Pharmacology Biochemistry and Behavior, Apr 30, 1994
AGMO, A., M. GOMEZ AND Y. IRAZABAL. Enkephalinase inhibition facilitates sexual behavior in the m... more AGMO, A., M. GOMEZ AND Y. IRAZABAL. Enkephalinase inhibition facilitates sexual behavior in the male rat but does not produce conditioned place preference. PHARMACOL BIOCHEM BEHAV 47(4) [771][772][773][774][775][776][777][778] 1994.-The effects of two enkephalina~ inhibitors, SCH 34826 and phospho-leu-phe, on male rat sexual behavior and conditioned place preference were evaluated. SCH 34826, administered intraperitoneally, reduced the ejaculation latency to both the first and second ejaculation at a dose of 30 mg/kg. This dose also reduced the first postejaculatory interval. No other effect was obtained with this drug. Phospho-leu-phe, administered intracerebroventricularly, increased mount and intromission latency at doses of 50 and 100/~g. A dose of 25 /~g reduced the latency to the first ejaculation as well as the number of preejaculatory intromissions. The postejaculatory interval was also reduced at this dose. SCH 34826, 100 and 30 mg/kg, and phospho-len--phe, 25 ~tg, had no effect in the conditioned place preference procedure. These observations seem to suggest that there is no functionally relevant tonic release of enkephalins. Therefore, the effects obtained on sexual behavior may indicate that enkephalins are released before and during the course of sexual activity. The function of such a release could be to facilitate ejaculatory mechanisms in the way found in the present studies. Previous work has shown that ejaculation-induced reward is opioid dependent, further supporting the hypothesis of opioid release during sexual activity. Taken together, these data suggest an important role for opioids, probably enkephalins, in the physiological control of sexual behavior.
Sexual behavior was evaluated in sexually experienced male rabbits after the administration of di... more Sexual behavior was evaluated in sexually experienced male rabbits after the administration of different serotonergic drugs. The serotonin 1A receptor agonist 8-OH-DPAT, 1 mg/kg, inhibited male rabbit sexual behavior when animals were tested 15 min after subcutaneous (SC) administration of this compound. Lower doses, 0.25 and 0.5 mg/kg, were ineffective at a test 30 min after drug injection. Furthermore, 8-OH-DPAT, 0.25 mg/kg, failed to revert the inhibitory effects upon sexual behavior produced by lidocaine application to the rabbit penis. Stimulation of 5-HT 1B/2C receptors by TFMPP, at doses between 0.625 and 2.5 mg/kg, produced a drastic inhibition of sexual behavior when the drug was administered SC 30 min before behavioral observation. Doses below 5 mg/kg were ineffective when given intraperitoneally 15 min before test. When the 5-HT 1D/2C receptors were stimulated by the agonist mCPP a reduced number of mounts and ejaculations was observed after the SC administration of 1.25 and 2.5 mg/kg. Similarly, the mixed 5-HT agonist/antagonist lisuride reduced the percentage of rabbits displaying mounting behavior at doses of 0.25 and 0.5 mg/kg SC. All compounds tested produced a clear inhibition of male rabbit sexual behavior independently of the receptor subtype activated. These results are at variance with previous observations in rats where 8-OH-DPAT and lisuride produced a drastic facilitation of masculine coital behavior. Moreover, while the inhibition of male sexual behavior in rats produced by TFMPP and mCPP is associated with a disruption of the execution of this behavior, in rabbits these compounds reduced sexual motivation. These results indicate that the effects of serotonergic drugs on sexual behavior are species specific.
Pharmacology Biochemistry and Behavior, Aug 31, 1988
AGMO, A. AND R. PAREDES. Opioids and sexual behavior in the male rat. PHARMACOL BIOCHEM BEHAV 30(... more AGMO, A. AND R. PAREDES. Opioids and sexual behavior in the male rat. PHARMACOL BIOCHEM BEHAV 30(4) 1021-1034, 1988.--Naloxone in the doses of 4 or 16 mg/kg failed to affect copulatory behavior of testosterone-treated castrated male rats. Morphine 10 mg/kg, administered 60 min before behavioral observation, reduced the proportion of animals displaying sexual behavior. Doses of 2.5 or 5 mg/kg reduced the latency to the second ejaculation, whereas the few animals still copulating after morphine 10 mg/kg showed a reduced latency to the first ejaculation. The same doses of morphine administered 5 min before behavioral observation produced a dose-dependent reduction of mount, intromission and ejaculation percentages. However, those animals that did copulate showed a normal copulatory behavior. D-Ala2-Met 5 enkephalinamide (DALA) infused into the left cerebral ventricle in a dose of 5/xg 5 or 60 min before tests had no effect. When the peptide was infused 30 sec after the first intromission, the number of intromissions as well as the latency to ejaculation were reduced. Opioids may facilitate ejaculatory mechanisms, perhaps as a consequence of their rewarding properties. Moreover, in animals treated with DALA after the first intromission, the number of intromissions and the latency to ejaculation were similar for the first and second copulatory series, while these parameters were much reduced upon the second ejaculation for control animals. It is possible that liberation of endogenous opioids is the cause of ejaculation-induced facilitation of subsequent sexual behavior.
Progabide inhibited male rat sexual behavior at a dose of 200 mg / kg. This dose had only modest ... more Progabide inhibited male rat sexual behavior at a dose of 200 mg / kg. This dose had only modest effects on ambulatory activity and no effect at all on motor coordination as evaluated by a rotarod test. The GABA A antagonist bicuculline, at a dose of 1 mg / kg, blocked the effects of progabide on sex behavior. In contrast, the GABA B antagonist CGP 35348, at doses of 50 and 100 mg / kg, was ineffective. These doses have previously been shown to block the actions of baclofen on sexual behavior. It was concluded that the GABA A but not the GABA B receptor is important for the inhibitory effects of progabide on that behavior. The actions of progabide on ambulatory activity were not blocked by bicuculline or CGP 35348 at any of the doses used (up to 2 and 200 mg / kg, respectively). Even the combination of both antagonists was ineffective. This suggests that the motor effects of progabide are mediated by either a non-GABAergic receptor or by a subtype of the GABA A or the GABA B receptor that is not sensitive to the antagonists. Present results show that the effects of progabide on motor functions depend on mechanisms different from those involved in its effects on sexual behavior. They further suggest that the GABA A receptor may be important for drug actions on male sexual behavior.
Methods in molecular biology (Clifton, N.J.), 2016
The ability to silence the expression of gene products in a chemically, spatially, and temporally... more The ability to silence the expression of gene products in a chemically, spatially, and temporally specific manner in the brains of animals has enabled key breakthroughs in the field of behavioral neuroscience. Using this technique, estrogen receptor alpha (ERα) has been specifically implicated in a multitude of behaviors in mice, including sexual, aggressive, locomotor, and maternal behaviors. ERα has been identified in a variety of brain regions, including the medial preoptic area, ventromedial hypothalamus, and amygdala. In this chapter we describe the techniques involved in the generation of the small hairpin RNAs (shRNAs) specifically designed to silence ERα, the construction of the adeno-associated viral (AAV) vector for delivery of the shRNA, the procedures to confirm the silencing of ERα (in vitro and in vivo) and in vivo delivery of the shRNAs to the brains of animals.
General arousal has been operationally defined as an enhanced motor activity and enhanced intensi... more General arousal has been operationally defined as an enhanced motor activity and enhanced intensity of response to sensory stimuli. Even though the effects of gonadal hormones on mating behavior have been much studied, their potential effect on generalized arousal, as defined above, has never been evaluated. In the present study we employed a thoroughly validated assay of general arousal to determine the effects of estradiol (E) and testosterone (T) in gonadectomized female and male mice, respectively. The steroids were administered in three different ways: A fast-acting, water soluble preparation given intraperitoneally, an oil solution given subcutaneously, and an oil solution in a subcutaneous Silastic capsule. Motor activity and responses to sensory stimuli were recorded for 24h, 91h, and seven days following hormone administration, respectively. All measures of arousal varied according to the day/night cycle. The water soluble steroid preparation had no reliable effect. When the same doses of estradiol and testosterone were administered subcutaneously in an oil vehicle no effect of either treatment on arousal was observed. The subcutaneously implanted capsule containing estradiol or testosterone had a delayed effect on motor activity in females (four to seven days) but no effect in males. The long time required by the gonadal hormones for affecting arousal would be consistent with, but does not prove, a genomic action. The limited effects of E and T in our arousal assay suggest to us that the strongest actions of these hormones on arousal occur in the context of sequences of responses to sexually relevant stimuli.
Previous studies have shown that the opiate antagonist naloxone blocks the anxiolytic-like effect... more Previous studies have shown that the opiate antagonist naloxone blocks the anxiolytic-like effects of benzodiazepines in several models of anxiety, including the elevated plus-maze. Although naloxone preferentially binds to the mu opioid receptor, its selectivity is rather low. The opioid receptor subtype important for anxiolytic-like actions of benzodiazepines in the plus-maze remains, therefore, unknown. In the present experiments, the ability of antagonists selective for subtypes of the opioid receptor to block the anxiolytic-like effects of chlordiazepoxide in the elevated plus-maze was evaluated in Swiss mice. Chlordiazepoxide, 5 mg/kg, increased the proportion as well as the number of open arms entries without modifying closed arms entries. Lower doses of the benzodiazepine were ineffective. The mu receptor antagonist beta-funaltrexamine, 10 and 20 mg/kg, the delta antagonist naltrindole, 10 mg/kg, and the kappa antagonist nor-binaltorphimine, 2.5 and 5 mg/kg, were then combin...
The administration of GABA--transaminase inhibitors (GABA-TIs) to male rats reduces the proportio... more The administration of GABA--transaminase inhibitors (GABA-TIs) to male rats reduces the proportion of mounts that result in intromissions. Copulatory pelvic thrusting remains normal, despite the fact that animals treated with GABA-TIs show gross deficiencies in other motor acts. In order to determine whether altered sexual behavior produced by GABA-TI could be due to deficiencies in activity of striated penile muscles, we recorded the electromyographic (EMG) activity of the ischiocavernosus (IC) muscle during copulation in male rats treated with sodium valproate. The duration of IC EMG bursts was reduced by sodium valproate in separate tests that allowed or prevented intromission. There was no effect on EMG amplitude or frequency. It is suggested that insufficient activity of the IC muscles reduces the likelihood of vaginal penetration. The actions of GABA may be localized to hypothalamic or brain stem nuclei with GA-BAergic projections to the spinal motoneurons controlling the IC muscles, or GABA may act directly on these neurons.
PAREDES, R. G. AND A. AGMO. GABA and behavior: The role of receptor subtypes. NEUROSCI BIOBEHAV R... more PAREDES, R. G. AND A. AGMO. GABA and behavior: The role of receptor subtypes. NEUROSCI BIOBEHAV REV 16 145-170, 1992.--The discovery of different GABA receptor subtypes has stimulated research relating this neurotransmitter to a variety of behavioral functions and clinical disorders. The development of new and specific GABAergic compounds has made it possible to try to identify the specific functions of these receptors. The purpose of the present review is to evaluate the data regarding the functions of the GABA receptor subtypes in different behaviors such as motor function, reproduction, learning and memory, and aggressive-defensive behaviors. A description of GABAergic functions (stress, peripheral effects, thermoregulation) that might directly or indirectly affect behavior is also included. The possible involvement of GABA in different neurological and psychiatric disorders is also discussed. Although much research has been done trying to identify the possible role of GABA in different behaviors, the role of receptor subtypes has only recently attracted attention, and only preliminary data are available at present. It is therefore evident that still much work has to be done before a clear picture of the behavioral significance of these receptor subtypes can be obtained. Nevertheless, existing data are sufficient to justify the prediction that GABAergic agents, in the near future, will be much used in the field of behavioral pharmacology. It is hoped that the present review will contribute to this. Some specific suggestions concerning the most efficient way to pursue future research are also made.
The effects of reduced somatosensory feedback from the penis and/or the preputial region upon the... more The effects of reduced somatosensory feedback from the penis and/or the preputial region upon the male rat's copulatory thrusting patterns and sexual behavior were analyzed. Copulatory thrusting was recorded with an accelerometric technique allowing for the determination of duration and frequency of the thrusting trains. Section of the dorsal penile nerves (denervation) or lidocaine applied to the distal part of the penis reduced the number of intromissions and the intromission ratio. These treatments had no effect on copulatory thrusting patterns. Lidocaine injected into the preputial region also reduced the number of intromissions and the intromission ratio. Moreover, the number of disorganized mounts, as revealed by the accelerometric record, was much increased by this treatment. In addition, the duration of the thrusting trains associated with mount and intromission was increased. No effect was found on thrusting frequency. These data suggest that somatosensory feedback from the penis is critical for the achievement of intromission, whereas feedback from the preputial region is important for the execution of copulatory thrusting. Furthermore, it is possible that the strong sensory stimulation of the prepuce associated with penile insertion participates in the termination of thrusting and penile withdrawal.
The locomotion-reducing effect of the GABAB agonist baclofen was compared with that of the GABAA ... more The locomotion-reducing effect of the GABAB agonist baclofen was compared with that of the GABAA agonists, aminopropanesulfonic acid (APSA) and THIP. It was found that baclofen was more potent than the other drugs. After intraventricular injection, baclofen induced almost complete immobility, whereas APSA did not affect locomotor activity. THIP had an intermediate effect. The GABA transaminase inhibitor gamma-acetylenic GABA (GAG) provoked a dose-dependent reduction of locomotion. Neither the effects of THIP nor those of GAG could be blocked by concurrent administration of bicuculline. The antagonist itself did not affect locomotor activity. It is concluded that the GABAA receptor is not important for the locomotion-reducing effects of GABAergic drugs.
The behavioral effects of racemic baclofen and the R and s enantiomers were studied in order to d... more The behavioral effects of racemic baclofen and the R and s enantiomers were studied in order to determine whether the stereospecificity found in receptor binding studies also applies to the behavioral actions of the drug. Racemic and R-baclofen inhibited sexual behavior, locomotor activity and motor execution at relatively low doses while s-baclofen was completely inactive even when a dose 40 times higher than the minimum effective dose of R-baclofen was used. The R enantiomer seems to be twice as active as racemic baclofen. These data strongly suggest that the behavioral effects of baclofen are the result of an action at the GABA-B receptor. In order to differentiate the effects of baclofen on sexual interactions from those on nonspecific social interactions, the sociosexual behavior was observed with a castrated male or a receptive female as stimulus animal. ~, s-baclofen had effects only upon sociosexual interaction with a receptive female. Moreover, the inhibitory effects of baclofen were restricted to behavioral items related to sexual interactions, primarily those constituting precopulatory behaviors. Since no effect was observed in social interactions with a castrated male, it is suggested that the inhibition of sociosexual behavior is not a consequence of impairment of motor execution. Rather it appears that baclofen has a specific inhibitory effect on behaviors associated with the initiation of copulatory activity. Therefore, once initiated, sexual behavior was not significantly modified by baclofen.
The role of dopaminergic systems in the control of sexual behavior has been a subject of study fo... more The role of dopaminergic systems in the control of sexual behavior has been a subject of study for at least 40 years. Not surprisingly, reviews of the area have been published at variable intervals. However, the earlier reviews have been summaries of published research rather than a critical analysis of it. They have focused upon the conclusions presented in the original research papers rather than on evaluating the reliability and functional significance of the data reported to support these conclusions. During the last few years, important new knowledge concerning dopaminergic systems and their behavioral functions as well as the possible role of these systems in sexual behavior has been obtained. For the first time, it is now possible to integrate the data obtained in studies of sexual behavior into the wider context of general dopaminergic functions. To make this possible, we first present an analysis of the nature and organization of sexual behavior followed by a summary of current knowledge about the brain structures of crucial importance for this behavior. We then proceed with a description of the dopaminergic systems within or projecting to these structures. Whenever possible, we also try to include data on the electrophysiological actions of dopamine. Thereafter, we proceed with analyses of pharmacological data and release studies, both in males and in females. Consistently throughout this discussion, we make an effort to distinguish pharmacological effects on sexual behavior from a possible physiological role of dopamine. By pharmacological effects, we mean here drug-induced alterations in behavior that are not the result of the normal actions of synaptically released dopamine in the untreated animal. The conclusion of this endeavor is that pharmacological effects of dopaminergic drugs are variable in both males and females, independently of whether the drugs are administered systemically or intracerebrally. We conclude that the pharmacological data basically reinforce the notion that dopamine is important for motor functions and general arousal. These actions could, in fact, explain most of the effects seen on sexual behavior. Studies of dopamine release, in both males and females, have focused on the nucleus accumbens, a structure with at most a marginal importance for sexual behavior. Since accumbens dopamine release is associated with all kinds of events, aversive as well as appetitive, it can have no specific effect on sexual behavior but promotes arousal and activation of non-specific motor patterns. Preoptic and paraventricular nucleus release of dopamine may have some relationship to mechanisms of ejaculation or to the neuroendocrine consequences of sexual activity or they can be related to other autonomic processes associated with copulation. There is no compelling indication in existing experimental data that dopamine is of any particular importance for sexual motivation. There is experimental evidence showing that it is of no importance for sexual reward.
~GMO, A., J. L. CONTRERAS AND R. PAREDES. Sexual behavior and copulatory thrusting patterns in ma... more ~GMO, A., J. L. CONTRERAS AND R. PAREDES. Sexual behavior and copulatory thrusting patterns in male rabbits treated with GABA transaminase inhibitors. PHYSIOL BEHAV 49(1) 73-78, 1991.--The effects of enhanced central nervous system GABA levels on sexual behavior and copulatory pelvic thrusting were evaluated in male New Zealand white rabbits. The GABA transaminase inhibitors sodium valproate and ~/-acetylen GABA (GAG), in doses of 100 and 200 mg/kg and 50 and 100 mg/kg, respectively, were intraperitoneally administered and sexual behavior recorded at several intervals after drug administration. At the same time, copulatory thrusting was registered using a polygraphic technique. Tests for gross motor functions were also performed. None of the drugs had any effect in these latter tests. Sodium valproate, in a dose of 100 mg/kg, had a slight inhibitory effect on sexual behavior at 280 min postinjection. A dose of 200 mg/kg inhibited sexual activity already 15 min postinjection, and the effect lasted for at least 280 min. GAG, 100 mg/kg, inhibited mounting behavior at 8 h postinjection, and ejaculation was reduced from 2 to at least 8 h postinjection. Copulatory thrusting patterns were not affected by the drug treatments. These data suggest that increased GABAergic activity reduces sexual arousal in the rabbit. GABA does not seem to be critically involved in the regulation of the motor patterns underlying pelvic thrusting. There are important quantitative and qualitative differences between rats and rabbits with regard to the actions of GABA transaminase inhibitors upon sexual functions.
Premature ejaculation is the most common sexual disorder in young men. Consequently, there is an ... more Premature ejaculation is the most common sexual disorder in young men. Consequently, there is an intense search for efficient and safe pharmacological treatments. Insofar, almost no effective treatment with acute effects is available. In this study, we evaluated the effects of the noradrenergic α 2 receptor agonist dexmedetomidine on sexual incentive motivation and copulatory behavior in male rats. Sexual incentive motivation was tested in a large rectangular arena connected to two small incentive stimulus cages containing either a male or sexually receptive female rat. There was no sexual interaction possible between the experimental subjects and the incentives during this test. Approach to the incentives constituted the measure of sexual incentive motivation. After the sexual incentive motivation test, the subjects were tested for copulatory behavior in a regular copulation test for 30 min. Doses of 0.1 and 1 μg/kg of dexmedetomidine (i.p.) had no effect on any of the indices of locomotor activity or on parameters of sexual incentive motivation. With regard to copulatory behavior, it was found that the dose of 1 μg/kg prolonged the latency to the first ejaculation, while the latency to second ejaculation showed a tendency to increase. The absence of an effect on indices of sexual incentive motivation or general activity showed that the actions of dexmedetomidine in this study were limited to ejaculatory mechanisms. Insofar as the ejaculation latency in the male rat is predictive of prolonged ejaculation latency in men, it can be proposed that dexmedetomidine is of potential utility for the treatment of premature ejaculation.
Pharmacology Biochemistry and Behavior, Apr 30, 1994
AGMO, A., M. GOMEZ AND Y. IRAZABAL. Enkephalinase inhibition facilitates sexual behavior in the m... more AGMO, A., M. GOMEZ AND Y. IRAZABAL. Enkephalinase inhibition facilitates sexual behavior in the male rat but does not produce conditioned place preference. PHARMACOL BIOCHEM BEHAV 47(4) [771][772][773][774][775][776][777][778] 1994.-The effects of two enkephalina~ inhibitors, SCH 34826 and phospho-leu-phe, on male rat sexual behavior and conditioned place preference were evaluated. SCH 34826, administered intraperitoneally, reduced the ejaculation latency to both the first and second ejaculation at a dose of 30 mg/kg. This dose also reduced the first postejaculatory interval. No other effect was obtained with this drug. Phospho-leu-phe, administered intracerebroventricularly, increased mount and intromission latency at doses of 50 and 100/~g. A dose of 25 /~g reduced the latency to the first ejaculation as well as the number of preejaculatory intromissions. The postejaculatory interval was also reduced at this dose. SCH 34826, 100 and 30 mg/kg, and phospho-len--phe, 25 ~tg, had no effect in the conditioned place preference procedure. These observations seem to suggest that there is no functionally relevant tonic release of enkephalins. Therefore, the effects obtained on sexual behavior may indicate that enkephalins are released before and during the course of sexual activity. The function of such a release could be to facilitate ejaculatory mechanisms in the way found in the present studies. Previous work has shown that ejaculation-induced reward is opioid dependent, further supporting the hypothesis of opioid release during sexual activity. Taken together, these data suggest an important role for opioids, probably enkephalins, in the physiological control of sexual behavior.
Sexual behavior was evaluated in sexually experienced male rabbits after the administration of di... more Sexual behavior was evaluated in sexually experienced male rabbits after the administration of different serotonergic drugs. The serotonin 1A receptor agonist 8-OH-DPAT, 1 mg/kg, inhibited male rabbit sexual behavior when animals were tested 15 min after subcutaneous (SC) administration of this compound. Lower doses, 0.25 and 0.5 mg/kg, were ineffective at a test 30 min after drug injection. Furthermore, 8-OH-DPAT, 0.25 mg/kg, failed to revert the inhibitory effects upon sexual behavior produced by lidocaine application to the rabbit penis. Stimulation of 5-HT 1B/2C receptors by TFMPP, at doses between 0.625 and 2.5 mg/kg, produced a drastic inhibition of sexual behavior when the drug was administered SC 30 min before behavioral observation. Doses below 5 mg/kg were ineffective when given intraperitoneally 15 min before test. When the 5-HT 1D/2C receptors were stimulated by the agonist mCPP a reduced number of mounts and ejaculations was observed after the SC administration of 1.25 and 2.5 mg/kg. Similarly, the mixed 5-HT agonist/antagonist lisuride reduced the percentage of rabbits displaying mounting behavior at doses of 0.25 and 0.5 mg/kg SC. All compounds tested produced a clear inhibition of male rabbit sexual behavior independently of the receptor subtype activated. These results are at variance with previous observations in rats where 8-OH-DPAT and lisuride produced a drastic facilitation of masculine coital behavior. Moreover, while the inhibition of male sexual behavior in rats produced by TFMPP and mCPP is associated with a disruption of the execution of this behavior, in rabbits these compounds reduced sexual motivation. These results indicate that the effects of serotonergic drugs on sexual behavior are species specific.
Pharmacology Biochemistry and Behavior, Aug 31, 1988
AGMO, A. AND R. PAREDES. Opioids and sexual behavior in the male rat. PHARMACOL BIOCHEM BEHAV 30(... more AGMO, A. AND R. PAREDES. Opioids and sexual behavior in the male rat. PHARMACOL BIOCHEM BEHAV 30(4) 1021-1034, 1988.--Naloxone in the doses of 4 or 16 mg/kg failed to affect copulatory behavior of testosterone-treated castrated male rats. Morphine 10 mg/kg, administered 60 min before behavioral observation, reduced the proportion of animals displaying sexual behavior. Doses of 2.5 or 5 mg/kg reduced the latency to the second ejaculation, whereas the few animals still copulating after morphine 10 mg/kg showed a reduced latency to the first ejaculation. The same doses of morphine administered 5 min before behavioral observation produced a dose-dependent reduction of mount, intromission and ejaculation percentages. However, those animals that did copulate showed a normal copulatory behavior. D-Ala2-Met 5 enkephalinamide (DALA) infused into the left cerebral ventricle in a dose of 5/xg 5 or 60 min before tests had no effect. When the peptide was infused 30 sec after the first intromission, the number of intromissions as well as the latency to ejaculation were reduced. Opioids may facilitate ejaculatory mechanisms, perhaps as a consequence of their rewarding properties. Moreover, in animals treated with DALA after the first intromission, the number of intromissions and the latency to ejaculation were similar for the first and second copulatory series, while these parameters were much reduced upon the second ejaculation for control animals. It is possible that liberation of endogenous opioids is the cause of ejaculation-induced facilitation of subsequent sexual behavior.
Progabide inhibited male rat sexual behavior at a dose of 200 mg / kg. This dose had only modest ... more Progabide inhibited male rat sexual behavior at a dose of 200 mg / kg. This dose had only modest effects on ambulatory activity and no effect at all on motor coordination as evaluated by a rotarod test. The GABA A antagonist bicuculline, at a dose of 1 mg / kg, blocked the effects of progabide on sex behavior. In contrast, the GABA B antagonist CGP 35348, at doses of 50 and 100 mg / kg, was ineffective. These doses have previously been shown to block the actions of baclofen on sexual behavior. It was concluded that the GABA A but not the GABA B receptor is important for the inhibitory effects of progabide on that behavior. The actions of progabide on ambulatory activity were not blocked by bicuculline or CGP 35348 at any of the doses used (up to 2 and 200 mg / kg, respectively). Even the combination of both antagonists was ineffective. This suggests that the motor effects of progabide are mediated by either a non-GABAergic receptor or by a subtype of the GABA A or the GABA B receptor that is not sensitive to the antagonists. Present results show that the effects of progabide on motor functions depend on mechanisms different from those involved in its effects on sexual behavior. They further suggest that the GABA A receptor may be important for drug actions on male sexual behavior.
Methods in molecular biology (Clifton, N.J.), 2016
The ability to silence the expression of gene products in a chemically, spatially, and temporally... more The ability to silence the expression of gene products in a chemically, spatially, and temporally specific manner in the brains of animals has enabled key breakthroughs in the field of behavioral neuroscience. Using this technique, estrogen receptor alpha (ERα) has been specifically implicated in a multitude of behaviors in mice, including sexual, aggressive, locomotor, and maternal behaviors. ERα has been identified in a variety of brain regions, including the medial preoptic area, ventromedial hypothalamus, and amygdala. In this chapter we describe the techniques involved in the generation of the small hairpin RNAs (shRNAs) specifically designed to silence ERα, the construction of the adeno-associated viral (AAV) vector for delivery of the shRNA, the procedures to confirm the silencing of ERα (in vitro and in vivo) and in vivo delivery of the shRNAs to the brains of animals.
General arousal has been operationally defined as an enhanced motor activity and enhanced intensi... more General arousal has been operationally defined as an enhanced motor activity and enhanced intensity of response to sensory stimuli. Even though the effects of gonadal hormones on mating behavior have been much studied, their potential effect on generalized arousal, as defined above, has never been evaluated. In the present study we employed a thoroughly validated assay of general arousal to determine the effects of estradiol (E) and testosterone (T) in gonadectomized female and male mice, respectively. The steroids were administered in three different ways: A fast-acting, water soluble preparation given intraperitoneally, an oil solution given subcutaneously, and an oil solution in a subcutaneous Silastic capsule. Motor activity and responses to sensory stimuli were recorded for 24h, 91h, and seven days following hormone administration, respectively. All measures of arousal varied according to the day/night cycle. The water soluble steroid preparation had no reliable effect. When the same doses of estradiol and testosterone were administered subcutaneously in an oil vehicle no effect of either treatment on arousal was observed. The subcutaneously implanted capsule containing estradiol or testosterone had a delayed effect on motor activity in females (four to seven days) but no effect in males. The long time required by the gonadal hormones for affecting arousal would be consistent with, but does not prove, a genomic action. The limited effects of E and T in our arousal assay suggest to us that the strongest actions of these hormones on arousal occur in the context of sequences of responses to sexually relevant stimuli.
Previous studies have shown that the opiate antagonist naloxone blocks the anxiolytic-like effect... more Previous studies have shown that the opiate antagonist naloxone blocks the anxiolytic-like effects of benzodiazepines in several models of anxiety, including the elevated plus-maze. Although naloxone preferentially binds to the mu opioid receptor, its selectivity is rather low. The opioid receptor subtype important for anxiolytic-like actions of benzodiazepines in the plus-maze remains, therefore, unknown. In the present experiments, the ability of antagonists selective for subtypes of the opioid receptor to block the anxiolytic-like effects of chlordiazepoxide in the elevated plus-maze was evaluated in Swiss mice. Chlordiazepoxide, 5 mg/kg, increased the proportion as well as the number of open arms entries without modifying closed arms entries. Lower doses of the benzodiazepine were ineffective. The mu receptor antagonist beta-funaltrexamine, 10 and 20 mg/kg, the delta antagonist naltrindole, 10 mg/kg, and the kappa antagonist nor-binaltorphimine, 2.5 and 5 mg/kg, were then combin...
The administration of GABA--transaminase inhibitors (GABA-TIs) to male rats reduces the proportio... more The administration of GABA--transaminase inhibitors (GABA-TIs) to male rats reduces the proportion of mounts that result in intromissions. Copulatory pelvic thrusting remains normal, despite the fact that animals treated with GABA-TIs show gross deficiencies in other motor acts. In order to determine whether altered sexual behavior produced by GABA-TI could be due to deficiencies in activity of striated penile muscles, we recorded the electromyographic (EMG) activity of the ischiocavernosus (IC) muscle during copulation in male rats treated with sodium valproate. The duration of IC EMG bursts was reduced by sodium valproate in separate tests that allowed or prevented intromission. There was no effect on EMG amplitude or frequency. It is suggested that insufficient activity of the IC muscles reduces the likelihood of vaginal penetration. The actions of GABA may be localized to hypothalamic or brain stem nuclei with GA-BAergic projections to the spinal motoneurons controlling the IC muscles, or GABA may act directly on these neurons.
PAREDES, R. G. AND A. AGMO. GABA and behavior: The role of receptor subtypes. NEUROSCI BIOBEHAV R... more PAREDES, R. G. AND A. AGMO. GABA and behavior: The role of receptor subtypes. NEUROSCI BIOBEHAV REV 16 145-170, 1992.--The discovery of different GABA receptor subtypes has stimulated research relating this neurotransmitter to a variety of behavioral functions and clinical disorders. The development of new and specific GABAergic compounds has made it possible to try to identify the specific functions of these receptors. The purpose of the present review is to evaluate the data regarding the functions of the GABA receptor subtypes in different behaviors such as motor function, reproduction, learning and memory, and aggressive-defensive behaviors. A description of GABAergic functions (stress, peripheral effects, thermoregulation) that might directly or indirectly affect behavior is also included. The possible involvement of GABA in different neurological and psychiatric disorders is also discussed. Although much research has been done trying to identify the possible role of GABA in different behaviors, the role of receptor subtypes has only recently attracted attention, and only preliminary data are available at present. It is therefore evident that still much work has to be done before a clear picture of the behavioral significance of these receptor subtypes can be obtained. Nevertheless, existing data are sufficient to justify the prediction that GABAergic agents, in the near future, will be much used in the field of behavioral pharmacology. It is hoped that the present review will contribute to this. Some specific suggestions concerning the most efficient way to pursue future research are also made.
The effects of reduced somatosensory feedback from the penis and/or the preputial region upon the... more The effects of reduced somatosensory feedback from the penis and/or the preputial region upon the male rat's copulatory thrusting patterns and sexual behavior were analyzed. Copulatory thrusting was recorded with an accelerometric technique allowing for the determination of duration and frequency of the thrusting trains. Section of the dorsal penile nerves (denervation) or lidocaine applied to the distal part of the penis reduced the number of intromissions and the intromission ratio. These treatments had no effect on copulatory thrusting patterns. Lidocaine injected into the preputial region also reduced the number of intromissions and the intromission ratio. Moreover, the number of disorganized mounts, as revealed by the accelerometric record, was much increased by this treatment. In addition, the duration of the thrusting trains associated with mount and intromission was increased. No effect was found on thrusting frequency. These data suggest that somatosensory feedback from the penis is critical for the achievement of intromission, whereas feedback from the preputial region is important for the execution of copulatory thrusting. Furthermore, it is possible that the strong sensory stimulation of the prepuce associated with penile insertion participates in the termination of thrusting and penile withdrawal.
The locomotion-reducing effect of the GABAB agonist baclofen was compared with that of the GABAA ... more The locomotion-reducing effect of the GABAB agonist baclofen was compared with that of the GABAA agonists, aminopropanesulfonic acid (APSA) and THIP. It was found that baclofen was more potent than the other drugs. After intraventricular injection, baclofen induced almost complete immobility, whereas APSA did not affect locomotor activity. THIP had an intermediate effect. The GABA transaminase inhibitor gamma-acetylenic GABA (GAG) provoked a dose-dependent reduction of locomotion. Neither the effects of THIP nor those of GAG could be blocked by concurrent administration of bicuculline. The antagonist itself did not affect locomotor activity. It is concluded that the GABAA receptor is not important for the locomotion-reducing effects of GABAergic drugs.
The behavioral effects of racemic baclofen and the R and s enantiomers were studied in order to d... more The behavioral effects of racemic baclofen and the R and s enantiomers were studied in order to determine whether the stereospecificity found in receptor binding studies also applies to the behavioral actions of the drug. Racemic and R-baclofen inhibited sexual behavior, locomotor activity and motor execution at relatively low doses while s-baclofen was completely inactive even when a dose 40 times higher than the minimum effective dose of R-baclofen was used. The R enantiomer seems to be twice as active as racemic baclofen. These data strongly suggest that the behavioral effects of baclofen are the result of an action at the GABA-B receptor. In order to differentiate the effects of baclofen on sexual interactions from those on nonspecific social interactions, the sociosexual behavior was observed with a castrated male or a receptive female as stimulus animal. ~, s-baclofen had effects only upon sociosexual interaction with a receptive female. Moreover, the inhibitory effects of baclofen were restricted to behavioral items related to sexual interactions, primarily those constituting precopulatory behaviors. Since no effect was observed in social interactions with a castrated male, it is suggested that the inhibition of sociosexual behavior is not a consequence of impairment of motor execution. Rather it appears that baclofen has a specific inhibitory effect on behaviors associated with the initiation of copulatory activity. Therefore, once initiated, sexual behavior was not significantly modified by baclofen.
The role of dopaminergic systems in the control of sexual behavior has been a subject of study fo... more The role of dopaminergic systems in the control of sexual behavior has been a subject of study for at least 40 years. Not surprisingly, reviews of the area have been published at variable intervals. However, the earlier reviews have been summaries of published research rather than a critical analysis of it. They have focused upon the conclusions presented in the original research papers rather than on evaluating the reliability and functional significance of the data reported to support these conclusions. During the last few years, important new knowledge concerning dopaminergic systems and their behavioral functions as well as the possible role of these systems in sexual behavior has been obtained. For the first time, it is now possible to integrate the data obtained in studies of sexual behavior into the wider context of general dopaminergic functions. To make this possible, we first present an analysis of the nature and organization of sexual behavior followed by a summary of current knowledge about the brain structures of crucial importance for this behavior. We then proceed with a description of the dopaminergic systems within or projecting to these structures. Whenever possible, we also try to include data on the electrophysiological actions of dopamine. Thereafter, we proceed with analyses of pharmacological data and release studies, both in males and in females. Consistently throughout this discussion, we make an effort to distinguish pharmacological effects on sexual behavior from a possible physiological role of dopamine. By pharmacological effects, we mean here drug-induced alterations in behavior that are not the result of the normal actions of synaptically released dopamine in the untreated animal. The conclusion of this endeavor is that pharmacological effects of dopaminergic drugs are variable in both males and females, independently of whether the drugs are administered systemically or intracerebrally. We conclude that the pharmacological data basically reinforce the notion that dopamine is important for motor functions and general arousal. These actions could, in fact, explain most of the effects seen on sexual behavior. Studies of dopamine release, in both males and females, have focused on the nucleus accumbens, a structure with at most a marginal importance for sexual behavior. Since accumbens dopamine release is associated with all kinds of events, aversive as well as appetitive, it can have no specific effect on sexual behavior but promotes arousal and activation of non-specific motor patterns. Preoptic and paraventricular nucleus release of dopamine may have some relationship to mechanisms of ejaculation or to the neuroendocrine consequences of sexual activity or they can be related to other autonomic processes associated with copulation. There is no compelling indication in existing experimental data that dopamine is of any particular importance for sexual motivation. There is experimental evidence showing that it is of no importance for sexual reward.
~GMO, A., J. L. CONTRERAS AND R. PAREDES. Sexual behavior and copulatory thrusting patterns in ma... more ~GMO, A., J. L. CONTRERAS AND R. PAREDES. Sexual behavior and copulatory thrusting patterns in male rabbits treated with GABA transaminase inhibitors. PHYSIOL BEHAV 49(1) 73-78, 1991.--The effects of enhanced central nervous system GABA levels on sexual behavior and copulatory pelvic thrusting were evaluated in male New Zealand white rabbits. The GABA transaminase inhibitors sodium valproate and ~/-acetylen GABA (GAG), in doses of 100 and 200 mg/kg and 50 and 100 mg/kg, respectively, were intraperitoneally administered and sexual behavior recorded at several intervals after drug administration. At the same time, copulatory thrusting was registered using a polygraphic technique. Tests for gross motor functions were also performed. None of the drugs had any effect in these latter tests. Sodium valproate, in a dose of 100 mg/kg, had a slight inhibitory effect on sexual behavior at 280 min postinjection. A dose of 200 mg/kg inhibited sexual activity already 15 min postinjection, and the effect lasted for at least 280 min. GAG, 100 mg/kg, inhibited mounting behavior at 8 h postinjection, and ejaculation was reduced from 2 to at least 8 h postinjection. Copulatory thrusting patterns were not affected by the drug treatments. These data suggest that increased GABAergic activity reduces sexual arousal in the rabbit. GABA does not seem to be critically involved in the regulation of the motor patterns underlying pelvic thrusting. There are important quantitative and qualitative differences between rats and rabbits with regard to the actions of GABA transaminase inhibitors upon sexual functions.
Premature ejaculation is the most common sexual disorder in young men. Consequently, there is an ... more Premature ejaculation is the most common sexual disorder in young men. Consequently, there is an intense search for efficient and safe pharmacological treatments. Insofar, almost no effective treatment with acute effects is available. In this study, we evaluated the effects of the noradrenergic α 2 receptor agonist dexmedetomidine on sexual incentive motivation and copulatory behavior in male rats. Sexual incentive motivation was tested in a large rectangular arena connected to two small incentive stimulus cages containing either a male or sexually receptive female rat. There was no sexual interaction possible between the experimental subjects and the incentives during this test. Approach to the incentives constituted the measure of sexual incentive motivation. After the sexual incentive motivation test, the subjects were tested for copulatory behavior in a regular copulation test for 30 min. Doses of 0.1 and 1 μg/kg of dexmedetomidine (i.p.) had no effect on any of the indices of locomotor activity or on parameters of sexual incentive motivation. With regard to copulatory behavior, it was found that the dose of 1 μg/kg prolonged the latency to the first ejaculation, while the latency to second ejaculation showed a tendency to increase. The absence of an effect on indices of sexual incentive motivation or general activity showed that the actions of dexmedetomidine in this study were limited to ejaculatory mechanisms. Insofar as the ejaculation latency in the male rat is predictive of prolonged ejaculation latency in men, it can be proposed that dexmedetomidine is of potential utility for the treatment of premature ejaculation.
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Papers by Anders Agmo