Activation Of Serotonin 1A Receptors Research Articles

Serotonin-1A receptor activation in the median raphe nucleus improves response learning-based strategy in 192IgG saporin-induced cognitive impairments

Deficits in the translation between egocentric-allocentric strategies may become another diagnostic mark for neurodegenerative disorders, especially Alzheimer's disease. Regarding the specific regional distribution of serotonin-1A receptor in brain areas mediating allocentric (externally-centered) spatial navigation to the escape location, here we studied the effects of median raphe nucleus serotonin-1A autoreceptors stimulation, [8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT); 4 μg/0.5 μl saline], of a selective cholinergic denervation by intracerebroventricular administration of the 192IgG saporin (1μl/each ventricle), on male Wistar rats search strategies in a Morris maze during acquisition, and before probe sessions. Despite some evidence of spatial hippocampal dependent knowledge to those PBS/Saline animals, their performance dropped to chance levels on probe trial. Therefore, we considered two probabilities and first analyzed the ability of the rats to make better use of one or more strategies. We showed statistically significant increases in the distances associated with egocentric (body-centered) non-spatial strategies, random searching in particular, in 192IgG/8OH rats, which led to their improved performance. Second, considering to what extent a shift in search strategy use improves performance indicated that 8-OH-DPAT alone did not affect learning since it appeared the related performance was impaired over days. However, the strategy choices made by 192IgG/8OH rats increased performance by more than 12% compared to 192IgG/Saline rats, an effect reversed with pre-treatment by serotonin-1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide (WAY 100635). The results strongly suggest the potential role of serotonergic system, via the serotonin-1A receptors, in spatial navigation. We argue that the receptors are of interest as therapeutic targets that can be used against age-related cognitive decline.

Serotonin inhibits axonal regeneration of identifiable descending neurons after a complete spinal cord injury in lampreys.

ABSTRACTClassical neurotransmitters are mainly known for their roles as neuromodulators, but they also play important roles in the control of developmental and regenerative processes. Here, we used the lamprey model of spinal cord injury to study the effect of serotonin in axon regeneration at the level of individually identifiable descending neurons. Pharmacological and genetic manipulations after a complete spinal cord injury showed that endogenous serotonin inhibits axonal regeneration in identifiable descending neurons through the activation of serotonin 1A receptors and a subsequent decrease in cyclic adenosine monophosphate (cAMP) levels. RNA sequencing revealed that changes in the expression of genes that control axonal guidance could be a key factor determining the serotonin effects during regeneration. This study provides new targets of interest for research in non-regenerating mammalian models of traumatic central nervous system injuries and extends the known roles of serotonin signalling during neuronal regeneration. This article has an associated First Person interview with the first author of the paper.

Human motoneurone excitability is depressed by activation of serotonin 1A receptors with buspirone.

In the adult turtle spinal cord, action potential generation in motoneurones is inhibited by spillover of serotonin to extrasynaptic serotonin 1A (5-HT1A ) receptors at the axon initial segment. We explored whether ingestion of the 5-HT1A receptor partial agonist, buspirone, decreases motoneurone excitability in humans. Following ingestion of buspirone, two tests of motoneurone excitability showed decreases. F-wave areas and persistence in an intrinsic muscle of the hand were reduced, as was the area of cervicomedullary motor evoked potentials in biceps brachii. Our findings suggest that activation of 5-HT1A receptors depresses human motoneurone excitability. Such a depression could contribute to decreased motoneurone output during fatiguing exercise if there is high serotonergic drive to the motoneurones. Intense serotonergic drive in the turtle spinal cord results in serotonin spillover to the axon initial segment of the motoneurones where it activates serotonin 1A (5-HT1A ) receptors and inhibits generation of action potentials. We examined whether activation of 5-HT1A receptors decreases motoneurone excitability in humans by determining the effects of a 5-HT1A receptor partial agonist, buspirone, on F waves and cervicomedullary motor evoked potentials (CMEPs). In a placebo-controlled double-blind study, 10 participants were tested on two occasions where either placebo or 20mg of buspirone was administered orally. The ulnar nerve was stimulated supramaximally to evoke F waves in abductor digiti minimi (ADM). CMEPs and the maximal M wave were elicited in biceps brachii by cervicomedullary stimulation and brachial plexus stimulation, respectively. Following buspirone intake, F-wave area and persistence, as well as CMEP area, were significantly decreased. The mean post-pill difference in normalized F-wave areas and persistence between buspirone and placebo days was -27% (-42, -12; 95% confidence interval) and -9% (-16, -2), respectively. The mean post-pill difference in normalized CMEP area between buspirone and placebo days showed greater variation and was -31% (-60, -2). In conclusion, buspirone reduces motoneurone excitability in humans probably via activation of 5-HT1A receptors at the axon initial segment. This has implications for motor output during high drive to the motoneurones when serotonin may spill over to these inhibitory receptors and consequently inhibit motoneurone output. Such a mechanism could potentially contribute to fatigue with exercise.

Postnatal Treadmill Exercise Alleviates Prenatal Stress-Induced Anxiety in Offspring Rats by Enhancing Cell Proliferation Through 5-Hydroxytryptamine 1A Receptor Activation.

Purpose:Stress during pregnancy is a risk factor for the development of anxiety-related disorders in offspring later in life. The effects of treadmill exercise on anxiety-like behaviors and hippocampal cell proliferation were investigated using rats exposed to prenatal stress.Methods:Exposure of pregnant rats to a hunting dog in an enclosed room was used to induce stress. Anxiety-like behaviors of offspring were evaluated using the elevated plus maze test. Immunohistochemistry for the detection of 5-bromo-2ʹ- deoxyuridine and doublecortin (DCX) in the hippocampal dentate gyrus and 5-hydroxytryptamine 1A receptors (5-HT1A) in the dorsal raphe was conducted. Brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) levels in the hippocampus were evaluated by western blot analysis.Results:Offspring of maternal rats exposed to stress during pregnancy showed anxiety-like behaviors. Offspring also showed reduced expression of BDNF, TrkB, and DCX in the dentate gyrus, decreased cell proliferation in the hippocampus, and reduced 5-HT1A expression in the dorsal raphe. Postnatal treadmill exercise by offspring, but not maternal exercise during pregnancy, enhanced cell proliferation and expression of these proteins.Conclusions:Postnatal treadmill exercise ameliorated anxiety-like behaviors in offspring of stressed pregnant rats, and the alleviating effect of exercise on these behaviors is hypothesized to result from enhancement of cell proliferation through 5-HT1A activation in offspring rats.

A latent serotonin-1A receptor-gated spinal afferent pathway inhibiting breathing.

Spinal afferents such as nociceptive afferents and group III-IV muscle afferents are known to exert an acute excitatory effect on breathing when activated. Here, we report the surprising existence of latent spinal afferents which exerted tonic inhibitory influence on breathing subliminally in anesthetized rats, an effect which was reversed upon activation of serotonin-1A receptors (5-HT1ARs) in lumbar spinal cord, lesion of pontine lateral parabrachial nucleus or suppression of the adjacent Kölliker-Fuse nucleus with NMDA receptor blockade. Small-interfering RNA knockdown of 5-HT1ARs in lumbar spinal cord unequivocally localized the site of 5-HT1AR-mediated gating of these respiratory-inhibiting interoceptive afferents to relay neurons in the spinal superficial dorsal horn at the lumbar level and not cervical spinal or supraspinal levels. Our results reveal a novel somatosensory/viscerosensory mechanism which exerts tonic inhibitory influence on homeostatic regulation of breathing independent from the classical chemoreflex excitatory pathways, and suggest a hitherto unrecognized therapeutic target in spinal dorsal horn for 5-HT1AR-based treatment of a variety of respiratory abnormalities.

Treadmill exercise alleviates stress-induced impairment of social interaction through 5-hydroxytryptamine 1A receptor activation in rats

Brain-derived neurotrophic factor (BDNF) and its receptors tyrosine kinase B (trkB), and cyclic adenosine monophosphate response element binding protein (CREB) have been suggested as the neurobiological risk factors causing depressive disorder. Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the pathogenesis of depression. We in-vestigated the effect of treadmill exercise on social interaction in relation with BDNF and 5-HT expressions following stress in rats. Stress was induced by applying inescapable 0.2 mA electric foot shock to the rats for 7 days. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks. Social interaction test and western blot for BDNF, TrkB, pCREB, and 5-HT1A in the hippocampus were performed. The results indicate that the spend time with unfamiliar partner was decreased by stress, in contrast, treadmill exercise increased the spending time in the stress-induced rats. Expressions of BDNF, TrkB, and pCREB were decreased by stress, in contrast, treadmill exercise enhanced expressions of BDNF, TrkB, and pCREB in the stress-induced rats. In addition, 5-HT1A receptor expression was de-creased by stress, in contrast, treadmill exercise enhanced 5-HT1A expression in the stress-induced rats. In the present study, treadmill exercise alleviated stress-induced social interaction impairment through enhancing hippocampal plasticity and serotonergic function in the hippocampus. These effects of treadmill exercise are achieved through 5-HT1A receptor activation.

The role of the sympathetic nervous system in the resuscitative effect of stimulating the central serotonin 1A receptors in haemorrhagic shock in rats

Haemorrhagic shock is a life threatening condition, and, as such, it is important to understand the mechanisms taking part in its reversal. In the 1990s, it was shown that activation of serotonin 1A receptors is responsible for the circulatory decompensation and development of the sympathoinhibitory phase. In previous reports, it was demonstrated that activation of serotonin 1A receptors induces resuscitative effects in haemorrhaged rats. However, the effectory mechanisms still require further investigation. The aim of the present study was to determine whether the sympathetic nervous system participates in the effects of serotonin through central serotonin 1A receptors in haemorrhagic shock in rats. In order to determine the role of the sympathetic nervous system alpha-1-, alpha-2-, and beta-adrenergic receptor agonists – prazosin, yohimbine and propranolol, respectively, were used. We found that stimulation of the central serotonin 1A receptors by the administration of a selective agonist – 8-hydroxy-2-(di-n-propylamino)tetralin, 1-(2,5-dimethoxy-4-iodophenyl)-aminopropane (8-OH-DPAT) into the lateral brain ventricle is connected with the activation of compensation mechanisms leading to the increase in the heart rate and blood pressure. The current results demonstrate that the stimulation of peripheral alpha-1-, alpha-2- and beta-adrenergic receptors plays an essential role in the resuscitative effect triggered by the stimulation of central serotonin 1A receptors.

Serotonin 1a receptor and associated G-protein activation in schizophrenia and bipolar disorder

Abnormalities in the serotonergic signalling system, including the serotonin 1a receptor, have been implicated in the pathogenesis of schizophrenia and bipolar 1 disorder. However, there is no consensus on whether the density of the serotonin 1a receptor and/or the activity of the G-proteins linking the receptor to the intracellular cascade are altered in these disease states. To address these issues, tissue obtained postmortem from four cortical regions was used to measure [ 3H] 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) binding and 8-OH-DPAT-stimulated guanosine 5′-[γ-thio]triphosphate (GTPγS) binding to determine if either parameter is altered in schizophrenia or bipolar I disorder. There was an effect of diagnosis on the level of [ 3H] 8-OH-DPAT binding that may indicate a global change in the density of serotonin 1a receptors, although this effect did not reach significance in any individual brain region. The activation of serotonin 1a receptors did not differ significantly with diagnoses. However, in the outer cortical layers, there appeared to be a dissociation between the number of receptors available and the extent of ligand-induced GTPγS binding, suggesting considerable receptor reserve. In addition, comparing gender independent of diagnoses, a decrease in the levels of serotonin 1a receptors was observed in the cortex of female subjects. These data indicates that there may be subtle changes in serotonin 1a receptors across the cortex in schizophrenia or bipolar I disorder and suggests a gender discordance in receptor levels.

P.4.b.004 Stimulation of the lateral habenula inhibits a panic-like behaviour by activation of serotonin-1A receptors in the rat dorsal periaqueductal gray

The transient receptors potential vanilloid type 1 channels (TRPV1) are expressed in several brain regions related to defensive behaviors, including the dorsolateral periaqueductal gray (dlPAG). The endocannabinoid anandamide, in addition to its agonist activity at cannabinoid type 1 (CB1), is also proposed as an endogenous agonist of these receptors, through which it could facilitate anxiety-like responses. The aim of this work was to test the hypothesis that TRPV1 in the dlPAG of rats would mediate panic-like responses in two models, namely the escape responses induced by chemical stimulation of this structure or by exposure to the elevated T-Maze (ETM). Antagonism of TRPV1 with capsazepine injected into the dlPAG reduced the defense response induced by local NMDA-injection, suggesting an anti-aversive effect. In the ETM, capsazepine inhibited escape response, suggesting a panicolytic-like effect. Interestingly, this effect was prevented by a CB1 antagonist (AM251). The present study showed that antagonism of TRPV1 in the dlPAG induces panicolytic-like effects, which can be prevented by a CB1 antagonist. Therefore, these antiaversive effects of TRPV1 blockade may ultimately occur due to a predominant action of anandamide through CB1 receptors.

Roles of extracellular signal‐regulated kinase and Akt signaling in coordinating nuclear transcription factor‐κB‐dependent cell survival after serotonin 1A receptor activation

To investigate the functional consequences of cross-talk between multiple effectors of serotonin (5-HT) 1A receptor, we employed transfected Chinese hamster ovary cells. Activation of 5-HT 1A receptor stimulated extracellular signal-regulated kinase (ERK)1/2, Akt and nuclear transcription factor-kappaB (NF-kappaB). Stimulation of cells with 5-HT 1A receptor agonist induced a rapid but transient ERK1/2 phosphorylation followed by increased phosphorylation of Akt. Elevated Akt activity in turn suppressed Raf activity and induced a decline in ERK activation. The activation of ERK and Akt downstream of 5-HT 1A receptor was sensitive to inhibitors of Ras, Raf and phosphatidylinositol 3-kinase (PI3K). Stimulation of 5-HT 1A receptor also resulted in activation of NF-kappaB through a decrease in inhibitor of nuclear transcription factor-kappaB. In support of the importance of 5-HT 1A receptor signaling for cell survival, inhibition of NF-kappaB facilitated caspase 3 activation and cleavage of poly (ADP-ribose) polymerase, while treatment of cells with agonist inhibited caspase 3, DNA fragmentation and cell death. Both agonist-dependent NF-kappaB activation and cell survival were decreased by Akt Inhibitor II or by overexpression of dominant-negative Akt. These findings suggest a role for 5-HT 1A receptor signaling in the Ras/Raf-dependent regulation of multiple intracellular signaling pathways that include ERK and PI3K/Akt. Of these, only PI3K/Akt and NF-kappaB activation were required for 5-HT 1A receptor-dependent cell survival, implying that the relative distribution of signals between competing transduction pathways determines the functional outcome of 5-HT 1A receptor activation.

High-Efficacy 5-Hydroxytryptamine 1A Receptor Activation Counteracts Opioid Hyperallodynia and Affective Conditioning

Pain may become intractable as tolerance develops to opioids and the opioids, paradoxically, induce pain. We examined the hypothesis that the analgesia produced by the novel analgesic and high-efficacy 5-hydroxytryptamine (5-HT)(1A) receptor agonist (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]methyl]piperidin-1-yl]methanone, fumaric acid salt (F 13640) may counteract opioid-induced pain. In studies of the somatosensory quality of pain in infraorbital nerve-injured rats, morphine infusion (5 mg/day) by means of osmotic pumps initially caused analgesia (i.e., decreased the behavioral response to von Frey filament stimulation), followed by hyperallodynia and analgesic tolerance. Infusion of F 13640 (0.63 mg/day) prevented the development of opioid hyperallodynia and reversed opioid hyperallodynia once established. In studies of the affective/motivational quality of pain, F 13640 both prevented and reversed the conditioned place aversion induced by naloxone (0.04 mg/kg i.p.) in morphine-infused rats; F 13640 also prevented and reversed the conditioned place preference induced by morphine injections (7.5 mg/kg i.p.). The data confirm that opioids produce bidirectional hypo- and proalgesic actions, and offer initial evidence that high-efficacy 5-HT(1A) receptor activation counteracts both the sensory and the affective/motivational qualities of opioid-induced pain. The data also indicate that F 13640 may be effective with opioid-resistant pain. It further is suggested that opioid addiction may represent self-therapy of opioid-induced pathological pain.

5-hydroxytryptamine 1a receptor activation reduces cutaneous vasoconstriction and fever associated with the acute inflammatory response in rabbits

5-Hydroxytryptamine 1A (5-HT1A) receptor activation reduces body temperature partially by dilating the thermoregulatory cutaneous vascular bed, thereby increasing heat transfer to the environment. Constriction of this vascular bed, with consequent reduction of heat transfer to the environment, contributes to fever associated with the acute inflammatory response. Thus activation of 5-HT1A receptors might inhibit thermoregulatory cutaneous vasoconstriction and reduce the fever associated with the acute inflammatory response. The present study tested this hypothesis in conscious unrestrained rabbits. The acute inflammatory reaction was induced with i.v. lipopolysaccharide (LPS, 0.5 μg/kg). Body temperature was measured with an i.p. telemetric probe, and ear pinna blood flow was measured with a chronically implanted Doppler ultrasonic probe. 5-HT1A receptors were activated with i.v. 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT). LPS increased body temperature by +1.7±0.2 °C during the first hour after administration. The ear pinna Doppler blood flow signal fell from 69±11 to 5±1 cm/s within 15 min ( n=7, P<0.01) and remained at a low level for approximately 1 h after LPS. When administered 45 min after LPS, 8-OH-DPAT (0.1 mg/kg i.v.) reversed this fall, increasing the Doppler signal from 6±1 to 55±7 cm/s ( P<0.01, n=6), and reduced the rise in body temperature. Treatment with 8-OH-DPAT (0.1 mg/kg i.v.) 5 min before and 30 min after LPS entirely prevented the LPS-induced fall in ear pinna blood flow, and reduced the rise in body temperature from 1.7±0.2 °C to 0.7±0.2 ( n=7, P<0.01). Treatment with WAY-100635 ( N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)- N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride) (0.1 mg/kg i.v.) prevented and reversed the effects of 8-OH-DPAT. Thus activation of 5-HT1A receptors reduces thermoregulatory cutaneous vasoconstriction and fever occurring as part of the acute inflammatory response. Our findings elucidate the neurotransmitter mechanisms underlying expression of an important component of the febrile response, and suggest that drugs with 5-HT1A agonist properties might be therapeutically useful when it is clinically important to reduce this response.

Hippocampal and hypothalamic function after chronic stress.

Hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis is often observed in association with and even prior to the onset of major depression. It is presently unclear (1) which molecular and cellular processes contribute to hyperactivity of parvocellular hypothalamic neurons (key regulators of the HPA system) and (2) how HPA axis hyperactivity can lead to attenuation of central serotonergic transmission, a crucial factor in the onset of clinical symptoms. In an attempt to address these issues in an experimental model we used rats exposed to chronic unpredictable stressors, a paradigm causing prolonged HPA-axis hyperactivity. In the first study spontaneous and evoked GABA-mediated input to parvocellular neurons in the paraventricular hypothalamic nucleus was recorded with the whole cell patch-clamp technique. The frequency, but not other properties, of spontaneous GABA-mediated inhibitory postsynaptic currents was reduced after chronic stress, resulting in a reduced amplitude of the evoked GABA current. This potentially would disinhibit parvocellular neurons, provided that other inputs are unchanged. In the second study, responses of CA1 hippocampal neurons to serotonin were recorded with microelectrodes. It appeared that the membrane hyperpolarization caused by activation of serotonin-1A receptors is attenuated in tissue from chronically stressed rats. However, no apparent changes in expression of the serotonin-1A or corticosteroid receptors were observed. This supports the notion that chronic stress eventually results in attenuation of serotonergic responsiveness by a mechanism not involving transcriptional regulation of the receptor. Follow-up studies will need to examine whether treatment with corticosteroid receptor antagonists can normalize the attenuated transmission after chronic stress.

5-hydroxytryptamine 1A receptor activation protects against N-methyl-D-aspartate-induced apoptotic cell death in striatal and mesencephalic cultures.

Apoptosis and glutamate-mediated excitotoxicity may play a role in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we investigated whether stimulation of the 5-hydroxytryptamine 1A (5-HT1A) receptor attenuates N-methyl-D-aspartate- (NMDA) and 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptotic cell death in cell culture models. A brief exposure (20 min) of M213-2O striatal cells to NMDA and glutamate produced a delayed increase in caspase-3 activity and DNA fragmentation in a dose- and time-dependent manner. NMDA-induced caspase-3 activity and DNA fragmentation were almost completely blocked by the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and (R)-5-fluoro-8 hydroxy-2-(dipropylamino)-tetralin (R-UH-301). Additionally, the protective effects of 8-OH-DPAT and R-UH-301 on NMDA-induced caspase-3 activation and apoptosis were reversed by pretreatment with the 5-HT1A antagonists N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635) and S-UH-301, respectively. Similarly, dose- and time-dependent increases in caspase-3 activity and DNA fragmentation were observed in rat primary mesencephalic neurons after a brief exposure to NMDA and glutamate. Caspase-3 activation and DNA fragmentation in primary mesencephalic neurons were almost completely inhibited by 8-OH-DPAT. This neuroprotective effect of 8-OH-DPAT was reversed by WAY 100635. Additionally, 8-OH-DPAT blocked tyrosine hydroxylase (TH)-positive cell death after NMDA exposure and also almost completely attenuated the NMDA-induced Ca(2+) influx in primary mesencephalic cultures. Furthermore, 8-OH-DPAT and R-UH-301 blocked apoptotic cell death in the primary mesencephalic neurons that were exposed to the Parkinsonian toxin MPP(+). Together, these results suggest that 5-HT1A receptor stimulation may be a promising pharmacological approach in the development of neuroprotective agents for PD.

Serotonergic modulation of astrocytic activity in the hamster suprachiasmatic nucleus

The present study was undertaken to explore the effects of central serotonin receptor activation on the expression of glial fibrillary acidic protein in the suprachiasmatic nucleus of Syrian hamsters. Immunoblot and immunohistochemical procedures were used to examine the effects of systemic application of the serotonin-1A and serotonin-7 receptor agonist, (±)-2-dipropylamino-8-hydroxyl-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT; 3.75 mg/kg) on the contents and distribution of glial fibrillary acidic protein in the suprachiasmatic nucleus. Administration of 8-OH-DPAT at midday caused a significant reduction in immunoreactive glial fibrillary acidic protein content within 1 h of injection, compared to vehicle controls. This effect was not evident 3 h after drug injection. Treatment with 8-OH-DPAT during the late dark phase had little effect on glial fibrillary acidic protein content. The 8-OH-DPAT-induced reduction in glial fibrillary acidic protein content seen at midday was blocked partially by pretreatment with the serotonin-2 and serotonin-7 receptor antagonist, ritanserin, and more substantially by pretreatment with the serotonin-1A receptor antagonist, NAN-190. Treatment with 8-OH-DPAT also caused a significant redistribution of immunoreactive glial fibrillary acidic protein, such that the dense mesh-like appearance seen in vehicle controls was significantly reduced. The 8-OH-DPAT treatment also significantly decreased expression of polysialic acid, a cell-surface molecule associated with neural plasticity. Immunoblot assessments of glial fibrillary acidic protein contents 2 h before and 1 h after lights off revealed a significant time-of-day difference in glial fibrillary acidic protein expression, with lowest levels occurring at the latter time-point, associated with maximal endogenous serotonin release in the suprachiasmatic nucleus. Collectively, these results indicate that acute plastic changes in glial fibrillary acidic protein-related astrocytic activity in the suprachiasmatic nucleus can be induced in response to serotonin-7 or serotonin-1A receptor activation in a phase-dependent manner. It is interesting to speculate that circadian reorganizations in astrocytic activity could be regulated by the daily rhythm in serotonin release in the suprachiasmatic nucleus.

Buspirone modulates basal and fluoxetine-stimulated dialysate levels of dopamine, noradrenaline and serotonin in the frontal cortex of freely moving rats: activation of serotonin 1A receptors and blockade of α 2-adrenergic receptors underlie its actions

The serotonin 1A receptor partial agonist, buspirone, also displays antagonist properties at D 2 receptors and is metabolized to the α 2-adrenergic receptor antagonist, 1-(2-pyrimidinyl-piperazine). Herein, we examined mechanisms underlying the influence of buspirone alone, and in association with the serotonin reuptake inhibitor, fluoxetine, upon extracellular levels of serotonin, dopamine and noradrenaline simultaneously quantified in the frontal cortex of freely moving rats. Buspirone (0.01–2.5 mg/kg, s.c.) dose-dependently decreased dialysate levels of serotonin (−50%), and increased those of dopamine (+100%) and noradrenaline (+140%). The reduction by buspirone of serotonin levels was abolished by the serotonin 1A receptor antagonist, WAY 100,635 (0.16), which did not, however, modify its influence upon dopamine and noradrenaline. In contrast to buspirone, the serotonin reuptake inhibitor, fluoxetine (10.0), increased frontocortical levels of serotonin (+120%), dopamine (+55%) and noradrenaline (+90%). Buspirone dose-dependently (0.01–2.5) decreased the induction by fluoxetine of serotonin levels yet potentiated (three-fold) its elevation of dopamine and noradrenaline levels. The serotonin 1A agonist, 8-hydroxy-2-(di- n-propylamino)-tetralin (0.16), mimicked the action of buspirone in reducing resting levels of serotonin (−60%) and in enhancing those of dopamine (+135%) and noradrenaline (+165%). Like buspirone, it attenuated the influence of fluoxetine upon serotonin levels, yet facilitated its influence upon dopamine and noradrenaline levels. In contrast, WAY 100,635 selectively potentiated the increase in levels of serotonin (two-fold) versus dopamine and noradrenaline elicited by fluoxetine. Further, WAY 100,635 abolished the inhibitory influence of buspirone upon fluoxetine-induced serotonin release, but only partly interfered with its potentiation of fluoxetine-induced increases in dopamine and noradrenaline levels. The D 2/D 3 receptor antagonist, raclopride (0.16), increased basal dopamine (+60%) levels but little influenced those of serotonin and noradrenaline, and failed to modify the action of fluoxetine. The α 2-adrenergic receptor antagonist, 1-(2-pyrimidinyl-piperazine) (2.5), which did not modify resting levels of serotonin, markedly increased those of dopamine (+90%) and noradrenaline (+190%) and potentiated (two-fold) the increases in dialysate levels of dopamine, noradrenaline and serotonin provoked by fluoxetine. Further, the α 2-adrenergic receptor agonist, S18616, attenuated the enhancement by buspirone of the fluoxetine-induced increase in levels of dopamine and noradrenaline. In conclusion, the inhibitory influence of buspirone upon resting and fluoxetine-stimulated serotonin levels reflects its agonist properties at serotonin 1A autoreceptors. The facilitatory influence of buspirone upon resting and fluoxetine-stimulated dopamine and noradrenaline levels may also involve its serotonin 1A properties. However, its principal mechanism of action in this respect is probably the α 2-adrenergic antagonist properties of its metabolite, 1-(2-pyrimidinyl-piperazine). The present observations are of significance to experimental and clinical studies of the influence of buspirone upon depressive states, alone and in association with antidepressant agents.

Serotonin 1A receptors, melatonin, and the proportional control thermostat in patients with winter depression.

In patients with seasonal affective disorder, light treatment lowers core temperature during sleep in proportion to its antidepressant efficacy. The regulation of the level of core temperature during sleep is linked with a proportional control thermostat in the central nervous system whose operation appears abnormal in patients with seasonal affective disorder. Because both melatonin and serotonin 1A receptor activation also lower core temperature, we investigated the relationship between (1) endogenous melatonin and core temperature profiles, (2) the proportional control thermostat, and (3) the core hypothermic response to the serotonin 1A receptor partial agonist ipsapirone hydrochloride in patients with seasonal affective disorder and healthy controls. Eighteen patients with seasonal affective disorder and 18 controls first completed a 24-hour study in which their melatonin profiles were characterized. Subjects then returned 3 to 5 days later for the first of 2 drug challenges (ipsapirone hydrochloride, 0.3 mg/kg, or placebo), each separated by 3 to 5 days. Overnight rectal and facial temperatures were recorded before and after each drug challenge. The magnitudes of the core hypothermic responses to ipsapirone were (1) not different between groups and (2) independently correlated with both the levels of the previous nights' core temperature minima (P=.002) and the amounts of nocturnal melatonin secreted (P<.001). The daytime regulation of core temperature by serotonin 1A receptors appears normal in seasonal affective disorder. The magnitude of serotonin 1A receptor-activated hypothermia is governed by a central nervous system proportional control thermostat whose operation appears modulated by both melatonin and the level of the core temperature minimum.

Endogenous serotonin inhibits epileptiform activity in rat hippocampal CA1 neurons via 5-hydroxytryptamine 1A receptor activation

The modulatory effects of endogenous serotonin on the synaptic transmission and epileptiform activity were studied in the rat hippocampus with the use of extracellular and intracellular recording techniques. Field excitatory postsynaptic potential was reversibly depressed by serotonin in a concentration-dependent manner. Intracellular recordings revealed that serotonin-mediated synaptic depression was unaffected by extracellular Ba 2+ or intracellular application of Cs + while the postsynaptic hyperpolarizing effect was completely blocked. Epileptiform activity induced by picrotoxin (50 μM), a GABA A receptor antagonist, was also dose-dependently suppressed by serotonin. The antiepileptic effect was mimicked by 5-hydroxytryptamine 1A agonist and was blocked by 5-hydroxytryptamine 1A antagonists. 5-hydroxytryptamine 2 antagonist had no effect on the modulation. Similarly, fluoxetine, a selective serotonin reuptake blocker, potently inhibited the epileptiform activity and this effect was blocked by 5-hydroxytryptamine 1A receptor antagonist. Depletion of endogenous serotonin by pretreating the slices with p-chloroamphetamine completely prevented the antiepileptic action of fluoxetine, without modifying the action of serotonin in the same cells. These results suggest that the antiepileptic action of fluoxetine is due to an enhancement of endogenous serotonin which in turn is mediated by 5-hydroxytryptamine 1A receptor. Endogenous serotonin transmission in the hippocampus is therefore capable of limiting the development and propagation of seizure activity.

A single pretreatment with 8-OH-DPAT reduces behavioral indices of serotonin 1A receptor activation in ovariectomized rats

The effects of prior treatment with 8-OH-DPAT on 8-OH-DPAT-induced eating behavior, hypothermia, flat body posture and forepaw treading were examined in ovariectomized rats. Twenty-four hours after a single pretreatment with 0.25 mg/kg of the drug, the eating behavior and flat body posture induced by 8-OH-DPAT were reduced relative to that seen following the first treatment with the drug. In contrast, within 24 hr of the prior drug treatment, the drug's effects on forepaw treading and rectal temperature were unchanged. However, 7 days after prior treatment with 8-OH-DPAT, eating behavior, flat body posture and hypothermia induced by the drug were suppressed. Only forepaw treading remained unchanged. These findings are discussed in reference to similar studies of 5-HT 1A receptor agonist-induced modulation of behaviors in male rats.

Activation of α2-adrenoceptors causes inhibition of calcium channels but does not modulate inwardly-rectifying K + channels in caudal raphe neurons

Many neurotransmitter receptors that interact with pertussis toxin-sensitive G proteins, including the α 2-adrenergic receptor, can modulate both voltage-dependent calcium channels and G protein-coupled inwardly-rectifying K + channels. Serotonergic neurons of the medulla oblongata (n. raphe obscurus, and n. raphe pallidus), which provide a major projection to sympathetic and motor output systems, receive a catecholaminergic input and express α 2-adrenergic receptors. Therefore, we tested the effects of norepinephrine on voltage-dependent calcium channels and G protein-coupled inwardly-rectifying K + channels in neonatal raphe neurons using whole-cell recording in a brainstem slice preparation. Calcium channel currents were inhibited by norepinephrine in the majority of raphe neurons tested (88%) and in all identified tryptophan hydroxylase-immunoreactive (i.e., serotonergic) neurons. When tested in the same neurons, the magnitude of calcium current inhibition by norepinephrine (∼25%) was less than that induced by 5-hydroxytryptamine (∼50%). The norepinephrine-induced calcium current inhibition was mediated by α 2-adrenergic receptors; it was mimicked by UK 14 304, an α 2-adrenergic receptor agonist and blocked by idazoxan, an α 2-adrenergic receptor antagonist, but not affected by prazosin or propanolol ( α 1 and β adrenergic antagonists, respectively). Calcium current inhibition by norepinephrine was essentially eliminated following application of ω-Conotoxin GVIA and ω-Agatoxin IVA, indicating that norepinephrine modulated N- and P/Q-type calcium channels predominantly. Calcium current inhibition by norepinephrine was voltage-dependent and mediated by pertussis toxin-sensitive G proteins. Thus, as expected, α 2-adrenergic receptor activation inhibited N- and P/Q-type calcium currents in medullary raphe neurons via pertussis toxin-sensitive G proteins. In parallel experiments, however, we found that norepinephrine had no effect on G protein-coupled inwardly-rectifying K + channels in any raphe neurons tested, despite the robust activation of those channels in the same neurons by 5-hydroxytryptamine. Together, these data indicate that α 2-adrenergic receptors can modulate N- and P/Q-type calcium channels in caudal medullary raphe neurons but do not couple to the G protein-coupled inwardly-rectifying K + channels which are also present in those cells. This is in contrast to the effect of 5-hydroxytryptamine 1A receptor activation in caudal raphe neurons, and indicates a degree of specificity in the signalling by different pertussistoxin-sensitive G protein-coupled receptors to voltage-dependent calcium channels and G protein-coupled inwardly-rectifying K + channels even within the same cell system.