Viveka Hillegaart

High doses of oxytocin cause sedation and low doses cause an anxiolytic-like effect in male rats.

The aim of the present investigation was to explore dose relationships for effects of oxytocin on spontaneous motor activity in the rat. Oxytocin in doses from 1-1000 micrograms/kg was given SC to male Sprague-Dawley rats, and spontaneous motor behavior was measured by means of photocell-operated open-field observations. In the rats treated with low doses of oxytocin (1-4 micrograms/kg), there was a decrease in peripheral locomotor activity. With increasing doses (250-1000 micrograms/kg), there were clear signs of sedative effects as indicated by a suppression of locomotor activity and rearing. The time course for the effect of oxytocin on peripheral activity (1 microgram/kg) and rearing (1 mg/kg) was tested. A maximal effect was obtained within 1 h and, thereafter, the behavior gradually returned to normal within 24 h. This spectrum of effects caused by oxytocin was similar to that of midazolam but different from that induced by raclopride.

Stimulation of 5-HT1A and 5-HT1B receptors in brain regions and its effects on male rat sexual behaviour

In the present series of experiments we compared the effect of injecting serotonin (40 micrograms/cannula), the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (5.0 micrograms/cannula), and the 5-HT1B/C agonist, trifluoromethyl-phenyl-piperazine (TFMPP) (1.0 micrograms/cannula), into the preoptic area, the nucleus accumbens and the nucleus raphe dorsalis. The dose injected was selected on the basis of dose-response curves. Injection of serotonin and TFMPP into the medial preoptic area and nucleus accumbens resulted in an inhibition of male sexual behaviour, as evidenced by an increase in the number of mounts and a prolongation of the ejaculation latency. Injection of 8-OH-DPAT into these brain areas facilitated copulatory behaviour as evidenced by a reduction in the number of mounts, intromissions and ejaculation latency. Administration of these compounds into the nucleus raphe dorsalis produced no effect, except for a prolongation of the intromission latency after serotonin. These results would suggest that at least some of the 5-HT1A receptors involved in the facilitation of male sexual behaviour are located postsynaptically in limbic brain areas that regulate male sexual behaviour. On the basis of the similarities between the inhibitory effects of serotonin and TFMPP, the present results further support the idea that endogenous serotonin acts via the stimulation of 5-HT1B receptors to inhibit male sexual behaviour.

Effects of 5-HT and 8-OH-DPAT on forebrain monoamine synthesis after local application into the median and dorsal raphe nuclei of the rat

5-HT (10 and 40 Μg) and 8-OH-DPAT (1 and 5 Μg) were locally applied into the dorsal or median raphe nuclei in awake, unrestrained, rats. All animals were also treated with the 5-HTP and DOPA decarboxylase inhibitor NSD-1015, 100mg kg−1 SC, 30 min before decapitation. 5-HT or 8-OH-DPAT were administered 5 min before NSD-1015. The regional brain in vivo rate of tyrosine and tryptophan hydroxylase activity was estimated by measuring the accumulation of DOPA and 5-HTP. The following brain regions were sampled: neocortex, hippocampus, dorso-lateral neostriatum, ventro-medial neostriatum, nucleus accumbens, olfactory tubercle, globus pallidus, septum and the amygdala. Compared to normal controls, there were small and inconsistent effects on forebrain 5-HTP accumulation by saline injections into the dorsal or the median raphe (an increase in 3 out of 36 experiments), whereas strong effects by the injection procedure were noted on forebrain DOPA accumulation (an increase in 15 out of 36 experiments). Injections of 5-HT (same effect by 10 or 40 Μg) into the dorsal raphe, produced a decrease in 5-HTP accumulation in all forebrain areas except for the hippocampus and the septum, whereas no effects were seen in any area after median raphe injections. In contrast, 8-OH-DPAT preferentially produced a decrease in forebrain 5-HTP accumulation after median raphe injections and less, but statistically significant effects by dorsal raphe injections. The 8-OH-DPAT injection into the median raphe primarily affected limbic forebrain areas (hippocampus, nucleus accumbens, ventro-medial neostriatum, amygdala and the septum). This dissociation of the effects of 5-HT and 8-OH-DPAT on forebrain 5-HT synthesis after local application into the dorsal or the median raphe strongly supports the contention of heterogeniety in the brain 5-HT receptor population in terms of receptor subtypes and/or receptor regulation.

Effects of Selective Serotonin and Dopamine Agonists on Plasma Levels of Glucose, Insulin and Glucagon in the Rat

Male Sprague-Dawley rats were given one of the 5-HT receptor agonists 8-OH-DPAT (0.5-2.0 mg kg-1), TFMPP (0.125-2.0 mg kg-1), DOI (0.125-2.0 mg kg-1), and m-CPBG (1.25-20.0 mg kg-1), selective for 5-HT1A, 5-HT1B, 5-HT2 and the 5-HT3 receptors, respectively, or one of the DA receptor agonists bromocriptine (2.0-32.0 mg kg-1), quinpirole (0.5-8.0 mg kg-1) and 7-OH-DPAT (0.2-3.2 mg kg-1), selective for DA D2, DA D2/D3 and DA D3 receptors, respectively. An additional group of animals was given buspirone (2.0-8.0 mg kg-1) a 5-HT1A receptor agonist and DA D2 receptor antagonist. Separate groups of rats were given both the 5-HT1A receptor antagonist pindolol and 8-OH-DPAT or both the DA D2/D3 receptor antagonist raclopride and 7-OH-DPAT. Blood samples were collected 30 min (in some cases 120 min) after drug administration and assayed for insulin, glucagon and glucose levels. The 5-HT1A receptor agonist 8-OH-DPAT produced a statistically significant decrease in plasma insulin levels and an increase in glucose, whereas glucagon levels were unaffected. The only effect observed after buspirone treatment was a small increase in plasma glucose levels. No significant effects on plasma insulin, glucagon or glucose were seen after treatment with the 5-HT1B, 5-HT2 or 5-HT3 agonists. The DA D3 receptor agonist 7-OH-DPAT produced a decrease in plasma insulin (3.2 mg kg-1, 120 min) and an increase in glucose levels. Administration of the DA D2/D3 receptor agonist quinpirole resulted only in increased plasma glucose, whereas the DA D2 receptor agonist bromocriptine had no effect. In support of a separate mediation of glucose secretion by 5-HT1A and DA D3 receptors, the effects of 8-OH-DPAT on glucose levels were antagonized by (-)pindolol pretreatment, and the 7-OH-DPAT-induced effects on glucose levels were antagonized by raclopride pretreatment. It is concluded that plasma glucose levels are under separate serotonergic and dopaminergic control, exerted via 5-HT1A and DA D3 receptors, respectively.

Median raphe, but not dorsal raphe, application of the 5-HT1A agonist 8-OH-DPAT stimulates rat motor activity

Local application of the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the median raphe of rats caused locomotor stimulation. In contrast, dorsal raphe application of the compound induced flat body posture, which was discontinuous and not dose-dependent, and therefore distinct from that characteristic for postsynaptic 5-HT receptor-mediated behaviour. Injection of 8-OH-DPAT into the dorsal raphe or median raphe caused neither forepaw treading nor head-weaving; stiff tail and sniffing occurred inconsistently. By activating somatodendritic 5-HT1A autoreceptors in the median raphe, 8-OH-DPAT may disinhibit locomotor-enforcing neural pathways that receive 5-HT afferents from this nucleus. The data suggest that median raphe and dorsal raphe 5-HT neurons have different roles in motor control.

Effects of local application of 5-HT into the median and dorsal raphe nuclei on male rat sexual and motor behavior

The local application of 10 micrograms 5-hydroxytryptamine (5-HT) into the dorsal or median raphe nucleus was found to facilitate male rat sexual behavior, as evidenced by a decrease in time to ejaculation, and in number of intromissions preceding ejaculation. The application of a higher dose, 40 micrograms, at either site, inhibited the initiation of sexual behavior. There was a clear distinction between the motor effects observed after local application of 5-HT into the dorsal or the median raphe nuclei. Injections into the median raphe produced a dose-dependent increase, whereas injections into the dorsal raphe nucleus produced a dose-dependent decrease, in motor activity. Present results suggests an inhibitory and excitatory role of the median and the dorsal raphe serotonergic projections, respectively, as regards motor behavior, whereas projections from both nuclei appear to have an inhibitory role in the mediation of male rat sexual behavior.

Effects of local application of 5-HT and 8-OH-DPAT into the dorsal and median raphe nuclei on motor activity in the rat

The spontaneous motor activity of male Wistar rats was recorded after the local application of 5-HT (10 or 40 micrograms) or 8-OH-DPAT (1 or 5 micrograms) into the dorsal raphe (DR) or median raphe (MR) nuclei. Motor activity was monitored for 30 min, beginning 10 min after injections. The injection volume was 0.5 microliters and injections were made by means of 31-ga needles at a rate of 0.33 microliters min-1. The raphe nuclei were approached at 30 degrees in order to avoid penetration of the cerebral aqueduct and also to avoid passage of the DR with injections aimed at the MR. The application of 5-HT into the DR produced a marked suppression of locomotor activity and rearing, and no or a slight increase in these variables were noted after MR injections. 8-OH-DPAT injections into the DR resulted in a decrease in locomotor activity and rearing after the 5- but not the 1-microgram dose, whereas a marked locomotor stimulation was found after injections into the MR. In the latter case 1 microgram of 8-OH-DPAT was more effective than 5 micrograms, possibly due to overstimulation by the higher dose. The results demonstrate different roles for serotonergic mechanisms in the DR and MR in the mediation of spontaneous motor activity in the rat, and also a possible specific role for 5-HT1 receptors. The involvement of 5-HT1 receptors was further supported by the ability of (-)pindolol, 2 mg kg-1 SC, to antagonise 8-OH-DPAT-induced hyperactivity after application into the MR.

Region-selective inhibition of male rat sexual behavior and motor performance by localized forebrain 5-HT injections: a comparison with effects produced by 8-OH-DPAT.

The local application of 5-HT (0-40 micrograms side-1) into the nucleus accumbens was found to inhibit male rat sexual behavior, as evidenced by an increase in number of mounts and intromissions preceding ejaculation and in time to ejaculation. There were no effects on male rat sexual behavior after similar 5-HT injections into other striatal areas, including the dorsolateral, the ventromedial and the posterior neostriatum, as well as the olfactory tubercle. The same groups of animals were also scored for motor activity and body posture after the injection of 5-HT, and only animals injected into the nucleus accumbens showed a statistically significant decrease in motor activity and an increase in the display of a flat body posture. 8-OH-DPAT (0-5 micrograms side-1), injected into the nucleus accumbens, produced a facilitation of the male rat sexual behavior, as evidenced by a decrease in number of mounts and intromissions to ejaculation, as well as in the postejaculatory interval. 8-OH-DPAT injections into the nucleus accumbens produced a decrease in motor activity and an increase in the per cent animals with a flat body posture. Injections into the olfactory tubercle had no effects on the sexual behavior or on the motor activity, whereas the per cent flat body posture was increased. Local application of 8-OH-DPAT (0-5 micrograms) into the median raphe nucleus, facilitated male rat sexual behavior, as evidenced by a decrease in number of intromissions preceding ejaculation and in time to ejaculation. The same doses of 8-OH-DPAT injected into the dorsal raphe had no effects on the sexual behavior. In an additional experiment, 3 groups of animals were injected with 5-HT (40 micrograms) or 8-OH-DPAT (5 micrograms) into the nucleus accumbens, the dorsal and the median raphe nuclei and thereafter observed for treadmill performance. No statistically significant effects were found after injections in any of these brain areas. The present results strongly suggest an inhibitory role of ventral forebrain 5-HT in the mediation of male rat sexual behavior. The facilitation produced by 8-OH-DPAT is possibly due to a blockade of 5-HT2 receptors. Facilitation by 8-OH-DPAT of the male rat copulatory performance after median raphe injections is probably due to stimulation of 5-HT1A autoreceptors in this brainstem region. In contrast to their opposite effects on sexual behavior, both compounds produced a decrease in motor activity and an increased display of flat body posture after accumbens injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Region-selective activation of brain monoamine synthesis by sexual activity in the male rat☆

In vivo catecholamine and 5-HT synthesis during sexual activity and treadmill locomotion was estimated in male rats by measuring the accumulation of DOPA and 5-HTP after inhibition of cerebral aromatic amino acid decarboxylase by means of NSD-1015 (100 mg.kg-1 i.p.). An increase in catecholamine as well as 5-HT synthesis during sexual activity was observed in both the neostriatum and the nucleus accumbens. An increase in catecholamine synthesis during treadmill locomotion was found in the neostriatum only. No significant changes in monoamine synthesis were found in the septal area or in the anterior hypothalamus.

Evidence for selective inhibition of limbic forebrain dopamine synthesis by 8-OH-DPAT in the rat

SummaryRegional dopamine synthesis in the rat striatum was estimated by measuring DOPA accumulation following inhibition of cerebral aromatic l-amino acid decarboxylase by means of NSD-1015, 100 mg kg−1 intraperitoneally. In animals treated with reserpine, 5 mg kg−1 subcutaneously −18 h, there was a statistically significant increase in DOPA accumulation in the nucleus accumbens, the ventro-medial neostriatum, the dorso-lateral neostriatum and in the posterior limb of the neostriatum. This increase in DOPA accumulation was antagonized dose-dependently in the nucleus accumbens and ventro-medial neostriatum, but not in the other two regions, by treatment with the 5-HT1A receptor agonist 8-OH-DPAT, 0.15–2.4 μmol kg−1, whereas the partial dopamine D2 receptor agonist (−)3-PPP, 2.5–10.0 μmol kg−1, or the full dopamine D2 receptor agonist quinpirole, 0.05–0.8 μmol kg−, antagonized the reserpine-induced increase in DOPA accumulation uniformly in all four regions of the striatum. The suppression of DOPA accumulation by 8-OH-DPAT in reserpine-treated animals, was completely antagonized by raclopride, 1 μmol kg−1, but not by (−)pindolol, 8 μmol kg−1. The accumulation of 5-HTP in all regions of the striatum as well as in the neocortex following decarboxylase inhibition and reserpine pretreatment, was also inhibited by 8-OH-DPAT, and this inhibition was unaffected by treatment with raclopride or (−)pindolol. It is concluded that 8-OH-DPAT, in addition to general effects on forebrain 5-hydroxytryptamine synthesis, selectively affects limbic forebrain dopamine synthesis. This latter effect is probably due to direct stimulation of dopamine autoreceptors, since it was obtained in reserpine-treated rats, and was completely antagonized by raclopride, but not (−)pindolol.