5-HT1A receptor responsivity in anxiety disorders and depression

1. Azapirones, selective partial agonists at the 5-HT_1A receptor subtype, induce hypothermia and corticotropin (ACTH)/cortisol release as specific functional correlates of central 5-HT_1A receptor activation.

2. Compared to controls, hypothermic and ACTH/cortisol responses to the azapirone ipsapirone are attenuated in patients with unipolar depression and panic disorder but not in patients with obsessive-compulsive disorder. The impaired thermic and neuroendocrine responses are associated with increased basal cortisol secretion in depressed patients but not in patients with panic disorder.

3. Chronic treatment with the selective 5-HT reuptake inhibitor fluoxetine decreases 5-HT_1A receptor-mediated responses in patients with obsessive-compulsive disorder, while long-term treatment with the tricyclic antidepressant amitriptyline further decreases hypothermia following ipsapirone but has no effect on ACTH/cortisol release.

4. Alteration of the 5-HT_1A receptor and/or its signal transduction pathways may play a role in the pathophysiology and treatment of anxiety disorders and depression.     

5-HT1A receptor responsivity in unipolar depression. Evaluation of ipsapirone-induced ACTH and cortisol secretion in patients and controls

The selective 5-HT1A receptor ligand ipsapirone (IPS) induces corticotropin (ACTH) and cortisol secretion in humans. To explore 5-HT1A receptor-mediated hypothalamic-pituitary-adrenal (HPA) system activation in depression, 24 subjects (12 patients with unipolar depression and 12 individually matched controls) were given 0.3 mg/kg IPS or placebo in random order. Compared with controls, the depressed patients exhibited significantly decreased ACTH and cortisol responses to IPS in association with increased basal cortisol secretion. The impaired HPA response following 5-HT1A receptor challenge in unipolar depression could have resulted from glucocorticoid-dependent subsensitivity of the (post-synaptic) 5-HT1A receptor itself and/or from a defective postreceptor signaling pathway [inhibitory guanine nucleotide-binding protein (Gi)-adenylate cyclase complex function], thus supporting the hypothesis that a disintegrated 5-HT and HPA system interaction may be present in depression. Future studies of the HPA response to direct-acting 5-HT1A ligands, such as IPS, should facilitate the assessment of 5-HT/HPA system integrity in various affective disorders and its involvement in psychotropic drug effects.     

Neuroendocrine response to meta-chlorophenylpiperazine and ipsapirone in relation to anxiety and aggression

The aim of this study was to establish the association of trait anxiety and anger with hormonal responses to acute challenges with two different 5-HT agonists in a mixed group of patients with depressed mood. Fifteen patients and 16 normal controls received single oral doses of 0.5 mg/kg meta-chlorophenylpiperazine (MCPP), a 5-HT(2C) agonist, and 10 mg of ipsapirone, a 5-HT(1A) agonist, according to a double-blind, placebo-controlled, cross-over design. Dutch-adapted versions of the Spielberger Trait-Anxiety Inventory and the Spielberger Trait-Anger Scale administered assessed at study entry. Hormonal responses, expressed as drug-placebo differences, to MCPP and ipsapirone (changes in cortisol, ACTH and prolactin) were measured. Blood levels of MCPP and ipsapirone were also measured. MCPP and ipsapirone elevated cortisol, ACTH and prolactin. In the patient group, there was a significant correlation between trait anxiety and the cortisol response to MCPP. No significant correlations between the ACTH and prolactin responses to MCPP and levels of anxiety/anger were observed in the patients. No significant correlations could be established between levels of anxiety/anger and hormonal responses to ipsapirone. This study provided evidence for an association between measures of anxiety/aggression and the hormonal response to MCPP. Thus, in subjects with depressed mood, high levels of anxiety suggest a higher probability of 5-HT(2C) disturbances.     

Effects of short-term administration of valproate on serotonin-1A and dopamine receptor function in healthy human subjects

OBJECTIVE: To examine the effects of short-term valproate treatment on human brain serotonin and dopamine function by means of challenge tests with ipsapirone, a partial agonist at 5-HT1A receptors, and apomorphine, a dopamine receptor agonist. DESIGN: Experimental challenge-rechallenge, within-subjects repeated measures, before and at the end of 14 days of treatment with valproate at a dosage of 625 mg/d (reached gradually over the first 5 days). PARTICIPANTS: Eight healthy male volunteers (mean age 38 years) selected for good physical and mental health who were nonsmokers. OUTCOME MEASURES: Pharmacological probes were used to evaluate the effects of valproate. In the ipsapirone challenge, changes in adrenocorticotropic hormone (ACTH), cortisol and body temperature were measured, and in the apomorphine challenge, growth hormone (GH) and prolactin were the dependent variables. RESULTS: Valproate treatment did not significantly alter the ACTH, cortisol or body temperature responses to ipsapirone (20 mg by mouth), which reached equivalent plasma levels at each challenge. Similarly, valproate treatment did not alter the GH or prolactin responses to apomorphine (5 micrograms/kg subcutaneously). CONCLUSIONS: These results suggest that short-term treatment with valproate at a dose of 625 mg/d does not alter hypothalamic or pituitary 5-HT1A or dopamine receptor responses to challenges with ipsapirone and apomorphine, respectively.     

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.     

5-HT(1A) receptor dysfunction in female patients with schizophrenia.

BACKGROUND: Serotonin (5-HT)(1A) receptors are of interest in the pathophysiology of schizophrenia (SCH) and the mechanism of action of atypical antipsychotic drugs. To test the hypothesis that 5-HT(1A) receptor responsivity is significantly different in patients with SCH compared to normal control subjects, the neuroendocrine study was performed using ipsapirone (IPS), a 5-HT(1A) partial agonist, as a probe. METHODS: Ipsapirone 0.5 mg/kg, p.o. or placebo were administered, in random order, to patients with SCH (n = 43; 32 male) and normal controls (n = 33; 21 male). Blood samples for plasma cortisol and body temperature were obtained from 30 min before to 180 min after administration of IPS or placebo. RESULTS: Female normal control subjects had markedly greater increases in plasma cortisol following IPS than did male control subjects. The placebo response-corrected plasma cortisol response to IPS was significantly blunted in female SCH compared to female normal control subjects (p =.0001). The IPS-stimulated plasma cortisol response in male SCH did not differ from that of male normal control subjects or female SCH. There were no significant differences in the IPS-induced hypothermia in men and women or between patients with SCH and normal control subjects. Behavioral responses to IPS, including nausea, dizziness, irritability, and feeling less well, did not differ between groups. CONCLUSIONS: These results suggest that the post-synaptic 5-HT(1A) receptor mediated endocrine response is diminished in female SCH compared to female normal control subjects, possibly secondary to an abnormality in intracellular signal transduction mechanism.     

Arginine vasopressin,but not corticotropin releasing factor,is a potent stimulator of adrenocorticotropic hormone following electroconvulsive treatment

Neuroendocrine responses to the hypothalamic pituitary-adrenal axis following electroconvulsive treatment (ECT) were evaluated in twelve depressed (6 males/6 females) patients. Plasma concentrations of arginine vasopressin (AVP), corticotropin releasing factor (CRF), corticotropin (ACTH), and cortisol were measured using radioimmunological methods at four different ECT occasions. At each occasion plasma samples were taken immediately before ECT, at the recovery of spontaneous breathing and at 10 and 30 minutes after the ECT. No changes were observed in the plasma CRF concentrations. A large and rapid increase in plasma AVP concentrations was seen after the ECTs. This was followed by increased plasma ACTH and plasma cortisol levels. It is generally believed that AVP exerts a modulatory potentiating action on the CRF-induced ACTH release. The present results demonstrate that AVP per se can cause a release of ACTH from the anterior pituitary.     

Effect of 5-hydroxytryptophan on serum cortisol levels in major affective disorders. III. Effect of antidepressants and lithium carbonate

Serum cortisol levels were significantly increased following administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, to patients with affective disorders. A three- to five-week period of treatment with lithium carbonate or monoamine oxidase (MAO) inhibitor augmented the mean 5-HTP-induced increase in serum cortisol concentration in manic or depressed patients, respectively: tricyclic antidepressant (TCA) and second-generation antidepressant treatment diminished the mean serum cortisol response in patients with major depression. These results are consistent with the hypothesis that lithium carbonate may enhance serotonin (5-HT) receptor sensitivity, whereas TCA and second-generation antidepressants diminish 5-HT receptor sensitivity. The enhancement of the cortisol response to 5-HTP by MAO inhibitors may be due to decreased metabolism of 5-HT. It is important to assess the effect of thymoleptic drug treatment on various responses to biogenic amine precursors or agonists in patients rather than laboratory animals.     

Functional effects of chronic electroconvulsive shock on serotonergic 5-HT(1A) and 5-HT(1B) receptor activity in rat hippocampus and hypothalamus

The aims of this work were to determine the influence of chronic electroconvulsive shock (ECS) on presynaptic 5-HT(1A) receptor function, postsynaptic 5-HT(1A) receptor function in hippocampus and hypothalamus, and presynaptic 5-HT(1B) receptor function in hippocampus and hypothalamus. This represents part of an on-going study of the effects of ECS on serotonergic receptor activity in selected brain areas which may be relevant to the effects of electroconvulsive therapy (ECT) in humans. Chronic ECS reduced the ability of the 5-HT(1A) receptor agonist 8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) (0.2 mg/kg s.c.) to decrease 5-HT levels in hypothalamus as shown by in vivo microdialysis, indicative of a reduction in sensitivity of presynaptic 5-HT(1A) autoreceptors. The ability of the 5-HT(1B) receptor antagonist GR 127935 (5 mg/kg s.c.) to increase 5-HT levels in both hippocampus and hypothalamus was unaffected by chronic ECS. 8-OH-DPAT (0.2 mg/kg s.c.) increased cyclic AMP levels in hippocampus measured by in vivo microdialysis approximately 2-fold. The degree of stimulation of cyclic AMP formation was not altered by chronic ECS. However the cyclic AMP response to forskolin (50 micro M) administered via the microdialysis probe, which was approximately 4-fold of basal in sham-treated rats, was almost completely abolished in ECS-treated rats. Since this indicates that either adenylate cyclase catalytic unit activity or Gs protein activity is reduced in the hippocampus after chronic ECS, the lack of change in 8-OH-DPAT-induced cyclic AMP formation may be taken as possible evidence of an increase in sensitivity of postsynaptic 5-HT(1A) receptors in the hippocampus by chronic ECS. Chronic ECS increased basal plasma levels of corticosterone, ACTH and oxytocin. The ACTH response to s.c. injections of 0.2 mg/kg or 0.5 mg/kg 8-OH-DPAT was reduced by chronic ECS. Postsynaptic 5-HT(1A) receptor activity in the hypothalamus, in contrast to the hippocampus, thus appears to be desensitized after chronic ECS. We conclude that chronic ECS has regionally specific effects on both pre- and post-synaptic 5-HT(1A) receptors, but, in contrast to some antidepressant drugs, does not affect presynaptic 5-HT(1B) receptor activity.     

Neuroendocrine evidence for decreased function of alpha 2-adrenergic receptor after electroconvulsive therapy.

Growth hormone (GH) and hypotensive responses to clonidine (150 micrograms, i.v.) were investigated before and after electroconvulsive therapy (ECT) in 16 depressed patients. Because of high baseline serum GH concentrations, results from only 10 patients could be evaluated. The level of GH secretion induced by clonidine was significantly reduced after ECT, but the hypotensive responses to clonidine remained unchanged. The results indicate downward regulation of the sensitivity of alpha 2-adrenergic receptors in the hypothalamus after ECT.     

Evidence for a mutual interaction between noradrenergic and serotonergic agonists in stimulation of ACTH and corticosterone secretion in the rat

We investigated the mutual interactions between hypothalamic norepinephrine (NE) and serotonin (5-HT) in mediating the ACTH and corticosterone responses to direct stimulation of the paraventricular nucleus (PVN) with adrenergic and serotonergic agonists. The hormone responses to the intrahypothalamic injection of the alpha1-adrenergic agonist phenylephrine (20 nmol/2 microl) were significantly reduced by prior depletion of hypothalamic 5-HT with intra-PVN injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), but not after depletion of hypothalamic NE by intra-PVN injection of the noradrenergic neurotoxin 6-hydroxydopamine (6-OHDA). The ACTH and corticosterone responses to intrahypothalamic injection of the 5-HT(1A) receptor agonist 8-OH-DPAT (20 n mol/2 microl) were significantly reduced by depletion of hypothalamic NE with 6-OHDA, but not after depletion of hypothalamic 5-HT with 5,7-DHT. These mutual interactions between the NE and 5-HT neuronal systems, which innervate the PVN, may explain previous findings of equivalent reductions in the hypothalamic-pituitary-adrenal axis responses to neural stimulation after neurotoxic lesioning of either the NE or 5-HT systems.     

Effects of selected serotonin 5-HT(1) and 5-HT(2) receptor agonists on feeding behavior: possible mechanisms of action

Serotonin (5-HT) receptor agonists with high affinity for the different subtypes (i.e. 5-HT(1A-1F), 5-HT(2A-2C)) of the 5-HT(1)- and 5-HT(2) receptor families have been shown to affect ingestive behavior. It has been assumed that: (1) stimulation of hypothalamic 5-HT(2C) or 5-HT(1B) receptors leads to a behaviorally specific hypophagic effect by accelerating satiety processes; (2) stimulation of 5-HT(2A) receptors leads to a disruption of the feeding cascade; and (3) stimulation of 5-HT(1A) and 5-HT(2B) receptors leads to a hyperphagic effect. The present paper reviews studies performed with the relatively selective receptor agonists ipsapirone (5-HT(1A)), CP-94,253 (5-HT(1B)), BW 723C86 (5-HT(2B)) and ORG 37684 (5-HT(2C)), as well as the nonselective receptor agonists TFMPP (5-HT(1B/2C)), m-CPP (5-HT(2C/1B)) and DOI (5-HT(2A/2C)) in a variety of feeding paradigms in rats, both after systemic and local injection. These studies support a role for other neuroanatomical regions (i.e. brain stem) and behavioral mechanisms (i.e. appetitive processes) in the hypophagic effects of these compounds, possibly as a function of the administered dose. Studies with 5-HT receptor antagonists indicate that the proposed role of particular 5-HT(1/2) receptor subtypes in the hypophagic effects of these 5-HT receptor agonists may be more complicated than originally thought. Further characterization of the role of 5-HT(1/2) receptor subtypes in the control of ingestive behavior will require extensive pharmacological and behavioral studies, using more selective receptor agonists and antagonists and different behavioral procedures, as well as verification in transgenic animals.     

Serotonin and GABA-induced depolarizations of frog primary afferent fibers

The interaction of gamma-aminobutyric acid (GABA) and serotonin (5-HT) on primary afferent terminals of the isolated frog spinal cord was investigated by sucrose gap recordings from dorsal roots. Application of 5-HT (1.0-100 microM) to the Ringer's solution significantly reduced afferent terminal depolarizations elicited by concentrations of GABA ranging from 0.1 to 1.0 mM. The reductions of GABA-depolarizations which were produced by 1.0 microM 5-HT were mimicked by the 5-HT1A agonists 8-OH-DPAT (8-hydroxy-2-(n-dipropylamino)tetralin) and ipsapirone. The effects of ipsapirone were reversed by the 5-HT1A antagonist spiperone. The decreases of GABA-depolarizations produced by high doses of 5-HT were duplicated by application of alpha-methyl-5-HT, a 5-HT1C/2 agonist and reversed by superfusion of the cord with manserin, a 5-HT1C/2 antagonist. The presumptive 5-HT1A receptor-mediated effects of 1.0 microM 5-HT and 8-OH-DPAT appeared to result from a direct action on afferent terminals because the reduction of GABA responses was unchanged by addition of TTX to the Ringer's solution. In contrast, the putative 5-HT1C/2 receptor actions of 100 microM 5-HT and alpha-methyl-5-HT were substantially reduced by TTX and are presumably caused by activation of receptors located on interneurons. GABAB receptors did not appear to be affected by addition of 5-HT at low or high concentrations because baclofen-induced afferent terminal hyperpolarizations remained unchanged during exposure to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biochemical effects of electroconvulsotherapy

ECT and ECS biochemical, pharmacological and electrophysiological effects on Norepinephrine, Dopamine, Serotonin, Acetylcholine, GABA and Opiates are reviewed. ECS and ECT seem to potentiate behavioral responses to Serotoninergic and Dopaminergic agonists, and up-regulate post-synaptic 5-HT2 receptors. However, the mechanism of the antidepressant effect remains unknown and probably involves several interacting neurotransmitters.     

5-HT neuroendocrine responses during psychotropic drug treatment: an investigation of the effects of lithium

Increasing brain 5-hydroxytryptamine (5-HT) function in humans raises plasma concentrations of prolactin, growth hormone and ACTH. Measurement of these hormonal responses provides an index of the functional activity of brain 5-HT pathways. More recent strategies have included the use of directly-acting 5-HT receptor agonists to probe the function of specific receptor subtypes; at present these studies are limited by the questionable selectivity of the agonists employed. Using 5-HT neuroendocrine testing it can be shown that lithium specifically increases the prolactin release mediated by 5-HT pathways. Further studies are needed to determine if this effect is caused by an enhanced sensitivity of post-synaptic 5-HT1A receptors.     

Hormone response to repeated electroconvulsive therapy: effects of naloxone

Plasma prolactin (PRL), cortisol, and growth hormone (GH) were measured before, and at 15-min intervals for 1 hr after, electroconvulsive therapy (ECT). This was repeated over a series of 6 consecutive treatments for each of 12 depressed drug-free inpatients. Patients received naloxone, 2 mg or 20 mg, by intravenous infusion before the third and fifth treatment. ECT was consistently followed by a release of PRL and cortisol, although two patterns of PRL response could be distinguished. In eight patients, the PRL response did not change significantly with repeated ECT, whereas in four patients, the plasma PRL increased tenfold after the first treatment and decreased after each successive treatment. The GH level varied widely, with no evidence of a reliable response to ECT. Opiate receptor blockade with low- or high-dose naloxone did not alter the release of PRL or cortisol after ECT. These findings demonstrate a reliable PRL and cortisol response to ECT, but do not support a role for endogenous opiates in these hormonal changes.     

5-Hydroxytryptamine and corticosterone in an animal model of depression

1. Rat plasma corticosterone increases during 2 hr restraint stress. The animals then exhibit hypophagia and decreased locomotion occurs on placement 24 hr later in an open field. Repeating the restraint daily for 5-7 days leads to adaptation. Failure to adapt is the depression model which is associated with three factors implicated in the illness ie increased plasma glucocorticoid level, female sex and inadequate 5-HT function as revealed by behavioural response to the agonist 5-methoxy-N,N-dimethyl 5-HT. However, the greater stress induced rise of corticosterone in female rats may reflect a greater response to activation of hypothalamic 5-HT receptors mediating corticoid release. 2. The model responds appropriately to chronic antidepressant pretreatment. Single injections of 5-HT1A agonists (8-OH-DPAT, buspirone, ipsapirone, gepirone) but not of benzodiazepine anxiolytics have similar effects. Therefore, 5-HT1A agonists may have antidepressant activity. Both behavioural and neurochemical evidence indicates that the adaptive effects of 5-HT1A agonists on the depression model are associated with desensitisation of somatodendritic 5-HT1A autoreceptors.     

Serotonergic and dopaminergic neuroendocrine responses of male depressive patients before and after a therapeutic ECT course

Background: Electroconvulsive therapy (ECT) is an effective treatment for major depressive illness, even for patients who do not respond to antidepressant drugs. According to the prevailing neurophysiological hypotheses for depression, it can be expected that an ECT therapeutic course modulates the responsivity of central neurotransmitter systems, but the results up to now have been inconclusive. To test such hypotheses, we studied possible changes in the serotonergic and in dopaminergic systems' responsivity in 11 male patients with major depression by performing neuroendocrine challenge tests before and after a therapeutic ECT course. Methods: Serotonergic responsivity was assessed by measuring the prolactin and cortisol responses to i. v. administration of the serotonin uptake inhibitor clomipramine (CMI test), and dopaminergic responsivity by measuring the prolactin responses to the dopamine receptor blocker haloperidol (HAL test), administered intramuscularly. The prolactin and cortisol responses during the first and the last ECT of the course (8 to 13 sessions) were also assessed. The CMI and HAL tests were also performed in 13 male healthy subjects. Results: The prolactin responses to CMI were significantly blunted in the patient group compared to the control group, and remained unaltered at the end of the ECT course, although the depressive symptomatology was substantially reduced from 27.8 ± 7.1 to 4.8 ± 2.3 points in the Hamilton Depression Rating Scale. The cortisol responses to CMI were blunted before the ECT course compared to controls, but not after the course: there was a moderate increase of cortisol at + 30 min in the CMI test after the ECT course compared to that before ECT (p = 0.05). The prolactin and cortisol responses to the electrical stimulus during the first and the last ECT were identical. Conclusions: The strong therapeutic effect of ECT in depression, observed already at the end of the course, is not a result of considerable modifications in central serotonergic or dopaminergic responsivity, as revealed by the neuroendocrine challenge tests and the hormone responses to the electrical stimulus. The enhancement of the cortisol responses to CMI after the course may indicate a moderate increase in 5-HT1A receptor responsivity. Received: 5 March 2002 / Accepted: 15 July 2002     

Lack of effect of HPA axis hyperactivity on hormonal responses to d-fenfluramine in major depressed patients: implications for pathogenesis of suicidal behaviour

There is evidence for inhibitory effects of adrenocorticosteroids on serotonergic (5-HT) activity. However, in depression the relationship between altered cortisol levels and brain 5-HT function remains to be clarified. The aim of this study was to investigate whether hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is associated with 5-HT dysfunction in depressed patients, especially in those with suicidal behaviour. Cortisol levels following the dexamethasone suppression test (DST, 1 mg PO) and prolactin, corticotropin and cortisol responses to the d-fenfluramine test (d-FEN, 45 mg PO) - a specific 5-HT releaser/uptake inhibitor - were measured in 71 drug-free DSM-IV major depressed inpatients (40 with a history of suicide attempt, 31 without) and 34 hospitalized healthy control subjects. Depressed patients showed higher post-DST cortisol levels but similar responses to d-FEN compared with control subjects. Hormonal responses to d-FEN were not correlated with cortisol levels (basal or post-DST). Among the depressed patients, DST suppressors and DST nonsuppressors exhibited no significant difference in endocrine responses to d-FEN. However, patients with a history of suicide attempt, when compared with patients without such a history, showed lower hormonal responses to d-FEN but comparable basal and post-DST cortisol levels. Taken together these results suggest that, in depression, HPA axis hyperactivity is not responsible for the reduced 5-HT activity found in patients with a history of suicidal behavior.