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The present study was undertaken to establish whether the conditioned place preference paradigm can be utilized to investigate and elucidate the neuroendocrine basis of the appetitive elements of female sexual behavior. Females were exposed to a male with which copulation occurred in a distinctive compartment of the place preference apparatus and did not receive an incentive in the alternative compartment. After six pairings to each compartment a place preference test was conducted. Both estradiol benzoate and estradiol benzoate plus progesterone treated, ovariectomized females showed a preference for the compartment associated with sexual interaction. A second group of estradiol plus progesterone treated females was exposed to a male with which copulation occurred in one compartment of the place preference apparatus and to a sexually active, but caged, male in the other. The females tended to prefer the compartment paired with the caged male. After noncontingent intromissions, immediately preceding an additional test, the females showed a place preference for the compartment paired with sexual interaction. The presented observations indicate the potential use of the place preference procedure in studying opposing motivational processes associated with the unconditioned sequence of responses that characterize the species-specific pattern of sexual behavior.

Experiments investigating the neural mechanisms underlying the expression of masculine sexual behaviour are discussed in the context of the hypothesis set out by Frank Beach that suggested the existence of separate sexual arousal and performance mechanisms. The results indicate that the medial preoptic area is crucially involved in consummatory aspects of sexual behaviour: lesions and chemical manipulations of the area profoundly affect mounts, intromissions and ejaculation, but tend not to alter appetitive sexual responses. By contrast, ventral striatal dopamine-dependent mechanisms primarily affect appetitive sexual responses, measured in a variety of paradigms, but tend not to alter copulatory behaviour itself. Finally, associative mechanisms, for example those by which arbitrary environmental stimuli come to control appetitive sexual responses through their predictive association with sexual reinforcement, are shown to depend at least in part on interactions between the basolateral amygdala and dopamine-dependent events in the ventral striatum. Thus, diverse neural and behavioural procedures have revealed that separable neural mechanisms appear to be involved more or less selectively with different components of the male rat's sexual response system. It may still be useful to conceptualize separate sexual arousal and intromission/ejaculatory mechanisms when studying the neuroendocrine basis of sexual behaviour. However, a major challenge is to understand the way in which elements of the telencephalic limbic system, the striatum and preoptic area, some of which are targets for the action of sex steroids, interact to produce an integrated pattern of sexual behaviour.

The effects on the sexual behaviour of male rats of excitotoxic amino acid-induced lesions of the medial preoptic area-anterior hypothalamic area (mPOA/AHA), infusions of beta-endorphin, alpha-melanocyte stimulating hormone and naloxone into the mPOA/AHA, systemic naloxone and castration were compared using different behavioural paradigms. These included measures of unconditioned copulatory behaviour, instrumental responses for an oestrous female presented under a second-order schedule of reinforcement, conditioned place preference and partner preference. The results demonstrate that manipulations of the mPOA/AHA markedly affect consummatory aspects of sexual behaviour (mounting, intromitting and ejaculating) but tend not to affect appetitive or reward-related aspects of sexual behaviour, although intra-mPOA/AHA alpha MSH did result in a small increase in instrumental responses, while beta-endorphin infused into the mPOA/AHA also abolished preference for an oestrous over an anoestrous female. Systemic naloxone, on the other hand, reduced instrumental behaviour and a place preference conditioned by prior sexual interaction, while the same compound infused into the mPOA/AHA markedly facilitated copulatory responses but did not affect other measures of appetitive sexual responses. Castration caused an extremely rapid attenuation of conditioned place preference which was apparent before the males had experienced reductions in their copulatory performance. This treatment only slowly reduced partner preference. The results indicate that the use of several behavioural procedures can reveal discrete actions of neuroendocrine treatments on separable psychological processes which underly the integrated pattern of masculine sexual behaviour. In particular, they suggest that the mPOA/AHA is especially concerned with the copulatory responses of mounting and intromitting, but is much less important for a variety of appetitive sexual acts as well as sexual reward, as measured in the place preference procedure. The marked effects of castration on conditioned place preference taken together with the lack of effect of lesions of the mPOA/AHA on this measure indicate that testosterone affects sexual reward-related processes by an action at a site other than the mPOA/AHA. The implications of these findings are discussed.

Active immunization of an ovariectomized rhesus monkey against testosterone-3(0-carboxymethyl)oxime-bovine serum albumin produced an antiserum with a high degree of specificity towards testosterone. Passive immunization of ovariectomized, oestrogen-treated monkeys with this antiserum resulted in significant reductions in proceptive and/or receptive behaviours in the majority of animals. This effect could be reversed by treatment with 17 alpha-methyltestosterone, a steroid which showed only 6% cross-reaction with the antiserum. Passive immunization caused an increase in the binding of testosterone by the gamma-globulin fraction of serum isolated by treatment with 2-ethoxy-6,9-diaminoacridine lactate. The present findings emphasize the importance of androgens of adrenal origin in the regulation of sexual behaviour in the female rhesus monkey.

The role of 5-hydroxytryptamine (5-HT) in the control of sexual receptivity in female rhesus monkeys has been studied in 24 adult females paired with 6 adult males. p-Chlorophenylalanine (PCPA, 75 mg/kg or 100 mg/kg, every fourth day), a selective inhibitor of 5-HT, was found to reverse unreceptivity induced by adrenalectomy in ovariectomised, oestrogen-treated females. PCPA-treated females presented more frequently and initiated more sexual behaviour, or else they refused fewer of the male's attempts to mount. These effects were in turn reversed by 5-hydroxytryptophan (5-HTP, 20 mg/kg every second day), when this was given to PCPA-treated animals. In addition, 5-HTP given alone to ovariectomised oestrogen-treated females reduced their receptivity. Parallel biochemical experiments showed that PCPA in the doses used lowered the levels of 5-HT in the brain as measured by the levels of 5-hydroxyindole-3-acetic acid (5-HIAA) in the CSF, and that these were restored by 5-HTP. Both oestradiol benzoate (15 mug/day for 10 days) and testosterone propionate (250 mug/day or 400 mug/day for 10 days) lowered the turn-over rates of 5-HT in the brain (as measured by the probenecid test) in ovariectomised female monkeys. These effects of oestradiol on turnover were antagonised by progesterone (15 mg/day for 10 days, given with oestradiol). A substance other than an adrenal androgen has thus been found to reverse the effects of adrenalectomy on sexual receptivity in female monkeys. It is therefore possible that androgens regulate receptivity in female monkeys by modifying the activity of 5-HT-containing neural systems.

The experiments described were concerned with elucidating the involvement of monoamines in the sexual behaviour of rhesus monkeys. The measurement of perturbations in the levels and turnover of the acid metabolites of serotonin and dopamine in cisternal cerebrospinal fluid, occurring in response to hormonal manipulations which alter proceptivity and receptivity, has not clarified the ways in which hormones and amines interact. However, the use of psychoactive drugs which alter the activity of monamine neurons in the brain has demonstrated that sexual activity can be profoundly influenced by such procedures. Thus, depletion of serotonin (5-hydroxytryptamine) in the brain using p-chlorophenylalanine reversed the decrease in proceptivity that followed adrenalectomy. Conversely, inhibition of serotonin uptake using chlorimipramine reduced proceptivity and receptivity to very low levels. Both findings point to the apparently important role of serotoninergic neurons in the control of sexual behaviour. Low doses of the dopamine agonist alpha-bromocriptine enhanced the proceptivity of female rhesus monkeys but high doses had no such effect. This behavioural change was not related to the concomitant suppression of serum prolactin and may have been related to presynaptic actions of the drug in a manner postulated to explain similar behavioural effects in rats. The beta-blocker oxprenolol had the interesting property of improving the sexual performance of male rhesus monkeys, a behavioural effect consistent with an anxiolytic action, although endocrine (prolactin, cortisol) measures did not provide support for such a view. Defining the nature of the interaction between hormones and monoamine-containing neurons in the brain in behavioural contexts is shown to depend largely on the application of precise neuroanatomical and neuropharmacological techniques. However, the use of systemic treatment with psychoactive drugs used widely in clinical practice, in carefully controlled, behavioural and and endocrine experiments, is likely to provide invaluable information on where and how to investigate the neural mechanisms involved.

Concentrations of oxytocin (OT) and vasopressin (AVP) were measured in cerebrospinal fluid (CSF) obtained from the cisterna magna of freely moving rats. Basal levels of OT and AVP were approximately 9 fmol/ml in both male and female. In the male rats this increased to approximately 18 fmol/ml 5 min after ejaculation, and 27 fmol/ml 20 min after ejaculation. No increase from basal levels occurred when males were placed with unreceptive females, or alone in the test environment. AVP levels were unchanged in any condition. Preliminary investigations indicate that discrete electrolytic lesions to the lateral and posterior parvocellular hypothalamic paraventricular nucleus (PVN) abolished this ejaculation-associated increase in CSF OT, prolonged mount and intromission latencies and reduced the absolute postejaculatory interval (PEI). We conclude that intracerebrally projecting OT systems may be activated during coitus and may contribute to the mechanisms underlying postejaculatory refractoriness.

The effects of nicotine alone or in combination with mecamylamine, and the effects of both in combination with DA agonists and antagonists and d-LSD (5-HT agonist) have been studied on the sexual behaviour of castrate, estrogen-treated female rats. The results show that nicotine (as low as 50 mug/kg) significantly increases sexual receptivity. The pharmacological analysis suggests this effect to be mediated by a central, nicotine-like cholinergic receptor whose relationship to DA and 5-HT pathways known to exert inhibitory influences on receptivity in the female rat is also discussed.

In the studies of sexual behaviour in male rats reported here, intrathecal administration of 5-hydroxytryptamine (5-HT) together with thyrotropin releasing hormone (TRH) caused a marked and specific increase in mount and intromission latencies. In contrast, injection of either of the two compounds alone elicited only minor effects. These findings are discussed in relation to the co-existence of 5-HT and TRH in nerve endings in the ventral horn of the spinal cord originating in supraspinal, medullary nuclei.

The involvement of indole- and catecholamines in the hormonal regulation of sexual receptivity has been investigated in ovariectomized female rats. Drugs that reduce 5-hydroxytryptamine, dopamine, and adrenaline or increase noradrenaline neurotransmission tended to facilitate the occurrence of estrous behavior in estrogen-treated females, and drugs having opposite effects tended to inhibit receptivity induced by estrogen and progesterone. Estrogen decreased noradrenaline turnover in cortex and brain stem; progesterone enhanced this effect in brain stem but prevented it in cortex. Both hormones tended to block noradrenaline uptake in hypothalamus in vitro. In a schedule used to induce receptivity, estrogen accelerated serotonin turnover, an effect prevented by progesterone. Thus a number of monoamines may be involved in the control by hormones of estrous behavior. Furthermore, hormones affect both amine turnover and uptake mechanisms.

Intraneuronal post-translational cleavage of pro-opiomelanocortin yields a variety of peptides including beta-endorphin, melanocyte stimulating hormone and corticotrophin-like intermediate polypeptide, some of which are subsequently N-acetylated. Such peptides may be co-released from neuronal terminals, and so these experiments explored the effects of co-administration of some of them on sexual behaviour in the male rat, which is known to be sensitive to hypothalamic infusions of beta-endorphin. Peptides were infused into the pre-optic-anterior hypothalamic area bilaterally in doses up to 320 pmol, and males allowed access to a sexually receptive female and/or a sweet solution (0.1% Acesulfame-K) for 15 min, so that both sexual and ingestive behaviour could be studied. beta-Endorphin(1-31) by itself inhibited sexual interaction, confirming our previous data. Acesulfame-K ingestion was inhibited in control-infused rats in the presence of a female, but this inhibition was released when sexual behaviour was itself diminished by beta-endorphin(1-31). Both the acetylated and non-acetylated forms of melanocyte stimulating hormone (alpha-melanocyte stimulating hormone and des-acetyl melanocyte stimulating hormone) stimulate sexual behaviour; latencies both to ejaculation and to resumption of copulatory behaviour after an ejaculation (post-ejaculatory interval) were reduced. However, infusion of either corticotrophin-like intermediate peptide or N-acetylated beta-endorphin (1-31) had no effect on either sexual or ingestive behaviour. Infusion of either acetylated melanocyte stimulating hormone or des-acetyl melanocyte stimulating hormone mixed with beta-endorphin(1-31) prevented the inhibitory effect of the latter on sexual behaviour. Dose-response studies showed that the behavioural effect of such mixtures depended upon the molar ratios of the two peptides, rather than their absolute concentrations. The higher the ratio in favour of alpha-melanocyte stimulating hormone or des-acetyl melanocyte stimulating hormone, the greater the display of sexual behaviour. Infusing either corticotrophin-like intermediate polypeptides or N-acetyl beta-endorphin(1-31) with beta-endorphin(1-31) did not prevent the inhibition of sexual activity expected with beta-endorphin(1-31) alone. These results are discussed in terms of the functional consequences of co-release of proopiomelanocortin peptides from hypothalamic nerve terminals.

Bilateral, N-methyl-D-aspartate-induced lesions of the basolateral region of the amygdaloid complex in male rats resulted in a marked decrease in instrumental responses maintained by a visual conditioned reinforcer in a paradigm in which sexual reinforcement was presented under a second-order schedule. There were no effects of lesions of the amygdala on the unconditioned sexual behaviour of the males, i.e. on behaviour elicited by primary reinforcers. Infusion of D-amphetamine bilaterally into the nucleus accumbens region of the ventral striatum resulted in a dose-dependent amelioration of the decrease in instrumental behaviour maintained by a conditioned reinforcer which followed lesions of the amygdala. This effect of D-amphetamine critically depended upon the presentation of the conditioned reinforcer (a previously neutral light which had gained reinforcing properties through its prior association with sexual interaction). The results indicate that the basolateral region of the amygdala may interact with dopamine-dependent processes in the ventral striatum in mediating the control by conditioned reinforcers over instrumental behaviour.

Bilateral adrenalectomy rendered ovariectomised, oestrogen-treated female rhesus monkeys sexually unreceptive. Small unilateral implants of testosterone propionate (mean weight 140 mug) into the anterior hypothalamus/preoptic area restored receptivity in 7 out of 8 of these monkeys. Cholesterol implanted into the same area, or similar amounts of testosterone propionate implanted into the posterior hypothalamus/pretectal area (4 females) or cerebral cortex/dorsal thalamus (5 monkeys) had no consistent effect on behaviour. It therefore seems likely that androgens regulate sexual receptivity in female monkeys by acting on some part of the anterior hypothalamus. Thus, though the hormonal control of receptivity in female primates differs from non-primates, the site on which hormones act to regulate this behaviour may be similar in both.

The role played by steroid hormones in regulating the sexual behavior of female primates is reviewed, with emphasis placed on experiments using nonhuman species. A distinction is made between the effects of hormones on female proceptivity (i.e., behaviors which incite mounting activity in the male) and receptivity (i.e., willingness to accept male mounting attempts). The rationale for distinguishing between proceptivity and receptivity is discussed, and the methods used for measuring each are described. Evidence shows that estrogen of ovarian origin facilitates sexual interaction primarily by stimulating the emission of non-behavioral cues which increase the female's sexual attractivity (i.e., the value of a female as a sexual stimulant for a male). Evidence is presented suggesting that ostrogen may enhance proceptivity by acting on the female's central nervous system; however, there is no clear demonstration that estrogen affects neural mechanisms controlling receptivity. Experiments show that proceptivity and to a lesser extent receptivity are modulated by adrenal androgens, and the possibility is raised that adrenal androgens may act synergistically with estrogen to facilitate sexual behavior. A disruptive effect of progesterone on sexual interaction is described, and evidence is presented suggesting that this effect of progesterone results primarily from a reduction in sexual attractivity caused by the action of the hormone in the female's vagina. Other literature indicates that proceptivity is often maximal at the periovulatory period of the female primate's menstrual cycle whereas cyclic variations in receptivity occur infrequently. Most hormone-dependent changes in sexual interaction associated with the menstrual cycle seem to result from fluctuations in nonbehavioral attributes of female sexual attractivity. The problem of distinguishing between the effects of steroid hormones on proceptivity and receptivity in human females is discussed.

In male New Zealand white rabbits, it was shown that oxytocin but not vasopressin concentrations in plasma were markedly raised after ejaculation. In male Wistar rats, oxytocin infused into the internal carotid artery reduced the number of intromissions made before ejaculation but had no other significant effect. Infusion of oxytocin into the third ventricle increased the latencies to the first mount and intromission and lengthened post-ejaculatory refractory periods. It is suggested that oxytocin released into the periphery during coitus, while not essentially involved in ejaculation, may exert effects on the genital periphery. Behavioural effects of centrally administered oxytocin suggest that it may play a role in the neural mechanisms underlying post-ejaculatory refractoriness.

We describe a novel procedure for measuring instrumental sexual behavior in the male rat by using a second-order schedule of presentation of sexual reinforcement, an estrous female. Experimental assessment and validation of the paradigm have been achieved by examining (a) the importance of the conditioned stimulus in maintaining instrumental responding by measuring the effects of its omission during a test session, (b) the effects and motivational specificity on instrumental behavior of the postejaculatory refractory period (a period of sexual unarousability) and of satiety for food by measuring the impact of each manipulation on animals working for food and for a female, (c) the effects of replacing an estrous female with an anestrous one as the earned reward, and (d) the correlations between conditioned and unconditioned measures of sexual behavior. We conclude that the second-order paradigm provides a means of distinguishing between the effects of neuroendocrine manipulations on incentive motivational and performance variables underlying the expression of sexual behavior.

Water replete rats allowed restricted access to a sweet nonnutritive solution (0.2% Acesulfame-K) spend about one third of their time drinking it. This ingestive response is markedly inhibited if the male rat is simultaneously presented with an estrous female, but not an anestrous female or another male, despite the fact that there is sufficient time for both sexual and ingestive behaviors to occur. Castration and the subsequent decline in sexual behavior is accompanied by an increase in Acesulfame ingestion in the presence of a receptive female. Treatment with testosterone reverses both these effects. Similarly treatment of castrate males with DHT and estradiol (the active metabolites of testosterone) maintains both full sexual behavior and suppression of the ingestive response. However, the steroid requirements for sexual activity do not correspond completely with those for the sexually-induced suppression of ingestive behavior. Treatment of castrate males with estradiol alone maintains mounting behavior (but no intromissions or ejaculations) but does not suppress ingestive behavior in the presence of a receptive female--indeed under these suboptimal hormone conditions sexual behavior appears to be reduced in the presence of Acesulfame. Steroid hormones, therefore, have at least two effects upon sexual behavior. They enable certain aspects of sexual behavior such as intromissions and ejaculations, and also alter the animal's priority of response to two competing (ingestive and sexual) stimuli.

Clomipramine markedly decreases the proceptivity and receptivity of female rhesus monkeys paired with males in the laboratory. These behavioural changes are correlated with cerebrospinal fluid levels of 5-hydroxyindoleacetic acid and with noradrenaline and serotonin uptake, both in vivo and in vitro. Detailed studies of this kind should help to elucidate the effects of antidepressant therapy on sexual activity in man, and the wider relationship between cerebral amines and behaviour.

beta-Endorphin was infused bilaterally into the medial preoptic area-anterior hypothalamic continuum at doses of 5, 10 and 40 pmol each side. The highest dose selectively abolished mounting, intromitting and ejaculating in sexually experienced male rats paired with an oestrous female. Males infused with 40 pmol beta-endorphin still followed the female, investigated her anogenital region and other parts of her body, but made abortive attempts to mount. A dose of 5 pmol beta-endorphin had no effect, but 10 pmol proved partially effective. The same males, in other tests, were allowed to ingest a highly preferred, sweet, non-calorific solution (acesulfame-K) in the absence of a female. beta-Endorphin infusions (up to 40 pmol) into the same area of the hypothalamus had no effect on this behaviour. Control males allowed simultaneous access both to an oestrous female and to the sweet solution copulated normally but reduced their ingestive behaviour, despite there being sufficient time during tests for both to occur. beta-Endorphin (40 pmol) infused into the preoptic area-anterior hypothalamic continuum under these conditions suppressed sexual interaction, but ingestion of acesulfame-K increased to values observed when the female was absent. beta-Endorphin infused into neighbouring areas of the brain had different behavioural effects. Sexual behaviour was not inhibited, and ingestion of acesulfame-K was unaltered, when beta-endorphin was infused either into the bed nucleus of the stria terminalis or the rostral ventromedial hypothalamus. However, infusions of cholecystokinin-8 into the ventromedial hypothalamus suppressed acesulfame-K ingestion in most animals, showing that the cannulae were placed in an area regulating ingestive behaviour. The inhibition of sexual behaviour after preoptic area-anterior hypothalamic continuum infusions of beta-endorphin was prevented by either pretreating rats with 1 mg/kg naloxone intraperitoneally, or by infusing a putative delta opiate receptor blocker (0.5 pmols ICI 174864) into the preoptic area-anterior hypothalamic continuum 5 min prior to beta-endorphin treatment. ICI 174864 administered alone significantly increased mount rate and reduced the post-ejaculatory refractory period in copulating males. These experiments suggest that there is both neurochemical and neuroanatomical specificity relating beta-endorphin to sexual behaviour in the male rat.

We studied effects of lesions to the medial preoptic area (POA), castration, and testosterone replacement on instrumental and unconditioned sexual behavior in male rats. We achieved instrumental measures of sexual motivation by training males to work for an estrous female, presented in an operant chamber under a second-order schedule of reinforcement. POA lesions abolished mounts, intromissions, and ejaculation but did not disrupt instrumental responses, investigation of the female, or abortive mounting attempts. Castration abolished attempts to copulate and also caused a marked decrease in instrumental responses. Testosterone resulted in the prompt reinstatement of instrumental responses and more gradual recovery of unconditioned sexual behavior. We discuss these results in terms of the motivational and performance effects of these neuroendocrine manipulations.