Biomedical subjects
Publications and source records attributed to S Ahlenius.
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.
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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.
In the present series of experiments, we have examined the endocrine profile of two stable colonies of Sprague-Dawley rats, here labeled Stock A, and Stock B, differing markedly in their ability to acquire a conditioned avoidance response. On separate occasions, the animals were subjected to five daily sessions (approximately 20 trials per 15 min session) of conditioned avoidance training, measurements of startle reactivity to an auditory stimulation and open-field spontaneous locomotor activity observations. The experiments were concluded by taking blood samples for later analysis of plasma glucose and plasma levels of the following hormones: insulin, gastrin, CCK, glucagon, somatostatin, oxytocin and corticosterone. The low-performing Stock B animals were characterized by [1] being more reactive to sensory stimulation: higher startle amplitude and shorter startle latency; [2] having higher plasma insulin and corticosterone levels, whereas plasma gastrin and oxytocin were significantly lowered and a strong tendency for a decrease also in plasma CCK. There were no differences in spontaneous locomotor activity between the two substrains. Taking total variability in avoidance performance into account, there was a statistically significant positive correlation between plasma oxytocin, as well as gastrin, levels and avoidance performance. The evidence obtained here, and in other laboratories, suggests that the Stock B animals display hormonal changes indicative of a submissive-defensive reaction pattern. Thus, the avoidance acquisition deficits displayed by the present Sprague-Dawley stocks A and B, are in all probability caused by emotional reactions when challenged with external stimuli requiring active responding.
The nonapeptide oxytocin is released into systemic circulation in situations of psychosocial interaction, and has been shown to be involved in mechanisms of social bonding and social recognition in laboratory studies. In view of disturbances in psychosocial relationships being a triggering factor for depression and anxiety, it is interesting to note that experimental studies have shown oxytocin to possess antidepressant- and anxiolytic-like actions. Thus. in the present study we examined effects of the SSRI citalopram (20 mg/kg i.p.) on plasma oxytocin, acutely and upon repeated administration, in adult male Sprague-Dawley rats. Plasma oxytocin, and some functionally related peptides (CCK, gastrin, somatostatin and insulin), were measured by standard radioimmunoassay techniques. Acute citalopram administration produced a statistically significant increase in plasma oxytocin and CCK levels. Administration of citalopram for 14 days did not attenuate the oxytocin-releasing effect to a challenge dose of the SSRI zimeldine (20 mg/kg s.c.), whereas CCK levels were not increased after the subchronic citalopram treatment. Thus, the SSRI citalopram produces increased plasma oxytocin levels acutely, and there appears to be no or little tolerance to this effect upon repeated administration. There were no, or variable, effects on plasma levels of gastrin, somatostatin or insulin. It is suggested that oxytocin release is an important aspect of the pharmacological actions of SSRIs, and this could be an important contributory factor for the clinical profile of this group of antidepressants with particular efficacy in disorders of psychosocial origin.
The receptor-mediated control of brain monoamine synthesis was used to examine the in vivo intrinsic efficacy of the 5-HT1A receptor antagonists NAD-299, S(-)-UH-301 and WAY-100,635. The rate of monoamine synthesis was estimated by measuring the accumulation of DOPA and 5-HTP in the ventral neostriatum and the ventral hippocampus in rats pretreated with an inhibitor of cerebral aromatic L-amino acid decarboxylase. S(-)-UH-301 (2.0-32.0 micromol kg(-1)), but not WAY-100,635 (0.08-1.2 micromol kg(-1)), produced a decreased 5-HTP accumulation in the neostriatum and in the hippocampus. The administration of NAD-299 (0.75-12.0 micromol kg(-1)) resulted in a slight increase in neostriatal, but not hippocampal, 5-HTP accumulation. Neostriatal DOPA accumulation was decreased by S(-)-UH-301, whereas treatment with WAY- 100,635 resulted in an increase. NAD-299 did not affect neostriatal DOPA levels. There were no effects by any of these agents on DOPA levels in the ventral hippocampus. It is concluded that S(-)-UH-301, but not WAY-100,635 or NAD-299, displays intrinsic efficacy at brain 5-HT1A and DA D2/3 receptors, whereas WAY-100,635 behaves as a DA D2/3 receptor antagonist. By this comparison, NAD-299 appears to be the most selective and specific 5-HT1A receptor antagonist.
A large number of ligand binding studies have shown that clozapine has a number of receptor affinities, including those of the dopamine (DA) D1 and D2 receptor families. The study of intrinsic efficacy at these receptors is less straight-forward. In the experiments summarised here, evidence is presented that clozapine behaves as an agonist at DA D1 receptors. Thus, the hypothermia produced by clozapine (2.5 mg kg(-1)) in the rat is fully antagonised by either of the selective DA D1 receptor antagonists SCH-23390 (0.1 mg kg(-1)) or NNC-687 (4 mg kg(-1)). These results provide an intriguing explanation for the clinical profile of clozapine as an atypical antipsychotic drug. Thus, there are supporting clinical and laboratory observations implicating DA D1 receptors in the prefrontal cortex in cognitive functions. Finally, clozapine displays features with regard to extrapyramidal motor mechanisms, and seizure thresholds, that could be explained by its properties as a DA D1 receptor agonist.
In d-amphetamine-treated (4.0 mg kg(-1) s.c.) rats the selective dopamine D1 and D2/3 receptor antagonists SCH-23390 (2.5-20.0 microg kg(-1) s.c.) and raclopride (12.5-100.0 microg kg(-1) s.c.), respectively, produced a biphasic pattern of effects on forward locomotion, as observed in an open-field arena (approximately 0.5 m2). Thus, at the low doses of SCH-23390 (2.5-10.0 microg kg(-1)) or raclopride (12.5-50.0 microg kg(-1)), there was a statistically significant increase in forward locomotion, followed by suppression of the behavior at the higher doses. The SCH-23390-induced (5.0 microg kg(-1)) stimulation of forward locomotion was partially antagonized by concomitant raclopride treatment (12.5-25.0 microg kg(-1)) and the corresponding raclopride-induced (12.5 microg kg(-1)) stimulation was fully antagonized by treatment with SCH-23390 (2.5-5.0 microg kg(-1)). Furthermore, the SCH-23390- or raclopride-induced stimulation of forward locomotion was also antagonized by treatment with the alpha1-adrenoceptor antagonist prazosin (1.0 mg kg(-1) s.c.). These observations suggest that under conditions of an increased general tone at brain dopamine receptors, there is a mutual inhibitory synergy between dopamine D1 and D2/3 receptors.
The administration of the 5-hydroxytryptamine (5-HT) precursor 5-hydroxytryptophan (5-HTP) (25 mg/kg i.p.), 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 (2 mg/kg s.c.). The 5-HT2A/C receptor agonist (+/-) 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125-0.5 mg/kg s.c.) did not by itself affect male ejaculatory behavior, but additional treatment with (-)-pindolol (2 mg/kg s.c.) 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 (4 mg/kg s.c.), but not by ritanserin (2 mg/kg s.c.) treatment. The selective 5-HT1A receptor antagonist WAY-100635 (0.15 mg/kg s.c.) 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 (0.25 mg/kg s.c.) of the ejaculatory behavior. WAY-100635 (0.04-0.60 mg/kg s.c.) 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.
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.
In the present study, dose relationships for effects of oxytocin (OXY) on spontaneous motor activity in female rats were investigated. Ovariectomized (OVX) and cycling female Sprague-Dawley rats were given OXY 10-1000 microg/kg s.c. or saline, 10 min before registration of motor activity in an open-field arena. In the OVX rats, 100 microg/kg of OXY increased the activity in the center of the arena, whereas 1000 microg/kg decreased locomotor activity (LA). In the cycling rats, OXY 100-1000 microg/kg decreased LA during diestrus, while 1000 microg/kg also decreased LA during metestrus. The latter dose also reduced the exploratory behavior during estrus. In a second experiment, OVX rats were pretreated with estradiol benzoate (EB) and progesterone (P). When P levels were predominant, OXY 10-1000 microg/kg decreased LA. Oxytocin 10-100 microg/kg given after pretreatment with EB increased the activity in the center of the arena, whereas 1000 micro/kg given in the presence of both EB and P increased peripheral activity (PA). These results show that the effects of OXY on motor activity in female rats are modified by female sex steroid hormones.
1. 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. 2. The 5-HT1A receptor agonist 8-OH-DPAT (0.25-4.00 micromol 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 micromol kg(-1) s.c.). NAD-299 by itself (0.75-3.00 micromol kg(-1) s.c.) did not affect the male rat ejaculatory behaviour. 3. The 5-HT1B receptor agonist anpirtoline (0.25-4.00 micromol 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 micromol kg(-1) s.c.) as well as by the new and selective antagonist (R)-(+)-2-(3-morpholinomethyl-2H-chromene-8-yl)oxymethylmorphol ino methansulphonate (NAS-181) (16 micromol kg(-1) s.c.). Isamoltane (1.0-16.0 micromol kg(-1) s.c.) and NAD-181 (1.0-16.0 micromol 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 micromol kg(-1) s.c.), did not antagonize the inhibition produced by anpirtoline. 4. 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.
The present study was designed to examine 1) functional interactions between 5-HT1A and 5-HT2A/C receptors in thermoregulation in rats and 2) the specific involvement of 5-HT2A and 5-HT2C receptors in such interactions. The 5-HT2A/C receptor agonist DOI (0.025 1.6 mg kg-1, subcutaneously) produced a dose-dependent hyperthermia in rats, which was enhanced by addition of either of two 5-HT1A receptor antagonists, (-)-pindolol (0.5-1.0 mg kg-1, subcutaneously) or WAY-100,635 (0.1-0.4 mg kg-1, subcutaneously). Furthermore, the DOI-induced hyperthermia was counteracted by pretreatment with the 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg kg-1, subcutaneously). The hyperthermia produced by DOI, alone or in combination with WAY-100,635, was fully antagonized by pretreatment with the 5-HT2A/C receptor antagonist ritanserin (1.0 mg kg-1, subcutaneously), as well as with the selective 5-HT2A receptor antagonist amperozide (2.0 mg kg-1, subcutaneously). The present results provide evidence for functional interactions between 5-HT1A and 5-HT2A receptors in temperature regulation in rats, and also suggest an important role for postsynaptic 5-HT2A receptors in the mediation of DOI-induced hyperthermia.
The selective dopamine D1 receptor agonist dihydrexidine (2.0-8.0 mg/kg, s.c.) caused a dose-dependent decrease in core temperature in rats. The hypothermia produced by dihydrexidine (4.0 mg/kg), was completely blocked by the dopamine D1 receptor antagonists SCH 23390 (0.1 mg/kg, s.c.) or NNC 687 (4.0 mg/kg, s.c.), but not by the dopamine D2/3 receptor antagonist raclopride (0.2 mg/kg, s.c.). Neither of the dopamine antagonists by themselves produced any effects on core temperature. The present results provide important evidence for the notion that activation of dopamine D1 receptors induces hypothermia in rats.
Intracerebroventricular (i.c.v.) forskolin infusion for 5 days resulted in a concentration-dependent increase in rat striatal dopamine (DA) D2 receptors measured with [3H]raclopride. In animals given 50 nmol/h forskolin, the highest concentration used, raclopride-mediated suppression of spontaneous locomotor activity was attenuated, and (+/-)-7-hydroxy-dipropyl-aminotetralin HBr (7-OH-DPAT)-mediated inhibition of striatal DA synthesis, as estimated by the accumulation of DOPA following inhibition of cerebral decarboxylase, was enhanced. These data suggest that the DA D2 receptor increase comprises receptors localized both post- and presynaptically. The density of striatal DA D1 receptors was also changed with the forskolin treatment, in a concentration-dependent fashion, but in the opposite direction to DA D2 receptors. These findings suggest that striatal DA receptor sensitivity can be changed by manipulation at the second messenger level (e.g. independent of direct neurotransmitter-receptor interactions) in vivo.
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The present experiments were undertaken in order to examine mechanisms of action for reported interactions between the beta-blocker (-)-pindolol and serotonergic agents. It was found that pretreatment with (-)-pindolol (2 mg kg-1 s.c.) potentiated the stereotyped forward locomotion induced by the 5-HT2A/C receptor agonist DOI (0.125-1.0 mg kg-1 s.c.) in rats observed in an open-field arena. This (-)-pindolol/DOI-induced stereotyped forward locomotion was fully antagonized by the 5-HT2A/C receptor antagonist ritanserin (2 mg kg-1 s.c.), suggesting that (-)-pindolol enhances serotonin release, resulting i.a. in postsynaptic 5-HT2A/C receptor activation. This effect by (-)-pindolol is in all probability indirect since this compound lacks affinity for 5-HT2A/C receptors, and could be explained by reported antagonism of inhibitory serotonergic somato-dendritic 5-HT1A autoreceptors, although other possibilities related to 5-HT1B receptors or beta-adrenoceptors can not be excluded at this time. Furthermore, (-)-pindolol treatment also enhanced 5-HTP-induced (12.5-100 mg kg-1 i.p.) effects on spontaneous motor activity. These effects, however, were of smaller magnitude, and less consistent than those seen in combination with DOI.
Administration of the 5-HT1A receptor agonist 8-OH-DPAT produced a biphasic pattern of effects on endurance performance of rats walking on top of a treadmill drum ([symbol: see text] = 166 mm, 16 rpm; approximately 8 m min-1), with enhanced performance at a low dose (0.1 mg kg-1 s.c.) followed by impairment (0.2-0.8 mg kg-1). The partial 5-HT1A receptor agonist (-)-pindolol improved the performance in the low dose range (0.5-2.0 mg kg-1 s.c.), whereas a higher dose (8 mg kg-1) was ineffective. The 5-HT1A receptor antagonist WAY-100,635 produced an impaired performance at a low dose (12.5 micrograms kg-1 s.c.), with a recovery of performance at higher doses (50-200 micrograms kg-1). It is suggested that the inhibition of central serotonergic neurotransmission produced by stimulation or blockade of 5-HT1A auto- and post-synaptic receptors, respectively, results in an improved endurance performance on the treadmill, whereas stimulation of postsynaptic 5-HT1A receptors has the opposite action. In support of this contention, the impaired performance produced by a high dose of 8-OH-DPAT (0.8 mg kg-1) was antagonized by pretreatment with (-)-pindolol (2 mg kg-1 s.c.).