behind the barrier or by voluntary running in an activity wheel. The amount of activity exerted in the running wheel was considerably greater than the motoric effort of copulation.

Consequences of dopamine release in the medial preoptic area

We shown that DA released in the MPOA is important for copulation. Microinjections of a DA agonist (apomorphine, APO) into the MPOA increased the rate and efficiency of copulation [35], and also increased the numbers of ex copula erections [78]. Furthermore, microinjection of APO into the MPOA reversed the impairment due to lesions of the medial amygdala [16]. Blocking DA’s access to receptors slowed the rate of copulation, decreased ex copula erections, and decreased specifically sexual

Hormonal influences on medial preoptic area dopamine release

The recent presence of testosterone is necessary for the precopulatory DA release and for copulation itself [36]. All gonadally intact males, all testosterone-replaced castrates, and 2/3 of oil-treated animals that had been castrated 1 week previously showed a precopulatory DA response to a female behind a barrier, and all of them copulated (Fig. 3). All 2-week oil-treated castrates and 1/3 of the one-week oil-treated castrates failed to show a precopulatory DA response, and all of these failed

The role of nitric oxide

DA release may be affected by influences on axon terminals, as well as changes in the firing rate of DA neurons. One particularly intriguing finding is that the gaseous messenger molecule, nitric oxide (NO), can enhance catecholamine release and inhibit reuptake, possibly by reversing the transporter [46], [81]. NO, a highly reactive gas, is given off when l-arginine is converted to l-citrulline by the enzyme NO synthase (NOS). NO has been implicated in the regulation of DA release in striatal

Medial preoptic area dopamine and female sexual behavior

We have recently asked whether DA may be released in the MPOA of females during sexual behavior [64]. In females injected with estradiol benzoate (EB, 2 μg) 48 h before testing and with progesterone (P, 500 μg) 4 h before testing, DA remained at baseline during the first 3 h and 20 min following P injection. However, the sample collected 3 h and 40 min after P showed a significant increase in DA. Furthermore, DA rose further at 4 h after injection, when a male was placed into the female’s

Fos: a possible intracellular mediator of some of dopamine’s effects

Some of the longer term effects of neural activity may be mediated through the induction of immediate-early genes, which are expressed transiently in response to stimulation. The protein products of these genes may serve as transcription regulators for other genes, which may in turn affect neural activity or response to future stimulation.

The immediate-early gene c-fos and its protein product Fos are expressed in several hormone-concentrating brain areas, including the MPOA, following sexual

Hormonal influences on dopamine in other brain areas

There are contradictory reports concerning the effects of hormones on mesolimbic and nigrostriatal systems. For example, tissue levels of DA and its major metabolite in the nucleus accumbens were decreased by castration [3], [69]. On the other hand, amphetamine-stimulated DA release in the ventral striatum (nucleus accumbens) was higher in castrates than in intact males [32], [61]. In the dorsal striatum DA tissue levels were reported to be either unaffected [3], [69] or increased [18] by

Ligand-independent activation of steroid receptors by dopamine

The full elicitation of female sexual behavior in ovariectomized rats typically requires a regimen of estrogen injections, followed by progesterone. However, recent reports have shown that DA agonists are as effective as progesterone in eliciting lordosis in estrogen primed, ovariectomized female rats [56], [58] and in wild-type, but not progesterone receptor knock-out, mice [57]. DA agonists, acting through the D₁ receptor cause the phosphorylation of progesterone receptors (PR), which in turn

The role of serotonin (5-HT) in copulation

DA is generally facilitative to sexual behavior; however, 5-HT is usually regarded as inhibitory. Antidepressants of the selective serotonin reuptake inhibitor class (SSRIs, including Prozac and Zoloft) impair ejaculatory/orgasmic function, and frequently erectile function as well [27]. Microinjection of large doses of 5-HT into the MPOA impaired male sexual behavior [24], [104]. Conversely, decreasing serotonergic activity, either by lesions or inhibition of synthesis, facilitated sexual

Summary

Stimuli from a receptive female elicit DA release in several integrative hubs that regulate different aspects of male sexual behavior. DA in the nigrostriatal system promotes the somatomotor patterns of copulation; in the mesolimbic system it facilitates numerous types of motivation; and in the MPOA it focuses motivation on sexual stimuli, coordinates genital reflexes, and increases the rate and efficiency of copulation. The recent presence of testosterone is permissive for DA release in the