Sven Ahlenius

Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5‐HT1A and 5‐HT1B receptor agonists 8‐OH‐DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD‐299 and NAS‐181

Ejaculatory problems and anorgasmia are well‐known side‐effects of the SSRI antidepressants, and a pharmacologically induced increase in serotonergic neurotransmission inhibits ejaculatory behaviour in the rat. In the present study the role of 5‐HT1A and 5‐HT1B receptors in the mediation of male rat ejaculatory behaviour was examined by use of selective agonists and antagonists acting at these 5‐HT receptor subtypes. The 5‐HT1A receptor agonist 8‐OH‐DPAT (0.25–4.00 μmol kg−1 s.c.) produced an expected facilitation of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the new selective 5‐HT1A receptor antagonist (R)‐3‐N,N‐dicyclobutylamino‐8‐fluoro‐3,4‐dihydro‐2H‐1‐benzopyran‐5‐carboxamide hydrogen (2R,3R) tartrate monohydrate (NAD‐299) (1.0 μmol kg−1 s.c.). NAD‐299 by itself (0.75–3.00 μmol kg−1 s.c.) did not affect the male rat ejaculatory behaviour. The 5‐HT1B receptor agonist anpirtoline (0.25–4.00 μmol kg−1 s.c.) produced a dose‐dependent inhibition of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the 5‐HT1B receptor antagonist isamoltane (16 μmol kg−1 s.c.) as well as by the new and selective antagonist (R)‐(+)‐2‐(3‐morpholinomethyl‐2H‐chromene‐8‐yl)oxymethylmorpholino methansulphonate (NAS‐181) (16 μmol kg−1 s.c.). Isamoltane (1.0–16.0 μmol kg−1 s.c.) and NAD‐181 (1.0–16.0 μmol kg−1 s.c.) had no, or weakly facilitatory effects on the male rat ejaculatory behaviour. The non‐selective 5‐HT1 receptor antagonist (−)‐pindolol (8 μmol kg−1 s.c.), did not antagonize the inhibition produced by anpirtoline. The present results demonstrate opposite effects, facilitation and inhibition, of male rat ejaculatory behaviour by stimulation of 5‐HT1A and 5‐HT1B receptors, respectively, suggesting that the SSRI‐induced inhibition of male ejaculatory dysfunction is due to 5‐HT1B receptor stimulation.

Evidence for an involvement of 5-HT1B receptors in the inhibition of male rat ejaculatory behavior produced by 5-HTP

Abstract The administration of the 5-hydroxytryptamine (5-HT) precursor 5hydroxytryptophan (5-HTP) (25mg/kg IP), in combination with an inhibitor of peripheral 5-HTP decarboxylase, produced a dose-dependent increase in the ejaculation latency of male rats, and this effect was enhanced by additional treatment with the 5-HT1 receptor antagonist (−)-pindolol (2mg/kg SC). The 5-HT2A/C receptor agonist (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125–0.5mg/kg SC) did not by itself affect male ejaculatory behavior, but additional treatment with (−)-pindolol (2mg/kg SC) produced a dose-dependent decrease in number of ejaculating animals. The increased ejaculation latency produced by 5-HTP was fully antagonized by treatment with the 5-HT1B receptor antagonist isamoltane (4mg/kg SC), but not by ritanserin (2mg/kg SC) treatment. The selective 5HT1A receptor antagonist WAY-100635 (0.15mg/kg SC) enhanced the inhibitory actions of 5-HTP on the male rat ejaculatory behavior, and this dose of WAY-100635 fully antagonized 8-OH-DPAT-induced facilitation (0.25mg/kg SC) of the ejaculatory behavior. WAY-100635 (0.04–0.60mg/kg SC) did not, by itself, significantly affect male rat sexual behavior. Taken together, the results suggest an inhibitory role for postsynaptic 5-HT1B receptors in the effects produced by 5-HTP on male rat ejaculatory behavior. Furthermore, 5-HTP-induced inhibition of male rat ejaculatory behavior is partially controlled by stimulation of inhibitory 5-HT1A autoreceptors, since the effects of 5-HTP were accentuated by treatment with (−)-pindolol, as well as by the more selective 5-HT1A receptor antagonist WAY-100635.

Suggestive evidence for inhibitory effects of galanin on mesolimbic dopaminergic neurotransmission.

The objective was to examine effects of galaninrat on forebrain monoamine synthesis and on spontaneous locomotor activity in the rat. The rate of monoamine synthesis was estimated by measuring the accumulation of l-DOPA and 5-HTP, following inhibition of cerebral aromatic l-amino acid decarboxylase by means of NSD-1015 (100 mg kg-1 i.p.), after i.c.v. or intracerebral administration of galanin in adult male Wistar rats. Spontaneous locomotor activity was observed in an automated open-field arena ( approximately 0.5 m2). The i.c.v. administration of galanin (0.5-5.0 nmol bilaterally) produced a dose-dependent, statistically significant, increase in DOPA accumulation throughout the neostriatum, and in the olfactory bulb, indicating an increase in the rate of DA synthesis. No increase was observed in brain areas where noradrenaline is the predominant catecholamine, such as the neocortex or the ventral hippocampus. In addition, there was a tendency for an increase in 5-HTP accumulation in the dorso-lateral neostriatum and in the accumbens. The same i.c.v. administration of galanin produced a dose-dependent, and statistically significant, decrease in spontaneous locomotor activity. The effect on forebrain DA synthesis could also be produced by local bilateral application of galanin (2x1 nmol) into the ventral tegmental area, but not the nucleus accumbens (2x2 nmol). There were no effects on forebrain DOPA or 5-HTP accumulation by the local application of galanin into the locus coeruleus, or into the dorsal raphe nucleus. It is concluded that the neuropeptide galanin modulates forebrain dopaminergic neurotransmission. The effect appears to be mediated at the somato-dendritic level of the meso-neostriatal pathway, and could perhaps be utilized to normalize perturbations ascribed to dysfunction in this neuronal pathway, such as schizophrenia.

Specific involvement of central 5-HT1A receptors in the mediation of male rat ejaculatory behavior

The aminotetralin 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), pharmacologically characterized as a 5-HT1A receptor agonist, produces a pronounced decrease in ejaculation latency in the male rat. Stimulation of 5-HT receptors by a pharmacologically induced increase in the synaptic availability of 5-HT has been shown to produce the opposite effect. The 8-OH-DPAT-induced decrease in ejaculation latency is specific for this compound, and some chemically related ergot derivatives. In this paper we review the evidence in support for stimulation of serotonergic auto-receptors of the 5-HT1A receptor subtype as a mechanism of action for effects by 8-OH-DPAT on male rat ejaculatory behavior. We also present the questions posed by the fact that quinpirole and lisuride both produce 8-OH-DPAT-like effects on male rat ejaculatory behavior. The effects by quinpirole, lisuride or 8-OH-DPAT are not sensitive to pretreatment with the DA D2/3 receptor antagonist raclopride. Continued studies will show whether the effects of quinpirole and lisuride can be related to stimulation of 5-HT1A receptors, or if all these compounds have as yet undefined common properties.

Enhancement of antipsychotic-like properties of the dopamine D2 receptor antagonist, raclopride, by the additional treatment with the 5-HT2 receptor blocking agent, ritanserin, in the rat.

The effects of 5-HT2 receptor blockade on the ability of a dopamine (DA) D2 receptor antagonist to produce suppression of conditioned avoidance response (CAR) and to produce catalepsy in rats were examined. It was found that ritanserin (2 mg kg-1 s.c.) enhanced the raclopride (0.1 mg kg-1 s.c.)-induced suppression of CAR without affecting raclopride-induced catalepsy at either maximal (4 mg kg-1 s.c.) or submaximal (0.2 mg kg-1 s.c.) doses. Considering the CAR performance as an index of mesocorticolimbic dopaminergic functions, it is concluded that 5-HT2 receptor blockade confers a limbic profile on the DA D2 receptor antagonist.

Synergistic actions of the 5-HT1A receptor antagonist WAY-100635 and citalopram on male rat ejaculatory behavior

The selective serotonin re-uptake inhibitor citalopram (0-40 mg kg(-1), s.c., - 60 min) did not affect the male rat ejaculatory behavior, and there were no statistically significant effects of the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCl (WAY-100635) (0.04-0.08 mg kg(-1), s.c., - 30 min). When combined, there was a marked, and statistically significant, prolongation of the ejaculation latency in comparison with saline treated controls, as well as in comparison with either drug by itself. This citalopram (10.0)/WAY-100635 (0.04)-induced effect was fully antagonized by the administration of the 5-HT1B receptor antagonist isamoltane (4.0 mg kg(-1)). There were no consistent effects on other aspects of the male rat sexual behavior, i.e., number of mounts and intromissions preceding ejaculation and the post-ejaculatory interval. Finally, the intromission latency was also markedly enhanced in animals receiving both citalopram and WAY-100635, and at the higher dose of WAY-100635 (0.08 mg kg(-1)) 7 out of 18 animals failed to initiate copulation. It is suggested that blockade of inhibitory 5-HT1A autoreceptors discloses inhibitory effects of the selective serotonin re-uptake inhibitor citalopram on male rat ejaculatory behavior mediated via stimulation of 5-HT1B receptors.

Effects of 5-HT agonists, selective for different receptor subtypes, on oxytocin, CCK, gastrin and somatostatin plasma levels in the rat

Adult male Sprague-Dawley rats were administered the 5-HT subtype selective receptor agonists 8-OH-DPAT (0.5-2.0 mg/kg), buspirone (2-8 mg/kg) (5-HT1A), TFMPP (0.125-2.0 mg/kg) (5-HT1B), DOI (0.125-2.0 mg/kg) (5-HT2A) and m-CPBG (1.25-20.0 mg/kg) (5-HT3), subcutaneously. Oxytocin, cholecystokinin (CCK), somatostatin and gastrin plasma levels were determined by standard RIA techniques 30 and 120 min after injection of the respective 5-HT receptor agonist. It was found that the 5-HT1A and the 5-HT2A/C, but not the 5-HT2B or the 5-HT3 receptor agonists produced an increase in plasma oxytocin levels and these effects were, at least partially, antagonized by the corresponding subtype selective antagonists (-)pindolol (2 mg/kg) and ritanserin (2 mg/kg), respectively, administered 10 min before 8-OH-DPAT (0.5 mg/kg) or DOI (0.5 mg/kg). The maximal response to the 5-HT1A receptor agonists (approx. 120 nmol/l) was from 8 to 5 times the maximal response to the 5-HT2A C receptor agonist. In addition, 8-OH-DPAT and DOI caused a decrease in plasma CCK levels, whereas the 5-HT1B receptor agonist TFMPP gave rise to an increase in plasma CCK levels. There were no statistically significant effects by any of the 5-HT receptor agonists on plasma somatostatin or gastrin levels under the present conditions. It is suggested that the clinical effects of new anxiolytic 5-HT1A receptor agonists, such as buspirone, to an extent may be mediated via an increased release of oxytocin.

Inhibition of kainic acid induced expression of interleukin-1β and interleukin-1 receptor antagonist mRNA in the rat brain by NMDA receptor antagonists

The cytokines interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1ra) are rapidly induced in response to excitotoxic and ischemic brain damage. The aim of the present study was to investigate the influence of a non-competitive (dizocilpine maleate, MK-801) and a competitive ((R)-CPP) NMDA receptor antagonist on the transient cytokine expression in the rat brain induced by systemic kainic acid administration. Peripheral administration of kainic acid (10 mg/kg, i.p.) results in a transient expression of IL-1 beta and IL-1ra mRNA, mainly in microglia, in regions showing neurodegeneration such as the hippocampus, thalamus, amygdala, and certain cortical regions. In addition, a few neurons expressing IL-1ra mRNA were observed in the piriform cortex and amygdala following kainic acid injection. Administration of MK-801 (i.p.) 1 h prior to kainic acid injection reduced cytokine expression in all of these regions. MK-801 at 3.0 mg/kg decreased the IL-1 beta mRNA expression, blocked or decreased the IL-1ra mRNA expression, depending on the brain region. MK-801 at 5.0 mg/kg abolished IL-1ra mRNA expression in all of the regions, whereas the IL-1 beta mRNA expression was decreased or blocked, depending on the brain region, or the time point investigated. Peripheral administration of (R)-CPP (15 mg/kg, i.p.) 15 min prior to the kainic acid injection abolished the IL-1 beta mRNA expression. The IL-1ra mRNA expression was abolished in all regions except for a few neurons in the piriform cortex. The finding that NMDA receptor antagonists inhibit the IL-1 beta and IL-1ra mRNA synthesis induced by kainic acid suggests that NMDA receptor activation may be involved in triggering cytokine synthesis following excitotoxic brain damage.

Sexual motivation promotes oxytocin secretion in male rats.

The present study examines plasma oxytocin levels in relation to performance of copulatory behavior in male rats. The animals were divided into three groups: A) home-cage controls, B) sexually naive and C) sexually experienced. Following 15 min of sexual interactions with a sexually proceptive female, brought into estrus by sequential injections of estradiol benzoate (12.5 micrograms animal-1, -48 h) and progesterone (0.5 mg animal-1, -6 h), the male rats were decapitated. Trunk blood was collected for preparation of plasma samples, and subsequent radioimmunoassay for oxytocin. Home-cage controls, not exposed to a sexually proceptive female, were decapitated at the same time as experimental animals. It was found that plasma oxytocin levels were significantly elevated in sexually naive rats following exposure to a sexually proceptive female, and that plasma oxytocin levels were highly correlated with intensity of copulatory performance in these animals. In addition, it was also found that plasma prolactin and glucose levels were increased, regardless of sexual experience, in comparison with home-cage controls. It is concluded that the emotional challenge, and the situation-specific demands for action, created by an encounter with a sexually proceptive female, are accompanied by an increased plasma concentration of oxytocin in sexually naive, but not sexually experienced, male rats.

Brain and Sexual Behavior

ABSTRACT: This chapter will give personal accounts of the neural basis of male rat sexual behavior from two somewhat different perspectives, one tilted towards neuroanatomy (K.L.), and one tilted towards monoaminergic pharmacology (S.A.). Both perspectives were strongly influenced by the Zeitgeist, the former imperceptibly merging into the latter as relations between the neural substrate for monoaminergic neurotransmission was elucidated. 1