Postsynaptic 5-HT1A Receptor Function Research Articles

Maternal Protein Deficiency Causes Region‐Specific and Sex‐Dependent Changes in 5‐HT1A Receptor Function in Adult Offspring

Protein insufficiency, rather than caloric restriction, during pregnancy leads to abnormalities in emotion and cognition in adult offspring. However, the underlying neural mechanisms are unclear. In rats, we examined serotonin1A (5‐HT1A) receptor function in adult offspring of mothers that were free‐fed standard (20%) or low (10%) protein isocaloric chow during pregnancy. Importantly, the maternal low protein diet did not affect the body weight of mothers or offspring. At P110‐117, 5‐HT1A receptor agonist DPAT (0.01‐1mg/kg, ip) induced stereotypic behaviors were measured. The potency of DPAT to induce flat body posture and lower lip retraction was reduced in female offspring, as indicated by rightward shifts (~3 fold) in the dose‐response curves. In littermates, we used quantitative autoradiography to measure the capacity of 5‐HT1A receptors to activate G proteins. The maternal low protein diet resulted in a 50% decrease in DPAT (1μM)‐stimulated [35S]GTPΥS binding in hippocampus of female offspring, with no change in frontal cortex, suggesting a region‐specific down‐regulation of postsynaptic 5‐HT1A receptor function. DPAT (1μM)‐stimulated [35S]GTPΥS binding was increased (54%) in dorsal raphe of female offspring, suggesting enhanced inhibition of serotonin neuronal activity. By contrast, no significant change in 5‐HT1A receptor function was observed in male offspring. Both in vivo and ex vivo data indicate that maternal protein deficiency causes profound region‐specific and sex‐dependent changes in 5‐HT1A receptor function, which may underlie abnormal emotion and cognition in adult offspring. Supported by Morrison Trust

Activation of postsynaptic 5-HT1A receptors improve stress adaptation

Serotonin-1A (5-HT1A) receptors modulate the stress response and have been implicated in the etiology and treatment of depression and anxiety disorders. A reduction in postsynaptic 5-HT1A receptor function in limbic areas has consistently been observed following exposure to chronic stress. To investigate the hypothesis that increased activation of 5-HT1A receptors in rats having reduced 5-HT function may improve stress adaptation and the behavioral sequelae commonly associated with chronic stress. One hundred forty-four Sprague-Dawley rats received injections of para-chlorophenylalanine to partially deplete 5-HT then were given daily systemic pretreatment with the 5-HT1A receptor agonist, 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), the antagonist, WAY 100635, or vehicle prior to either restraint stress (6h/day for 10 daily sessions) or control conditions. Anxiety- and depressive-like behaviors were then assessed using the open field and sucrose preference tests. Protein level of hippocampal glucocorticoid receptors (GR) and mineralocorticoid receptors was detected by immunohistochemistry and brain-derived neurotrophic factor (BDNF) was determined by in situ hybridization. 8-OH-DPAT pretreatment prior to stress exposure attenuated later stress-induced anxiety- and depression-like behaviors and increased GR and BDNF mRNA expression in the hippocampus relative to vehicle- and WAY 100635-pretreated, stressed animals. The stress-related impairments associated with 5-HT deficiency can be improved by 8-OH-DPAT pretreatment prior to stress exposure and are associated with an augmentation of GR-like immunoreactivity and BDNF mRNA expression in the hippocampus. It suggested that selective activation of 5-HT1A receptors may be a potential treatment strategy for stress-related disorders such as anxiety and depression.

Prolactin response to buspirone is not impaired in drug-naïve first episode patients with major depressive disorder

BackgroundAn altered postsynaptic 5-HT1A receptor function along with hypercortisolemia has been associated with major depressive disorder (MDD). However, several methodological considerations related to data interpretation arise when subjects previously exposed to psychotropic medication are included in the study population. To address those issues we designed a study in a well defined cohort of first-episode, treatment-naïve MDD patients. MethodsThis cross-sectional case–control pharmacologic challenge study was designed to investigate the prolactin (PRL) response to buspirone in 21 non-late-life adult, treatment-naïve MDD patients with the first affective episode and in 20 age- and sex-matched healthy controls. Depressed patients showed a basal score in the Hamilton Rating Scale for Depression (HAMD-17) higher than 20. ResultsNo significant difference in PRL response to buspirone between first-episode, treatment-naïve patients with MDD and controls, was observed. The correlation between basal cortisol levels and PRL response was not observed in MDD group while significant negative correlation was found in healthy controls. The significantly higher PRL response to buspirone was observed in melancholic patients as compared to non-melancholic subjects. LimitationsThe current study is limited by its cross-sectional design, small sample size, factors related to neuroendocrine challenge methodology, and no placebo control. ConclusionThese results indicate no consistent changes in the hormonal response to the 5-HT1A agonist buspirone in major depression. Taken into account the interpretation of the buspirone test the present study does not support the hypothesis of an altered functional activity with down-regulation of the postsynaptic 5-HT1A receptor and/or in the postsynaptic receptor signal transduction in the hypothalamus in the pathogenesis of MDD.

Hormonal responses to the 5-HT1A agonist buspirone in remitted endogenous depressive patients after long-term imipramine treatment

The serotonin-1A (5-HT1A) receptor subtypes are considered as targets of a variety of antidepressant drugs. Previous studies have suggested different adaptive changes in pre- and post-synaptic 5-HT receptors in the brain after treatment with non-selective tricyclic antidepressants (TCA) and selective 5-HT re-uptake inhibitors (SSRIs). The present study aimed to investigate the adaptive effect of the TCA imipramine on the post-synaptic 5-HT1A receptor function in the hypothalamus. A longitudinal design was used in 14 patients with major depressive disorder (DSM-IV) with endogenous features (Newcastle Scale) in order to assess the functional status of post-synaptic 5-HT1A receptors before and after successful antidepressant treatment with imipramine. The effect of the 5-HT1A receptor agonist, buspirone, on ACTH, cortisol, and prolactine (PRL) plasma levels was used to assess the functional status of hypothalamic 5-HT1A receptors. A group of 15 concurrent normal subjects were used as control. Endogenous depressed patients in remission and currently receiving treatment with imipramine (mean length of treatment 145 days, SD=27) presented significantly lower buspirone responses to ACTH and cortisol than in the pre-treatment condition (Deltamax p< or =.05; AUC p<.001) and to ACTH in comparison with healthy controls (Deltamax p<.01; AUC p<.05). No significant differences were found between the post-treatment and pre-treatment PRL responses, or between patients in both conditions and controls; nevertheless, the PRL response in patients in remission and receiving treatment almost reached the values seen in controls. This study extends previous findings from our group using the SSRI citalopram as an antidepressant. Imipramine and citalopram induce similar changes in the endocrine response to buspirone in depressed patients. As the direction of change in ACTH-cortisol and PRL responses after treatment is the opposite, we cannot substantiate increases or decreases in the sensitivity of post-synaptic 5-HT1A receptors in the hypothalamus by long-term imipramine treatment and/or resolution of illness. Therefore, the hormonal changes may result from different or multiples unknown mechanisms.

Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats

While individual differences in vulnerability to psychostimulants have been largely attributed to dopaminergic neurotransmission, the role of serotonin is not fully understood. To study the rewarding and motivational properties of cocaine in the serotonin transporter knockout (SERT-/-) rat and the involvement of compensatory changes in 5-HT1A receptor function are the objectives of the study. The SERT-/- rat was tested for cocaine-induced locomotor activity, cocaine-induced conditioned place preference, and intravenous cocaine self-administration. In addition, the function and expression of 5-HT1A receptors was assessed using telemetry and autoradiography, respectively, and the effect of 5-HT1A receptor ligands on cocaine's psychomotor effects were studied. Cocaine-induced hyperactivity and conditioned place preference, as well as intravenous cocaine self-administration were enhanced in SERT-/- rats. Furthermore, SERT-/- rats displayed a reduced hypothermic response to the 5-HT1A receptor agonist 8-OHDPAT. S-15535, a selective somatodendritic 5-HT1A receptor agonist, reduced stress-induced hyperthermia (SIH) in wild-type controls (SERT+/+), while it increased SIH in SERT-/- rats. As 5-HT1A receptor binding was reduced in selective brain regions, these thermal responses may be indicative for desensitized 5-HT1A receptors. We further found that both 8-OHDPAT and S-15535 pretreatment increased low-dose cocaine-induced locomotor activity in SERT-/- rats, but not SERT+/+ rats. At a high cocaine dose, only SERT+/+ animals responded to 8-OHDPAT and S-15535. These data indicate that SERT-/- -associated 5-HT1A receptor adaptations facilitate low-dose cocaine effects and attenuate high-dose cocaine effects in cocaine supersensitive animals. The role of postsynaptic and somatodendritic 5-HT1A receptors is discussed.

Hormonal response to buspirone is not impaired in major depression

It has been suggested that interactions between hypothalamic pituitary adrenal (HPA) axis and serotonin-1A (5-HT(1A)) receptor system are involved in the pathophysiology of major depression. Pharmacologic challenge test with 5-HT(1A) receptor agonists is a useful approach to study the sensitivity of 5-HT(1A) receptors in depressed patients and the interaction of these systems. A cross-sectional case-control study was designed to assess the effect of the 5-HT(1A) receptor agonist, buspirone, on 5-HT(1A) receptor function in 30 patients with major depression (DSM-IV) and in 30 age- and sex-matched healthy controls. Depressed patients showed a basal score in the Hamilton Rating Scale for Depression (HRSD) higher than 17. After the administration of a single oral dose of buspirone (30 mg), corticotrophin (ACTH), cortisol, and prolactin (PRL) peak response minus baseline (Delta) and area under the curve (AUC) were evaluated. No significant difference in the hormonal response between depressed patients and controls was observed. No correlation with the severity of depression (HRSD score) was found. These results indicate no consistent changes in the hormonal response to the 5-HT(1A) agonist buspirone in depressed patients. Therefore, this study does not support the hypothesis of an altered postsynaptic 5-HT(1A) receptor function in major depression.

Mice overexpressing CRH show reduced responsiveness in plasma corticosterone after a5-HT1A receptor challenge.

Corticotropin-releasing hormone (CRH) overproduction and serotonergic dysfunction have both been implicated in a range of psychiatric disorders, such as anxiety and depression, and several studies have shown interactions between these two neurotransmitter systems. In this study, we investigated the effects of CRH challenge on hypothalamo-pituitary-adrenal (HPA) axis activity in female transgenic mice overproducing CRH. Furthermore, the effects of mild stress on HPA axis activity and body temperature were investigated in these mice. Pre- and post-synaptic 5-HT1A receptor function were studied by monitoring body temperature and plasma corticosterone levels after challenge with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT). Hypothermia in response to 8-OH-DPAT treatment did not differ between transgenic and wild type mice, indicating unaltered somatodendritic 5-HT1A autoreceptor function in mice overproducing CRH. In wild type mice 8-OH-DPAT increased plasma corticosterone levels, but not in transgenic animals. CRH injection, however, increased corticosterone levels in both groups. These data suggest desensitization of post-synaptic, but not pre-synaptic, 5-HT1A receptors in mice overproducing CRH. These findings resemble those seen in depressed patients following 5-HT1A challenge, which is in accord with the hypothesized role of CRH in the pathogenesis of depression.

Corticosterone responses in 5-HT1B receptor knockout mice to stress or 5-HT1A receptor activation are normal.

Previous research found no adaptations in presynaptic 5-HT1A receptors in mice lacking 5-HT1B receptors (5-HT1B KO). Stress and 5-HT1A receptor agonists induce corticosterone release in mice via hypothalamus-pituitary-adrenal (HPA) axis activation. 5-HT1B KO mice are hyperreactive to mild stressors and this might be reflected in altered postsynaptic 5-HT1A receptor sensitivity. Our aim was to determine whether the activity of the HPA axis was increased in 5-HT1B KO mice in response to mild stress and pharmacological activation of 5-HT1A receptors as an indication of putative adaptive changes in postsynaptic 5-HT1A receptor function. The effect of mild stress [i.e., the stress-induced hyperthermia (SIH) paradigm], induced by rectal temperature measurement, was determined on temperature and corticosterone over time (0, 5, 10, 20, 30, 60, and 90 min) in 5-HT1B KO and wildtype mice. In addition, corticosterone was measured 60 min after 5-HT1A receptor activation by flesinoxan (0, 0.03, 0.1, 0.3, 1, and 3 mg/kg s.c.). Blood was collected and plasma corticosterone levels were determined by radioimmunoassay. Both genotypes showed comparable time-dependent SIH responses, whereas basal temperature was higher in 5-HT1B KO mice. The effect of SIH on temperature was mirrored by mild increases in plasma corticosterone. Activation of 5-HT1A receptors caused a strong dose-dependent release of corticosterone in both genotypes. Neither response observed showed differences between both genotypes. Although 5-HT1B KO mice are hyperreactive to mild stress, this reactivity is not reflected by stronger corticosterone responses in the SIH paradigm. The lack of shift in dose-response curves for flesinoxan suggests that postsynaptic 5-HT1A receptor function is unaffected in 5-HT1B KO mice.

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

The increase of extracellular 5-HT in brain terminal regions produced by the acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT1A autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre- and postsynaptic 5-HT1A receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA3 pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective β-adrenoceptor antagonist metoprolol (15 mg/kg, i.p.). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT1A receptors was suggested by its complete reversal by the 5-HT1A antagonist WAY 100635 (100 μg/kg, i.v.). A short-term treatment with VLX (20 mg/kg/day × 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day × 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT1A receptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT1A autoreceptor, but not its postsynaptic congener. These results support and extend previous findings providing a biological substratum for the efficacy of pindolol as an accelerating strategy in major depression.

Behavioural profiles in the mouse defence test battery suggest anxiolytic potential of 5-HT(1A) receptor antagonists.

Compounds varying in selectivity as 5-HT1A receptor antagonists have recently been reported to produce anxiolytic-like effects comparable to those of benzodiazepines in the mouse elevated plus-maze procedure. In view of the potential clinical significance of these findings, the present experiments compared the behavioural effects of diazepam (0.5-3.0 mg/kg) with those of several non-selective 5-HT1A receptor antagonists [NAN-190, 0.1-3.0 mg/kg, MM-77, 0.03-1.0 mg/kg, (S)-UH-301, 0.3-3.0 mg/kg and pindobind-5-HT1A, 0.03-1.0 mg/kg], and three selective 5-HT1A receptor antagonists (WAY100635, 0.01-3.0 mg/kg, p-MPPI, 0.1-3.0 mg/kg and SL88.0338, 0.3-3.0 mg/kg) in the mouse defence test battery (MDTB). In this well-validated anxiolytic screening test, Swiss mice are directly confronted with a natural threat (a rat) as well as situations associated with this threat. Primary measures taken during and after rat confrontation were flight, risk assessment (RA), defensive threat/attack and escape attempts. Diazepam significantly decreased flight reactions after the rat was introduced into the runway, reduced RA activities of mice chased by the rat, increased RA responses displayed when subjects were constrained in a straight alley and reduced defensive upright postures and biting upon forced contact. All the selective 5-HT1A receptor antagonists and NAN-190 also reduced flight, RA in the chase test, and defensive threat and attack behaviours. (S)-UH-301 and pindobind-5-HT1A reduced RA in the chase test, but only partially modified defensive threat and attack. Unlike the other drugs tested, MM-77 produced significant effects only at doses which also markedly reduced spontaneous locomotor activity, suggesting a behaviourally non-specific action. In contrast to diazepam, the 5-HT1A receptor ligands failed to affect RA in the straight alley test. Following removal of the rat from the test area, only diazepam and (S)-UH-301 reduced escape behaviour (contextual defence) at doses which did not decrease locomotion. Overall, the present findings indicate that except for one RA behaviour and escape responses, the 5-HT1A receptor ligands studied modified the same defensive behaviours as diazepam, suggesting potential therapeutic efficacy in the management of anxiety disorders. However, the magnitude of the effects of the 5-HT1A compounds on defence was generally smaller than that of the benzodiazepine. As all of the 5-HT1A compounds tested in this series share antagonistic activity in models of postsynaptic 5-HT1A receptor function, it is proposed that this action accounts for their effects on defence.

Methodological issues in studies on rapid onset of depression

The increase of extracellular 5-HT in brain terminal regions produced by the acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT1A autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre- and postsynaptic 5-HT1A receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA3 pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective β-adrenoceptor antagonist metoprolol (15 mg/kg, i.p.). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT1A receptors was suggested by its complete reversal by the 5-HT1A antagonist WAY 100635 (100 μg/kg, i.v.). A short-term treatment with VLX (20 mg/kg/day × 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day × 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT1A receptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT1A autoreceptor, but not its postsynaptic congener. These results support and extend previous findings providing a biological substratum for the efficacy of pindolol as an accelerating strategy in major depression.

Pindolol augmentation: Single or multiple targets in the brain

The increase of extracellular 5-HT in brain terminal regions produced by the acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT1A autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre- and postsynaptic 5-HT1A receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA3 pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective β-adrenoceptor antagonist metoprolol (15 mg/kg, i.p.). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT1A receptors was suggested by its complete reversal by the 5-HT1A antagonist WAY 100635 (100 μg/kg, i.v.). A short-term treatment with VLX (20 mg/kg/day × 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day × 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT1A receptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT1A autoreceptor, but not its postsynaptic congener. These results support and extend previous findings providing a biological substratum for the efficacy of pindolol as an accelerating strategy in major depression.

Orcadian Rhythm in the Hypothermic Response to Serotonin1A Agonist 8-Oh-Dpat in Rats

In a recent study, we found a circadian rhythm in the serotonin (5-HT) syndrome (forepaw treading, head weaving, and flat body posture) in the response to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tet-ralin (8-OH-DPAT). The present study examined the rhythm in the responsiveness to 8-OH-DPAT by observing hypothermia, another index of the 5-HT1A receptor function. Rats standardized to L(1800–0600): D(0600–1800) were subcutaneously administered with 0.16 mg/kg 8-OH-DPAT at one of the following times of day: 00:00, 04:00, 08:00, 12:00, 16:00, 20:00h. Two parameters of assessing the hypothermic response, the maximum decrease in temperature after the administration (MAXDT) and the area under the curve of the decrease in temperature (AUCDT), displayed significant circadian rhythms with the peaks in the middark phase (12:00h). The waveform of the rhythms observed was similar to that of the rhythms that we observed previously in the 5-HT syndrome. The evidence presented here further supports that the central postsynaptic 5-HT1A receptor function exhibits a circadian rhythm. (Chronobiology International, 14(3), 267–273, 1997)

P.1.023 - Synergistic increases of noradrenaline and 5-HT neurotransmission induced by milnacipran with pindolo

The increase of extracellular 5-HT in brain terminal regions produced by the acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT1A autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre- and postsynaptic 5-HT1A receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA3 pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective β-adrenoceptor antagonist metoprolol (15 mg/kg, i.p.). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT1A receptors was suggested by its complete reversal by the 5-HT1A antagonist WAY 100635 (100 μg/kg, i.v.). A short-term treatment with VLX (20 mg/kg/day × 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day × 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT1A receptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT1A autoreceptor, but not its postsynaptic congener. These results support and extend previous findings providing a biological substratum for the efficacy of pindolol as an accelerating strategy in major depression.