Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain

The sustained administration of the 5-HT1A agonist gepirone (15 mg/kg/day, s.c.) in the rat produced an initial decrease of the firing activity of dorsal raphe 5-HT neurons which was followed by a progressive recovery to normal after 14 days of treatment. At this point in time, the effect of intravenous lysergic acid diethylamide (LSD) on the firing activity of 5-HT neurons was markedly reduced, whereas those of 8-hydroxy-2-N,N-propylamino-tetralin (8-OH-DPAT) and of gepirone were unchanged; however, the responsiveness of 5-HT neurons to direct microiontophoretic application of 5-HT, LSD, 8-OH-DPAT, and gepirone, but not of GABA, was reduced. The responsiveness of postsynaptic dorsal hippocampus pyramidal neurons to 5-HT, 8-OH-DPAT, and gepirone was not altered by the 14-day gepirone treatment. The effectiveness of the electrical stimulation of the ascending 5-HT pathway in reducing pyramidal neuron firing activity was not significantly modified in rats treated with gepirone for 14 days. Furthermore, this treatment did not alter the function of the terminal 5-HT autoreceptor. It is concluded that the progressive restoration of the firing activity of 5-HT neurons, due to a desensitization of the somatodendritic 5-HT autoreceptor, combined with the direct activation of normosensitive postsynaptic 5-HT1A receptor by gepirone, should result in an augmented tonic activation of postsynaptic 5-HT1A receptors. The progressive appearance of this phenomenon would be consistent with the time course of the clinical anxiolytic, and possibly antidepressant, effects of gepirone.     

Hippocampal asymmetry in the behavioral responses to the 5-HT1A receptor agonist 8-OH-DPAT

The present study examined the behavioral responses of rats to unilateral and bilateral injections of the selective serotonin 1A (5-HT1A)-receptor agonist 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) 1 μg into the hippocampal CA1 area of male Wistar rats. 8-OH-DPAT increased locomotor activity, which was most pronounced with injections into the left hippocampus. The agonist impaired learning and memory (shuttle-☐), especially when injected into the right hippocampus. The elevated plus-maze experiments showed that neither left nor right nor bilateral hippocampal injections of 8-OH-DPAT produced any anxiogenic effect. However, with Vogel's conflict test, right injections of 8-OH-DPAT produced anxiety. The present study has revealed hippocampal asymmetry in the behavioral responses to the 5-HT1A-receptor agonist 8-OH-DPAT.     

Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists

A direct comparison was made of the effects of serotonin 5-HT1A and 5-HT1B selective compounds on the spontaneous firing rate of dorsal raphe serotoninergic neurons in chloral-hydrate-anesthetized rats. Following intravenous administration, the 5-HT1A selective compounds ipsapirone (TVX Q 7821) and LY 165163 potently inhibited single-unit activity in a dose-dependent manner whereas the 5-HT1B selective compounds, m-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine (TFMPP), displayed only weak or irregular actions. Low microiontophoretic currents of ipsapirone and LY 165163 were also effective in suppressing spontaneous firing; dose-response relationships for the 5-HT1A compounds were indistinguishable from that of 5-HT itself. In contrast, dorsal raphe neurons were only weakly responsive to microiontophoretic application of mCPP and TFMPP; dose-response relationships for the 5-HT1B compounds were significantly displaced from that of 5-HT. In intracellular studies, ipsapirone and LY 165163, when added to the media bathing brain slices, mimicked the actions of 5-HT in hyperpolarizing dorsal raphe cell membranes and decreasing input resistance; however, the maximal effects of the 5-HT1A compounds on these membrane properties exceeded those of 5-HT. In summary, dorsal raphe 5-HT neurons appear highly responsive to 5-HT1A, but not to 5-HT1B compounds; these findings are discussed with regard to the 5-HT receptor subtypes as candidates for the somatodendritic autoreceptor of dorsal raphe neurons.     

Effects of citalopram treatment on hypothermic and hormonal responses to the 5-HT1A receptor agonist buspirone in patients with major depression and therapeutic response

Serotonin (5-HT) 5-HT1A receptor seems to play an important role in the pathophysiology of major depression and in the mechanism of action of antidepressants. In vivo function of 5-HT1A receptors can be monitored using specific pharmacological challenge tests. The present study aimed at exploring the adaptative 5-HT1A receptor changes in depressed patients before and after 8 week treatment with citalopram. The study population consisted of 30 consecutive outpatients of both sexes aged 18-45 years with major depressive disorders (DSM-IV). Basal score in the Hamilton Rating Scale for Depression (HRSD) was higher than 17. Therapeutic response was defined as a 50% decrease in the HRSD score. The hypothermic and endocrine responses (ACTH, cortisol, and prolactin) induced by the 5-HT1A receptor agonist, buspirone (30 mg p.o.) were measured. After 8 weeks on citalopram, the delta max of hypothermic response elicited by buspirone was markedly decreased (p<0.001). Patients showed a decrease in responses to ACTH (delta max p=0.005; AUC p=0.028) and cortisol (delta max p=0.05). However, the prolactin response increased (delta max p=0.02; AUC p=0.005). There was a significant correlation between the therapeutic effect and reductions of ACTH (r=0.883; p<0.001) and cortisol (r=0.610; p=0.001) responses. Changes induced by citalopram support an alteration of 5-HT1A receptors in major depression. A decrease in the overactivity of the HPA axis may be one factor associated with the response to citalopram.     

Multiple hormone responses to clonidine administration in depressed patients and healthy volunteers

Abnormalities in several hypothalamic-pituitary-target organ axes in depression may reflect alterations in central neurotransmitter receptor function. As the alpha 2-adrenergic receptor has been implicated in a variety of neuroendocrine abnormalities in depression, we assessed the role of alpha 2-adrenoceptor dysfunction in mediating response abnormalities of growth hormone, cortisol, and prolactin after intravenous clonidine administration (an alpha 2-adrenergic receptor agonist) in 18 patients with major depression (12 with melancholic features, 6 without melancholic symptoms) and 9 healthy volunteers. In particular, we examined the hypothesis that these abnormalities might be more evident in patients with DSM-III melancholic depression. After clonidine, the mean growth hormone response was significantly lower in melancholic depressives compared to controls (p = 0.02), and the shape of the growth hormone response profile was also significantly different in melancholic patients (p = 0.04). There was an overall decrease in the mean cortisol concentration after clonidine in melancholic patients and control subjects (p = 0.02), as well as a larger cumulative prolactin response in melancholic patients compared to those without melancholic features (p = 0.02). The present results confirm prior observations of a blunted growth hormone response after clonidine and suggest that alterations in alpha 2-adrenergic receptor activity might also contribute to several neuroendocrine abnormalities in patients with melancholic depression.     

Treatment of cerebellar ataxia with 5-HT1A agonist

Effective, pharmacologic approaches to the treatment of cerebellar ataxia are lacking or inadequate. We recently reported preliminary evidence that tandospirone citrate (tandospirone), a 5-HT1A agonist, improved cerebellar ataxia in patients with Machado-Joseph disease (MJD). In the course of that study, we found that such treatment also alleviated the pain associated with cold sensations in the legs, insomnia, anorexia, and depression, all of which are thought to be mediated through activation of the 5-HT1A receptor. In this paper, we reviewed the few published clinical trials that involved the use of 5-HT1A receptor agonists for the treatment of cerebellar ataxia, and discussed the current theories regarding their mechanism of action. Cortical cerebellar atrophy (CCA) was reported, in a double-blind study, to be amenable to treatment with tandospirone. Other types of spinocerebellar degeneration (SCD) i.e., olivopontocerebellar atrophy (OPCA) and Machado-Joseph disease (MJD) have also been reported to respond to the drug, but these have been small studies. Responsive patients exhibited only mild ataxia. The doses of 5-HT1A agonists that have been used successfully ranged from 12.5 mg/day to 60 mg/day (or 1 mg/kg), and were well tolerated by most patients.     

Cortisol in the CSF of depressed and suicidal patients

Cortisol concentrations in CSF were measured by radioimmunoassay in healthy controls, depressed patients, patients who had attempted suicide but were not depressed, and obsessive-compulsive patients. The factors that contributed most to the variance in CSF cortisol levels were a diagnosis of depression, height, and important life changes during the six months preceding the investigation. Depression was by far the most important factor. The depressed patients had significantly higher CSF cortisol levels than the controls. In obsessive-compulsive and depressed patients treated with clomipramine hydrochloride, the levels were significantly correlated with mean urinary cortisol excretion. Of the three monoamine metabolites measured, only 5-hydroxy-indoleacetic acid level was weakly correlated with CSF cortisol level. This correlation was confined to the depressed patients and could be accounted for by the common correlation with height.     

Growth hormone, prolactin and thyrotropin responses to gonadotropin-releasing hormone in depressed patients and healthy volunteers

Growth hormone (GH), prolactin (PRL) and thyrotropin (TSH) release following gonadotropin-releasing hormone (GnRH) administration were examined in 56 patients with major affective disorder (37 unipolar, 19 bipolar) and 38 normal healthy subjects. There were no differences in GH, PRL or TSH responses after GnRH infusion between the patients and the normal subjects, in contrast to previously reported abnormalities in depressed patients. Serum GH concentration increased after GnRH in both normal and depressed men; serum TSH increased after GnRH in both normal women and bipolar women, but not in unipolar depressed women. Further studies comparing GnRH to saline infusion will be necessary to determine if the GH and TSH responses seen in this study are due to GnRH or result from the stress of the experimental procedures.     

Pituitary and adrenocortical responses to the ovine corticotropin releasing hormone in depressed patients and healthy volunteers

It has been suggested that limbic system-hypothalamic "overdrive" may be the underlying mechanism causing an augmented secretion of corticotropin releasing hormone (CRH), heightened adrenocortical responsiveness to corticotropin (adrenocorticotropic hormone) (ACTH), and alteration in cortisol feedback regulatory mechanisms as demonstrated by the dexamethasone suppression test. We examined pituitary and adrenocortical responses after morning administration of ovine CRH (oCRH) in 26 depressed patients and 11 healthy volunteers. Basal plasma ACTH concentrations were similar in both groups, whereas patients had a significantly diminished cumulative ACTH response after administration of oCRH. In contrast, basal total cortisol concentrations and cumulative cortisol responses to oCRH were similar in depressed patients and controls. Patients with melancholic features demonstrated the most profound ACTH blunting after oCRH, whereas patients separated according to dexamethasone suppression test results had similar ACTH and cortisol responses to oCRH. The present results extend data from prior studies utilizing oCRH in the evening and demonstrate a dysregulation of the functional integrity of the hypothalamic-pituitary-adrenocortical axis in depressive illness after a morning oCRH test at both central and peripheral hypothalamic-pituitary-adrenocortical axis sites.     

Chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT differentially desensitizes 5-HT1A autoreceptors of the dorsal and median raphe nuclei

The present study investigated alterations of the regulation of serotonin (5-hydroxytryptamine; 5-HT) release by 5-HT_1A autoreceptors following single and repeated treatment with the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT). Rats were pretreated with 8-OH-DPAT (1.0 mg/kg, s.c.) for 1, 7, or 14 days. The ability of an acute challenge administration of 8-OH-DPAT (1.0 mg/kg, i.p.) to decrease 5-HT release in the ventral striatum and the ventral hippocampus of rats maintained under chloral hydrate anesthesia was examined 24 h after the last pretreatment injection using in vivo microdialysis. The decrease of 5-HT release in the striatum produced by the challenge dose of the 5-HT_1A receptor agonist was diminished following 7 and 14 days of pretreatment, but not after 1 day of pretreatment, with 8-OH-DPAT. In contrast, decreases of 5-HT release in the hippocampus by the 8-OH-DPAT challenge were not altered after 1 or 7 days of pretreatment, and only a trend for attenuation appeared after pretreatment for 14 days. The results of the present study indicate that desensitization of 5-HT_1A autoreceptors regulating 5-HT release in different brain regions by repeated treatment with 8-OH-DPAT occurs at different rates. Synapse 25:107–116, 1997. © 1997 Wiley-Liss, Inc.     

Evidence that spinal 5-HT1, 5-HT2 and 5-HT3 receptor subtypes modulate responses to noxious colorectal distension in the rat

This study examined whether the antinociception produced following the intrathecal (i.t.) administration of serotonin (5-hydroxytryptamine, 5-HT) and other 5-HT receptor agonists in a model of visceral pain that utilizes colorectal distension (CRD) as the noxious visceral stimulus is mediated through interaction with spinal 5-HT1, 5-HT2, or 5-HT3 receptor subtypes. CRD in conscious rats reliably elicits two pseudaffective reflexes: a vigorous pressor response and a visceromotor response. Antinociception is characterized by inhibition of both pseudaffective responses. The effects of 5-HT receptor agonists and antagonists on resting blood pressure were also examined. The i.t. administration of 5-HT resulted in a dose-dependent elevation of the visceromotor threshold and inhibition of the pressor response to CRD. The 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist RU-24969, the 5-HT2 receptor agonists DOI, MK-212 and alpha-methyl-5-HT and the 5-HT3 agonist 2-methyl-5-HT all dose-dependently inhibited the pressor response and dose-dependently elevated the visceromotor threshold to noxious CRD. The rank order of potency of these agonists was the same for both pseudaffective responses to CRD: DOI greater than or equal to 8-OH-DPAT greater than or equal to MK-212 = RU-24969 greater than or equal to alpha-methyl-5-HT = 2-methyl-5-HT much greater than 5-HT. The antinociceptive effects of 5-HT, RU-24969, alpha-methyl-5-HT and DOI were antagonized by i.t. pretreatment with methysergide. Intrathecal pretreatment with ketanserin antagonized the antinociceptive effects of MK-212 and MDL-72222 antagonized the effects produced by 2-methyl-5-HT in response to CRD. The antinociceptive effects produced by 8-OH-DPAT were not antagonized by i.t. pretreatment with methysergide. These results demonstrate that 5-HT1, 5-HT2 and 5-HT3 receptors in the spinal cord mediate antinociception in response to noxious CRD in conscious rats.     

Effects of serotonin 5-HT1A agonist in advanced Parkinson's disease.

Intermittent stimulation of striatal dopaminergic receptors seems to contribute to motor dysfunction in advanced Parkinson's disease (PD). With severe dopaminergic denervation, exogenous levodopa is largely decarboxylated to dopamine in serotonergic terminals. If 5-HT1A autoreceptors regulate dopamine as well as serotonin release, in parkinsonian patients inhibition of striatal serotonergic neuron firing might help maintain more physiological intrasynaptic dopamine concentrations and thus ameliorate motor fluctuations and dyskinesias. To evaluate this hypothesis, effects of a selective 5-HT1A agonist, sarizotan, given orally at 2 and 5 mg twice daily to 18 relatively advanced parkinsonian patients, were compared with baseline placebo function during a 3-week, double-blind, placebo-controlled, proof-of-concept study. Sarizotan alone or with intravenous levodopa had no effect on parkinsonian severity. But at safe and tolerable doses, sarizotan coadministration reduced levodopa-induced dyskinesias and prolonged its antiparkinsonian response (P < or = 0.05). Under the conditions of this study, our findings suggest that 5-HT1A receptor stimulation in levodopa-treated parkinsonian patients can modulate striatal dopaminergic function and that 5-HT1A agonists may be useful as levodopa adjuvants in the treatment of PD.     

Effect of a low tryptophan diet on the prolactin responses to the 5-HT2A agonist DOI in the rat

Low tryptophan (TRP) diets decrease brain serotonin (5-HT) content and produce an up-regulation of the function of some but not all 5-HT receptor subtypes. The aim of the present study was to assess the effect of a two week low TRP containing diet on the plasma prolactin (PRL) response to the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) in the rat. The low TRP diet significantly reduced plasma total TRP as well as brain 5-HT for the two weeks of the study although plasma free TRP was decreased only for the first week of the diet. The PRL response to DOI was significantly increased in the first week of the diet but returned to normal in the second. The results suggest that a low TRP diet produce a transient up-regulation of brain 5-HT2A receptors.     

Cortisol,prolactin, growth hormone and neurovegetative responses to emotions elicited during an hypnoidal state

The present study describes the responses of cortisol, prolactin and growth hormone (GH) to emotions elicited during sessions in which an hypnoidal state was induced. The purpose of the study was to provide answers for the following questions: 1) Do sessions with an emotional content have more hormonal surges than baseline, relaxation-only, sessions? 2) Does the induction of a fantasy of pregnancy and nursing elicit a prolactin response? 3) Are there any associations between surges of different hormones? 4) Are hormonal responses related to the intensity, type, or mode of expression of the emotions? For this purpose, thirteen volunteers and twelve patients with minor emotional difficulties were studied during sessions under hypnosis. The period of observation lasted for about three hours. Heart rate (HR), skin conductance (SC) and vagal tone (VT) were monitored. Serum cortisol, prolactin and growth hormone were sampled every 15 minutes. The volunteers had three types of sessions- "blank", consisting of relaxation only (12 sessions), "breast feeding", in which a fantasy of pregnancy and breast feeding was induced (12 sessions) and "free associations" in which the subjects were encouraged to evoke experiences or feelings (17 sessions). The patients had only sessions of free associations (38 sessions). Sessions of free associations had more hormonal surges than "blank" and "breast feeding" sessions. This was true for cortisol (8/17 v.3/24; p < 0.03), prolactin (7/17 v. 3/24; p < 0.05) and GH (9/17 v. 4/24; p < 0.02). During the 55 sessions of free associations (volunteers plus patients) there were 32 surges of cortisol, 18 of prolactin and 28 of GH. Cortisol and prolactin surges were negatively correlated (p < 0.03). GH had no significant association with either cortisol or prolactin. Visible emotions were positively associated with GH surges (p < 0.05). but not with cortisol or prolactin. Cortisol surges were correlated positively with evocations of real events (p < 0.01) and negatively with evocations containing defensive elements (p < 0.01). Cortisol correlated positively with shock and intimidation (p < 0.02) and negatively with rage (p < 0.04). The AUC of the cortisol peaks during shock and intimidation was significantly higher than that of the pool of all other cortisol peaks (12.4 micromol x min x l(-1) v. 7.1 micromol x min x l(-1); p < 0.005). Rage had a marginally significant positive association with prolactin surges (p=0.07). The distribution of GH surges did not show any significant association with types of emotions. The present study provides evidence that cortisol, prolactin and GH respond to psychological stress in humans. However, they are regulated differently from one another. Cortisol and prolactin surges appear to be alternative forms of response to specific emotions. GH surges depend on the intensity of the emotion, probably as a consequence of the associated muscular activity. The current paradigm of stress, implying corticotrophin-releasing hormone (CRH) as the initial step of a cascade of events, is insufficient to account for the diversity of hormonal changes observed in psychological stress in humans.     

Cortisol secretion in depressed patients. Review of the literature

The authors present a critical overview of the multiple and contradictory studies of cortisol production in depressed patients. Some notions of physiology are first recalled. A main part of the review discusses the dexamethasone suppression test, but studies of the cortisol secretion profile and of other dynamic tests are also presented. One can describe in depressed people: cortisol overproduction, an impaired negative feedback mechanism, an adrenocortical hyperreactivity to ACTH and a phase advance in the circadian rhythm of cortisol secretion. These anomalies are more frequently encountered in patients exhibiting severe depressions of the endogenomorphic type. However, none of them can be considered as a biological marker of depression, nor as a marker for a particular type of depression. The relation between endocrine disturbances and the clinical parameters of depression is still controversial.     

NAN-190: agonist and antagonist interactions with brain 5-HT1A receptors

NAN-190 has been reported to be a 5-HT1A antagonist in drug discrimination studies. In order to determine if the effect of NAN-190 was directly due to competitive inhibition at 5-HT1A receptors, 5-HT1A-mediated inhibition of adenylyl cyclase in hippocampal membranes was investigated. NAN-190 (10(-10)-10(-5) M), by itself, was found to have no effect on forskolin-stimulated adenylyl cyclase. NAN-190, however, did shift the 5-carboxamidotryptamine (a 5-HT1A agonist) log-concentration inhibition curve to the right in a concentration-dependent manner, typical of competitive antagonism. Schild analysis revealed a KB of 1.9 nM for NAN-190. Thus, NAN-190 appeared to be a potent competitive 5-HT1A antagonist using the in vitro adenylyl cyclase system. [3H]NAN-190 was synthesized and its 5-HT1A receptor binding properties were characterized and compared with the 5-HT1A agonist radioligand, [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT). The 5-HT1A agonists, serotonin (5-HT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) competed with equal affinities regardless of the radioligand used to label the 5-HT1A receptors. [3H]NAN-190 and [3H]8-OH-DPAT labeled the same number of sites in rat hippocampus, striatum and frontal cortex. Guanosine-5'-O-(3-thio)triphosphate (GTP gamma S) and 5-guanylyl-imidodiphosphate (GppNHp), non-hydrolyzable analogs of GTP, inhibited specific [3H]NAN-190 binding. Adenosine-5'-O-(3-thio)triphosphate (ATP gamma S) and 5-adenylyl-imidodiphosphate (AppNHp) were ineffective. This guanylyl nucleotide-specific effect is generally associated with agonist radioligand binding to a GTP-binding protein coupled receptor. However, [3H]8-OH-DPAT was far more sensitive than [3H]NAN-190 to the Bmax reducing effects of GTP and GTp gamma S. We propose that the test for a reduction in Bmax by non-hydrolyzable guanylyl nucleotides may be more sensitive than other tests for quantifying agonist activity and may demonstrate that NAN-190 has low intrinsic activity. In summary, NAN-190 displayed antagonist-like properties in functional models of 5-HT1A receptor activity and possibly partial agonist-like properties in radioligand binding experiments.