Opioids and sexual behavior.

Opioids have long been known to inhibit sexual behavior. However, it is only within the last decade that the effects of opioids on sexual behavior have been studied extensively and a number of hormonal and neurochemical correlates established. In this review, the experimental literature on opioids and sexual behavior in humans and laboratory animals is examined. Clinical and anecdotal accounts of opioid use are also discussed, in addition to the pharmacology, neuroendocrinology, and biochemistry of opioid administration, to provide a synthesis of critical information. New research directions involving the study of endogenous opioid systems, opioid receptor subtypes, and the opioid modulation of neurotransmitter systems are outlined. Finally, a comprehensive bibliography of the human and animal literature is included.

Sex differences in the effects of 1-(m-trifluoromethylphenyl) piperazine and 1-(m-chlorophenyl) piperazine on copulatory behavior in the rat.

Peripheral administrations of TFMPP (0.2- 1 mg/kg) or MCPP (1 mg/kg) facilitated lordosis behavior in female rats treated with estradiol benzoate, and had no effects in females primed with estradiol benzoate and progesterone. In contrast, TFMPP (1 mg/kg) and MCPP (1 mg/kg) inhibited copulatory behavior in male rats. It is concluded that there are sex differences in the effects of TFMPP and MCPP on copulatory behavior in the rat. Moreover, it is suggested that the effects of these drugs on copulatory behavior may be mediated by activation of 5-HT1B and/or 5-HT1C receptors, or by blockade of activity at 5-HT3 receptors.

Methysergide inhibits and facilitates lordosis behavior in the female rat in a time-dependent manner.

Reports in the literature have indicated a facilitatory effect of the serotonin antagonist methysergide on lordosis behavior, suggesting an inhibitory role for serotonergic activity. In the present series of experiments, methysergide (7 mg/kg) was found to inhibit lordosis behavior 30 min after intraperitoneal administration to females, treated chronically with estradiol benzoate, or acutely with estradiol benzoate and progesterone. However, methysergide was found to facilitate lordosis behavior 200 and 300 min after administration to female rats treated acutely with estradiol benzoate. These data suggest a time-dependent inhibitory effect of methysergide, and are consistent with the hypothesis that the activity of serotonin type 2 receptors facilitates lordosis behavior in the female rat.

Neonatal testosterone propionate treatment in the female gerbil: morphological and behavioral effects.

The present experiment examined the effects of a single neonatal injection of 1 mg or 100 micrograms of testosterone propionate (TP) on the sexual behavior and morphology of the female Mongolian gerbil. Four groups were created: vehicle-treated males (VM), 1-mg TP-treated females (HTP), 100-micrograms TP-treated females (LTP), and vehicle-treated females (VF). In adulthood, tests of sexual behavior were carried out after gonadectomy and appropriate hormone replacement therapy. Results indicated that LTP, HTP, and VM animals were significantly less receptive than VF animals. In addition, VM animals displayed significantly more male sexual activity than HTP, LTP, or VF animals. Immediately after the final test for male sexual behavior, subjects were weighed, anogenital distances recorded, and scent glands measured (length and width). Results indicated that a significant degree of morphological masculinization had occurred in HTP subjects for all measures and for LTP subjects for scent gland width and anogenital distance. These findings suggest that in the gerbil, significant morphological masculinization and behavioral defeminization can both occur in teh absence of significant behavioral masculinization.

Effects of 5-HT3 agonists on reproductive behaviors in rats.

Activity at 5-HT1 and 5-HT2 receptor sites influences sexual behavior in male and female rats. 5-HT3 antagonists reportedly have no effect on copulatory activity in rats of either sex although they influence a variety of other behaviors. The effects of 5-HT3 agonists on sexual behavior are unknown. The following experiments were undertaken to assess the influence of the 5-HT3 agonists 1-phenylbiguanide (PBG) and 2-methyl-serotonin (2-Me-5-HT) on sexual behavior, when administered intracerebroventricularly. Consistent with earlier reports indicating that 5-HT1 and 5-HT2 receptor activity influences reproductive activity in a sex-dependent manner, PBG was found to facilitate male, but not female, rat sexual behavior. 2-Me-5-HT, however, failed to modify either female or male rat sexual activity. Evidence that PBG, but not 2-Me-5-HT, induces carrier-mediated dopamine release suggests that the effect of PBG in male rats is due to dopaminergic mediation. Overall, the present data indicate that 5-HT3 receptor activation has only slight effects on rat sexual behavior.

Melatonin protects against the effects of chronic stress on sexual behaviour in male rats.

The effects of chronic mild stress (CMS) on both sexual behaviour and wet dog shakes (WDS), a serotonergic type 2A (5-HT2A) receptor-mediated behaviour, were explored in the male rat. In addition, the possible attenuation of these effects by chronic treatment with melatonin, a putative 5-HT2A antagonist, was examined. The CMS procedure resulted in a significant increase in WDS and an overall decrease in all aspects of sexual behaviour. Concurrent melatonin administration attenuated the CMS-induced effects on sexual behaviour, but not the effects on either spontaneous WDS or WDS in response to the 5-HT2A agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, suggesting a mechanism of action other than exclusive 5-HT2A antagonism. These results are the first to demonstrate that melatonin significantly protects against the detrimental effects of a chronic stressor on sexual behaviour.

Selective activation of opioid receptors differentially affects lordosis behavior in female rats.

The effects of opioid peptides that are highly selective ligands for mu receptors (morphiceptin). delta receptors (delta-receptor peptide), kappa receptors (dynorphin 1-9), and the mu/delta complex (beta-endorphin), were tested on lordosis behavior in ovariectomized rats primed with estrogen and progesterone. Intracerebroventricular infusions of beta-endorphin or morphiceptin both inhibited and facilitated lordosis in a dose-dependent fashion whereas all doses of delta-receptor peptide facilitated lordosis. Dynorphin 1-9 had no significant effect at any dose, although a trend toward increased lordosis quotients was observed 30 min after infusion. The effects of beta-endorphin, morphiceptin, and delta-receptor peptide were reversed with naloxone, although naloxone alone had no effect on lordosis behavior. These results indicate that the specific activation of opioid receptor subtypes differentially affects lordosis behavior. It appears that binding to high-affinity mu 1 receptors exerts an inhibitory influence on lordosis, whereas binding to low-affinity mu 2 receptors or delta receptors exerts a facilitatory influence. Binding to kappa receptors does not appear to affect lordosis behavior.

Short and long term inhibitory actions of alpha-melanocyte stimulating hormone on lordosis in rats.

The effects of 200 ng of intracerebroventricularly (ICV) and 20 micrograms of subcutaneously (SC) administered alpha-melanocyte stimulating hormone (MSH) on lordosis in rats were examined. Previous research, employing crossover designs, has revealed significant effects of MSH on lordosis. The results of Experiments 1a and 1b suggest that similar designs produce significant effects even in the absence of MSH. Thus, it is not clear that previous results were due exclusively to an action of MSH. Experiment 2 employed a modification of previous procedures and indicated that MSH administered either SC or ICV inhibited receptivity in subjects displaying high levels of responding. Moreover, MSH administered SC was also found to facilitate receptivity in subjects displaying low levels of responding. However, a possible long term inhibitory action of MSH on receptivity was also revealed. Because animals were tested repeatedly, this brought into question the results of Experiment 2. Procedures were revised accordingly and the effects of MSH re-examined. The results of Experiment 3 indicated that MSH administered SC facilitated receptivity while MSH administered ICV inhibited receptivity. In addition, MSH administered ICV exerted an inhibitory effect one week after administration. Therefore, MSH appears to exert both short and long-acting effects on sexual receptivity.

Oxytocin-induced facilitation of lordosis behaviour in rats is progesterone-dependent.

Oxytocin was administered intracerebroventricularly to ovariectomized female rats and its effect on lordosis was examined. In Experiment 1a, oxytocin (0.17 mU in 4 microliters saline) failed to facilitate lordosis behaviour in animals primed acutely with 10 micrograms estradiol benzoate (EB) and 300 micrograms progesterone (P). In Experiment 1b, however, oxytocin significantly facilitated lordosis in animals primed acutely with 10 micrograms EB and 250 or 200 micrograms P. In Experiments 2a and 2b, oxytocin failed to facilitate lordosis in animals treated acutely with 10 micrograms EB, or chronically with 0.8 micrograms EB daily for eight days prior to testing. These results support the hypothesis that the facilitation of lordosis in ovariectomized rats by centrally-administered oxytocin is progesterone-dependent.

Oxytocin effects on lordosis frequency and lordosis duration following infusion into the medial pre-optic area and ventromedial hypothalamus of female rats.

When infused into the medial preoptic area of ovariectomized female rats treated with estradiol benzoate (3 micrograms) and progesterone (150 micrograms), oxytocin was found to increase the lordosis frequency and the lordosis duration. Oxytocin administered into the ventromedial hypothalamus increased the lordosis duration but not the lordosis frequency. In the mesencephalic central grey, oxytocin did not significantly affect lordosis. Oxytocin in the ventromedial hypothalamus facilitated lordosis duration at doses which were ineffective in the medial preoptic area. This contrasts with the pattern of results observed for lordosis frequency. These results lend support to the hypothesis that the lordosis-facilitating actions of oxytocin in the ventromedial hypothalamus are due to a permissive effect of progesterone and that the ventromedial hypothalamus and medial pre-optic area may control different aspects of lordosis.

beta-endorphin inhibits and facilitates lordosis behaviour in rats depending on ventricular site of administration.

beta-endorphin was administered intracerebroventricularly into the lateral and third ventricles of ovariectomized, oestrogen- and progesterone-primed rats, and its effect on lordosis and ear-wiggling was assessed. A dose of 2 micrograms beta-endorphin facilitated lordosis when infused into the lateral ventricle, but inhibited lordosis when infused into the third ventricle. The effects were the same whether measured at 30, 60 or 90 min following infusion. beta-endorphin had no significant effect on ear-wiggling frequency when administered in either ventricle. The differential effects of beta-endorphin depending on site of administration may reflect the activation of distinct opioid receptor subtypes within the brain.

Artificial neural network and classical least-squares methods for neurotransmitter mixture analysis.

Identification of individual components in biological mixtures can be a difficult problem regardless of the analytical method employed. In this work, Raman spectroscopy was chosen as a prototype analytical method due to its inherent versatility and applicability to aqueous media, making it useful for the study of biological samples. Artificial neural networks (ANNs) and the classical least-squares (CLS) method were used to identify and quantify the Raman spectra of the small-molecule neurotransmitters and mixtures of such molecules. The transfer functions used by a network, as well as the architecture of a network, played an important role in the ability of the network to identify the Raman spectra of individual neurotransmitters and the Raman spectra of neurotransmitter mixtures. Specifically, networks using sigmoid and hyperbolic tangent transfer functions generalized better from the mixtures in the training data set to those in the testing data sets than networks using sine functions. Networks with connections that permit the local processing of inputs generally performed better than other networks on all the testing data sets. and better than the CLS method of curve fitting, on novel spectra of some neurotransmitters. The CLS method was found to perform well on noisy, shifted, and difference spectra.

Measurement of some small-molecule and peptide neurotransmitters in-vitro using a fiber-optic probe with pulsed ultraviolet resonance Raman spectroscopy.

Many techniques have been developed to investigate the chemistry associated with brain activity. These techniques generally fall into two categories: fast techniques with species-limited sensitivity; and generally slower techniques with broader species sensitivity. Therefore, a need exists for a fast, minimally invasive technique that is sensitive to a wide array of biologically relevant compounds in order to measure chemical brain events in real time. The work presented here describes the development of a novel spectroscopic neurotransmitter probe for the rapid and simultaneous detection of a variety of neurotransmitters. A fiber-optic-linked Raman and tunable ultraviolet resonance Raman system was assembled with custom designed optical fiber probes. Using this system, the ultraviolet resonance Raman spectra of some small-molecule and peptide neurotransmitters were measured in-vitro with a fiber-optic probe and are reported here for the first time. The probe has furthermore been used to measure neurotransmitter secretions obtained from depolarized rat pheochromocytoma (PC12) cells. These results demonstrate the general utility of this approach which, due to the fiber-optic implementation, could potentially also be applied to in-vivo neurotransmitter determinations.

The influence of corticosterone on serotonergic stereotypy and sexual behavior in the female rat.

The effects of adrenalectomy and chronic corticosterone treatment on sexual behavior in the ovariectomized female rat were investigated. The serotonergic type 2A (5-HT2A) receptor-mediated behavior 'wet dog shakes' (WDS) was measured concurrently. In Experiment 1, adrenalectomy reduced the frequency of WDS following the administration of the 5-HT(2A/2C) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) but had no effect on spontaneous WDS. In Experiment 2, chronic corticosterone treatment increased DOI-induced WDS in both adrenalectomized and sham-adrenalectomized rats. In Experiment 3, adrenalectomized and sham-adrenalectomized rats were compared on measures of spontaneous WDS and sexual behavior following the administration of estrogen alone, or estrogen in combination with progesterone. Chronic corticosterone and acute progesterone administration increased WDS and facilitated sexual receptivity and proceptivity, while adrenalectomy decreased WDS, facilitated sexual receptivity and inhibited proceptivity. These findings suggest that the behavioral effects seen following hypothalamic-pituitary-adrenal (HPA) axis disruption may, in part, be mediated by altered 5-HT2A receptor responsivity.

Sexual behavior and wet dog shakes in the male rat: regulation by corticosterone.

The potential involvement of adrenal steroids in the regulation of 'wet dog shakes' (WDS) and sexual behavior was investigated in male rats treated or not with the serotonergic type 2A (5-HT2A) agonist DOI (5-HT2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane). In Experiment 1, the frequency of both spontaneous and DOI-induced WDS were compared in adrenalectomized and sham-adrenalectomized rats. Adrenalectomy significantly reduced the frequency of DOI-induced WDS. In Experiment 2, adrenalectomized and sham-adrenalectomized rats received either corticosterone or oil chronically and were again scored for WDS behavior. Corticosterone effectively blocked the adrenalectomy-induced reduction of WDS in the DOI treatment condition. In Experiment 3, intact male rats were chronically administered either corticosterone or oil treatment. Animals were then compared on measures of both spontaneous and DOI-induced WDS and sexual behavior. Corticosterone significantly increased WDS and inhibited sexual behavior in both the spontaneous and DOI treatment conditions. These results suggest that the adrenal steroid corticosterone is important in the regulation of WDS and sexual behavior in the male rat and that this regulation may be mediated by activity at 5-HT2A receptors.

Effects of 5-HT1A selective anxiolytics on lordosis behavior: interactions with progesterone.

Ipsapirone and gepirone, but not buspirone, facilitated lordosis in estrogen-treated rats, whereas all three drugs inhibited this behavior in rats treated with estrogen and progesterone. When administered at higher doses, ipsapirone, gepirone and buspirone inhibited lordosis in rats treated with either estrogen or estrogen and progesterone. These data are consistent with the proposal that 5-HT1A receptors mediate lordosis-inhibiting effects of 5-HT, and further suggest that some 5-HT1A agonists may facilitate lordosis by activity at autoreceptors. Finally, these data show that progesterone may modulate activity at 5-HT1A receptors.

Intraventricular administration of l-kynurenine and kynuramine facilitates lordosis in the female rat.

Intraventricular administration of the tryptophan metabolites l-kynurenine (2-32 micrograms) and kynuramine (0.064-8 micrograms) facilitated lordosis behavior in estrogen-primed ovariectomized rats. The facilitatory effects of these drugs were not attenuated by pretreatment with the progesterone antagonist RU 38486, indicating that the effects were not mediated by release of adrenal progesterone. It is suggested that l-kynurenine and kynuramine may serve a physiological role in the modulation of female sexual behavior.

Ketanserin attenuates the behavioural effects of corticosterone: implications for 5-HT(2A) receptor regulation.

The effects of chronic corticosterone treatment on sexual behaviour and wet-dog shakes were investigated in both female and male rats. The serotonergic type 2A (5-HT(2A)) receptor antagonist ketanserin was administered to test the hypothesis that the behavioural effects of corticosterone were mediated by increased 5-HT(2A) receptor activity. Rats were randomly assigned to one of four chronic treatment groups: control, ketanserin alone, corticosterone alone, or ketanserin and corticosterone. Ketanserin attenuated the corticosterone-induced changes in both sexual behaviour and wet-dog shakes. Ketanserin alone had no effect on these behaviours. Results suggest that increased 5-HT(2A) receptor activity mediates the effects of corticosterone on sexual behaviour and wet-dog shakes.

Paradoxical effects of chronic corticosterone on forced swim behaviours in aged male and female rats.

The effects of chronically administered corticosterone on forced swim test and open field test behaviours were explored in aged male and female rats. Though corticosterone has typically been associated with depressive behaviours, recent data have suggested a putative antidepressive effect of corticosterone. The current study used the forced swim test as a model of antidepressant efficacy in order to explore this. Aged male and female rats received either corticosterone (20 mg/kg) or the vehicle for 10 days before testing in the forced swim test, then for an additional 3 days before testing in the open field test. On day 11, each animal was individually tested on the duration of swimming, immobile, and struggling behaviours, and on day 14, for the display of rearing and line crossing behaviours. Results revealed that corticosterone significantly increased swimming and decreased immobility behaviour in females, but failed to do so in males. Additionally, there was a main effect of corticosterone on struggling behaviour such that it decreased it in males. There were no effects of corticosterone or sex on open field test behaviours, suggesting that the present findings are not accounted for by a general effect of corticosterone on motor behaviour. Overall, the data suggest that chronically administered corticosterone possesses effects that are sex-specific, and that it may exert mildly antidepressive effects in females, but the opposite effects in males. These data are consistent with emerging evidence that corticosterone may play a paradoxical antidepressive effect.