Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor.
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Both orexin and serotonin (5-HT) have important roles in the regulation of sleep-wakefulness, as well as in feeding behavior. We examined the effects of 5-HT on orexin/hypocretin neurons, using hypothalamic slices prepared from orexin/enhanced green fluorescent protein (EGFP) transgenic mice in which EGFP is expressed exclusively in orexin neurons. Patch-clamp recording from EGFP-expressing cells showed that 5-HT hyperpolarized all orexin neurons in a concentration-dependent manner. The response was inhibited by the 5-HT1A receptor antagonist WAY100635. A 5-HT1A receptor agonist, 8-hydroxy-2-(dl-N-propyl-amino)tetralin, also evoked hyperpolarization on orexin neurons with potency comparable with 5-HT. A low concentration of Ba2+ (30 microM) inhibited 5-HT-induced hyperpolarization. Single-channel recording revealed that the conductance of 5-HT-induced channel activity was 33.8 pS, which is in good agreement with that of the G-protein-coupled inward rectifier potassium channel (GIRK). Moreover, 5-HT1A receptor-like immunoreactivity was observed on orexin neurons, and 5-HT transporter immunoreactive nerve endings are in close apposition to orexin neurons. Intracerebroventricular injection of the 5-HT1A receptor-selective antagonist WAY100635 (100 ng) increased locomotor activity during the latter half of dark phase in wild-type mice but not in orexin/ataxin-3 mice in which orexin neurons are specifically ablated, suggesting that activation of orexin neurons is necessary for the WAY100635-induced increase in locomotor activity. These results indicate that 5-HT hyperpolarizes orexin neurons through the 5-HT1A receptor and subsequent activation of the GIRK and that this inhibitory serotonergic input to the orexin neurons is likely to be important for the physiological regulation of this neuropeptide system. (+info)
The therapeutic role of 5-HT1A and 5-HT2A receptors in depression.
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The selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressant drugs, because they are well tolerated and have no severe side effects. They rapidly block serotonin (5-HT) reuptake, yet the onset of their therapeutic action requires weeks of treatment. This delay is the result of presynaptic and postsynaptic adaptive mechanisms secondary to reuptake inhibition. The prevention of a negative feedback mechanism operating at the 5-HT autoreceptor level enhances the neurochemical and clinical effects of SSRIs. The blockade of 5-HT2A receptors also seems to improve the clinical effects of SSRIs. These receptors are located postsynaptically to 5-HT axons, mainly in the neocortex. Pyramidal neurons in the prefrontal cortex are particularly enriched in 5-HT2A receptors. Their blockade may affect the function of prefrontal-subcortical circuits, an effect that probably underlies the beneficial effects of the addition of atypical antipsychotic drugs, which are 5-HT2A receptor antagonists, to SSRIs in treatment-resistant patients. (+info)
Serotonergic cell signaling in an animal model of aging and depression: olfactory bulbectomy elicits different adaptations in brain regions of young adult vs aging rats.
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Aging involves neuronal and synaptic loss, and maintenance of function depends on adaptations in cellular responsiveness. We studied olfactory bulbectomy (OBX), a model that recapitulates monoaminergic dysfunction in depression, in 10-week vs 19-month-old rats, and evaluated 5HT (5-hydroxytryptamine, serotonin) mechanisms. OBX elicited little change in 5HT1A receptors in the cerebral cortex or striatum of either age group. In contrast, 5HT2 receptors showed disparate effects, with a decrease in the cerebral cortex of young OBX but not aging OBX rats, whereas the latter group showed a selective decrease in striatal 5HT2 receptors. Greater differences were apparent for 5HT-mediated cell signaling, assessed for the adenylyl cyclase (AC) cascade. In young animals, 5HT had a stimulatory effect on AC that was unaltered by OBX. However, in aging animals, the pattern of 5HT responses showed marked alterations in response to OBX: under basal conditions, stimulatory effects were enhanced but when AC was activated with forskolin, 5HT became markedly inhibitory in the striatum of aged OBX animals. Assessment of the relative AC responses to two direct stimulants that act on different epitopes of the enzyme, forskolin and Mn2+, pointed to a shift in the AC isoform and/or its ability to associate with G-proteins as the mechanism underlying the age-related differences for OBX effects. These data indicate that there are biological distinctions in the response of 5HT systems to OBX in young adult vs aging animals, which, if present in geriatric depression, could provide a mechanistic basis for differences in responses to antidepressants that act on 5HT. (+info)
Serotonin 1A receptor binding and treatment response in late-life depression.
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Depression in late life carries an increased risk of dementia and brittle response to treatment. There is growing evidence to support a key role of the serotonin type 1A (5-HT(1A)) receptor as a regulator of treatment response, particularly the 5-HT(1A) autoreceptor in the dorsal raphe nucleus (DRN). We used [11C]WAY 100635 and positron emission tomography (PET) to test our hypothesis that 5-HT(1A) receptor binding in the DRN and prefrontal cortex is altered in elderly depressives and that these measures relate to treatment responsivity. We studied 17 elderly subjects with untreated (nonpsychotic, nonbipolar) major depression (four men, 13 women; mean age: 71.4+/-5.9) and 17 healthy control subjects (eight men, nine women; mean age: 70.0+/-6.7). Patients were subsequently treated with paroxetine as part of a clinical trial of maintenance therapies in geriatric depression. [11C]WAY 100635 PET imaging was acquired and binding potential (BP) values derived using compartmental modeling. We observed significantly diminished [11C]WAY 100635 binding in the DRN in depressed (BP = 2.31+/-0.90) relative to control (BP = 3.69+/-1.56) subjects (p = 0.0016). Further, the DRN BP was correlated with pretreatment Hamilton Depression Rating Scores (r = 0.60, p = 0.014) in the depressed cohort. A trend level correlation between DRN binding and time to remission (r = 0.52, p = 0.067) was observed in the 14 depressed patients for whom these data were available. Our finding of decreased [11C]WAY 100635 binding in the brainstem region of the DRN in elderly depressed patients supports evidence of altered 5-HT(1A) autoreceptor function in depression. Further, this work indicates that dysfunction in autoreceptor activity may play a central role in the mechanisms underlying treatment response to selective serotonin reuptake inhibitors in late-life depression. (+info)
Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT1A and 5-HT2A receptors. Part III.
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The preparation of new 4-aryl-hexahydropyridol 1,2-c]pyrimidine derivatives III-XXVI with an arylpiperazinylbutyl moiety in N-2 position has been described. Multi-stage synthesis techniques were used to obtain 4-arylhexahydro-1H,3H-pyrido[1,2-c]pyrimidine-1,3-dione Ia-f derivatives, being the starting compounds for further modification. N-alkylation of the imide group in compounds Ia-f followed, using 1,4-dibromobutane to yield bromobutyl derivatives IIa-f. The final products III-XXVI were obtained by condensation of aryl- or heteroaryl- piperazine with the bromobutyl derivatives IIa-f. Compounds XII, XIV, XIX, XX, XXIV-XXVI will be submitted to a pharmacological investigation for their affinity towards 5-HT1A, 5-HT2A and alpha1 adrenergic receptor, using radioligand binding assay. (+info)
A GFP fluorescence-based approach to determine detergent insolubility of the human serotonin1A receptor.
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Insolubility in non-ionic detergents such as Triton X-100 is a widely used biochemical criterion for characterization of membrane domains. We report here a novel green fluorescent protein fluorescence-based approach to directly determine detergent insolubility of specific membrane proteins. We have applied this method to explore the detergent resistance of an important G-protein coupled receptor, the serotonin1A (5-HT1A) receptor. Our results show, for the first time, that a small yet significant fraction of the 5-HT1A receptor exhibits detergent insolubility. These results are validated by control experiments involving fluorescent lipid probes and protein markers. Our results assume relevance in the context of localization of the 5-HT1A receptor in membrane domains and its significance in receptor function and signaling. (+info)
Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences.
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Our previous studies found that serotonin transporter (SERT) knock-out mice showed increased sensitivity to minor stress and increased anxiety-like behavior but reduced locomotor activity. These mice also showed decreased density of 5-hydroxytryptamine (5-HT1A) receptors in the hypothalamus, amygdala, and dorsal raphe. To evaluate the contribution of hypothalamic 5-HT1A receptors to these phenotypes of SERT knock-out mice, two studies were conducted. Recombinant adenoviruses containing 5-HT1A sense and antisense sequences (Ad-1AP-sense and Ad-1AP-antisense) were used to manipulate 5-HT1A receptors in the hypothalamus. The expression of the 5-HT1A genes is controlled by the 5-HT1A promoter, so that they are only expressed in 5-HT1A receptor-containing cells. (1) Injection of Ad-1AP-sense into the hypothalamus of SERT knock-out mice restored 5-HT1A receptors in the medial hypothalamus; this effect was accompanied by elimination of the exaggerated adrenocorticotropin responses to a saline injection (minor stress) and reduced locomotor activity but not by a change in increased exploratory anxiety-like behavior. (2) To further confirm the observation in SERT-/- mice, Ad-1AP-antisense was injected into the hypothalamus of normal mice. The density and the function of 5-HT1A receptors in the medial hypothalamus were significantly reduced in Ad-1AP-antisense-treated mice. Compared with the control group (injected with Ad-track), Ad-1A-antisense-treated mice showed a significant reduction in locomotor activity, but again no changes in exploratory anxiety-like behaviors, tested by elevated plus-maze and open-field tests. Thus, the present results demonstrate that medial hypothalamic 5-HT1A receptors regulate stress responses and locomotor activity but may not regulate exploratory anxiety-like behaviors. (+info)
Puerarin acts through brain serotonergic mechanisms to induce thermal effects.
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The present study was attempted to investigate the effect of puerarin, an isoflavone compound isolated from Pueraria lobata, on both the basal body temperature and pyrogenic fever in unanesthetized, restrained rats. Intraperitoneal administration of puerarin or crude extracts of Pueraria lobata elicited hypothermia. Direct administration of a small amount of puerarin into the lateral cerebral ventricle produced the same extent of hypothermia. Systemic or central administration of puerarin causes a decrease in both colonic temperature and hypothalamic 5-HT efflux in rats. The puerarin-induced hypothermia and decreased 5-HT efflux in the hypothalamus were attenuated by selective depletion of hypothalamic 5-HT produced by intracerebroventricular injection of 5,7-dihydroxytryptamine. Furthermore, the puerarin-induced hypothermia was almost completely abolished by treatment with a 5-HT2A-receptor agonist (DOI or quipazine) or a 5-HT1A-receptor antagonist [(-)-pindolol]. A 5-HT2A-receptor antagonist (ketanserin) or a 5-HT1A-receptor agonist (8-OH-DPAT) had additive effects with puerarin. Intracerebroventricular administration of interleukin-1 caused an increase in both colonic temperature and hypothalamic 5-HT efflux. The interleukin-1-induced hyperthermia and increased 5-HT efflux in the hypothalamus were attenuated by treatment with systemic administration of puerarin. The data indicate that puerarin exerts its hypothermic and antipyretic effects by activating 5-HT1 receptor and/or antagonizing 5-HT2A receptors in the hypothalamus. (+info)