Interaction between 5-HT1A and nicotinic cholinergic receptors in the regulation of water maze navigation behavior

The interaction between serotonin (5-HT)_1A and nicotinic cholinergic reptors in the regulation of spatial navigation behavior in the Morris water maze (WM) test was studied. Pretraining intraperitoneal (i.p.) injections of a combination of subthreshold doses of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (a 5-HT_1A receptor agonist) at 30 μg/kg and mecamylamine (a nicotinic cholinergic receptor antagonist) at 2500 μg/kg greatly impaired WM navigation to a hidden platform and slightly, but not statistically significantly, impaired WM navigation to a visible platform. Post-training i.p. injections of this combination had no effect on WM navigation performance. Serotonin depletion induced byp-chlorophenylalanine (PCPA) increased the performance impairing action of pretraining injected combination of 8-OH-DPAT 30 μg/kg and mecamylamine 2500 μg/kg. In trained rats combined injections of 8-OH-DPAT 30 μg/kg and mecamylamine 2500 μg/kg given pretraining had no effect on the navigation to a hidden platform located in a familiar or in a novel position. Pretraining trial injected combination of hexamethonium 2000 μg/kg (a peripherally acting nicotinic antagonist) and 8-OH-DPAT 30 μg/kg had no effect on navigation. These data suggest that a combined treatment with a 5-HT_1a receptor agonist and a nicotinic cholinergic receptor antagonist more severely impair non-mnemonic acquisition performance processes than consolidation and retrieval processes.     

The 5-HT1A agonist 8-OH-DPAT increases the number of spike-wave discharges in a genetic rat model of absence epilepsy

The effects of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) on the epileptiform activity has been investigated in adult WAG/RIJ rats. Either intraperitoneal (0.1–0.5 mg/kg) or intracerebroventricular (2–20 μg/rat) administration of 8-OH-DPAT caused marked, dose-dependent increases in the number and mean cumulative duration of spike-wave discharges. These effects were attenuated by NAN-190, a 5-HT_1A receptor antagonist. These data indicate that serotonergic system regulates the epileptiform activity in this genetic model of human absence epilepsy.     

Partial antagonism of 8-OH-DPAT'S effects on male rat sexual behavior with a D2, but not a 5-HT1A, antagonist

The serotonin agonist 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), injected systemically or directly into the medial preoptic area (MPOA), reduces the ejaculatory threshold in male rats. While 8-OH-DPAT has been characterized as an agonist at the 5-HT_1A receptor, it also acts at other receptor sites including the dopamine D₂ receptor. The current experiments investigated whether 8-OH-DPAT injected into the MPOA facilitates male sexual behavior through stimulation of the 5-HT_1A receptor or the dopamine D₂ receptor. Experiment 1 co-administered 8-OH-DPAT (6 μg) with either the 5-HT_1A antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide hydrochloride (MPPI) (10 μg) or the D₂ antagonist raclopride (10 μg). Raclopride blocked 8-OH-DPAT's facilitative effects on ejaculation frequency and latency, while the 5-HT_1A antagonist was ineffective. In Experiment 2, 8-OH-DPAT (500 μM), retrodialyzed into the MPOA through a microdialysis probe, enhanced male copulatory behavior similarly to the microinjection, increasing ejaculation frequency and decreasing ejaculation latency, postejaculatory interval and mount frequency. Retrodialyzing 8-OH-DPAT through a microdialysis probe in the MPOA had been previously shown to increase extracellular levels of dopamine and serotonin. The data from the present studies suggest that the effects of 8-OH-DPAT in the MPOA on male rat copulatory behavior may be mediated, at least in part, either directly through 8-OH-DPAT's activity at D₂ receptors or indirectly through 8-OH-DPAT's ability to increase extracellular dopamine.     

The role of spinal cord 5-HT1A and 5-HT1B receptors in the modulation of a spinal nociceptive reflex

The role of the 5-hydroxytryptamine (5-HT) receptor subtypes in the spinal cord in the regulation of nociception is unknown. This study examined whether administration of different 5-HT₁ receptor agonists into the spinal subarachnoid space of mice modulates the nociceptive tail-flick reflex, and whether effects on the tail-flick reflex involve changes in tail skin temperature. The tail-flick latencies (the time needed to evoke the tail-flick reflex by noxious radiant heat) were significantly increased after intrathecal (i. th.) injection of 5-HT (10–20 μg), the 5-HT_1A/5-HT_1B receptor agonist5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 10–20 μg), the selective 5-HT_1A receptor agonist8-hydroxy-2-di-n-propylamino)tetralin (8-OH-DPAT, 20 μg), and after i.th. injection of1(m-chlorophenyl)piperazine (mCPP, 5–20 μg) and5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 5–20 μg) which have high affinity for the 5-HT_1B receptors. None of the 5-HT₁ receptor agonists had the ability to change the tail skin temperature. The results show that in the mouse i.th. injection of both 5-HT_1A and 5-HT_1B receptor agonists has the ability to inhibit the tail-flick reflex without interfering with the tail skin temperature.     

Indications of pre- and post-synaptic 5-HT1A receptor interactions in feeding behavior and neuroendocrine regulation

This bipartite study uses behavioral and biochemical means to explore the involvement of both pre- and post-synaptic 5-HT_1A receptors in the control of food intake and neuroendocrine regulation. In the pharmacological study, the administration of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 60 μg/kg b.wt., i.p.) to rats caused a significant increase in 2 h intake of a high carbohydrate (CARB)/sugar diet (P < 0.05) during the relatively inactive feeding period of the late light cycle. No significant change was detected in the intake of Purina laboratory chow at 2 h, or of the intake of either diet at 4 h and 24 h after 8-OH-DPAT administration. Injection of 8-OH-DPAT induced a drop in insulin levels in rats maintained on high CARB/sugar diets only (−90%; P<0.05). It also caused an increase in circulating glucose levels in both high CARB/sugar (240%; P<0.01) and chow fed (123%; P<0.05) rats; it did so more intensely in high CARB/sugar-fed rats. In the biochemical study, radioligand binding techniques were used to assess 5-HT_1A receptor density in the hypothalamus, as well as the relationship between 5-HT_1A receptors and circulating levels of insulin and glucose. Chronic and acute administration (25 mg/kg b.wt./5 injections, and 50 mg/kg b.wt., respectively, i.p.) of the potent hypoglyce mic agent tolbutamide (TOL) caused a significant increase in 5-HT_1A receptor density (+243% and +132.6%, respectively; P<0.05) in the medial hypothalamus but not in the lateral hypothalamus, as compared to vehicle-treated rats. Chronic glucose replacement therapy showed a trend towards reversing the depressed circulating glucose levels as well as the medial hypothalamic 5-HT_1A receptor density to control levels. These studies indicate that the pre-synaptic mechanism of 8-OH-DPAT-induced hyperphagia may require specific circulating levels of insulin and glucose, which are regulated via post-synaptic 5-HT_1A receptors.     

Characterization of the K current mediated by 5-HT1A receptor in the acutely dissociated rat dorsal raphe neurons

The action of 5-hydroxytryptamine (5-HT) via the 5-HT_1A receptor on dissociated rat dorsal raphe neurons was characterized under the whole-cell mode by using the nystatin-perforated patch-clamp technique. Under voltage-clamp conditions, 5-HT induced an inwardly rectifying K⁺ current (I_5-HT) in a concentration-dependent manner. I_5-HT was mimicked by 8-OH-DPAT and buspirone, which are both 5-HT_1A receptor agonists. I_5-HT was reversibly blocked by such 5-HT_1A receptor antagonists as (S)-UH-301 and spiperone but not by ketanserin, a 5-HT₂ receptor antagonist, granisetron, a 5-HT₃ receptor antagonist, and GR-113808, a 5-HT₄ receptor antagonist. I_5-HT was antagonized concentration-dependently by such K⁺ channel blockers as quinine, Ba²⁺ and 4-aminopyridine but was relatively insensitive to both Cs⁺ and tetraethylammonium. When the neurons were loaded with guanosine 5′-O-3-thiotriphosphate through a patch pipette, the K⁺ current induced by 5-HT became irreversible. N-ethylmaleimide (NEM), a sulfhydryl alkylating agent, irreversibly blocked I_5-HT. The intracellular perfusion with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA), a Ca²⁺ chelator, or neomycine, a phospholipase C inhibitor, never significantly affected the 5-HT-induced response. 12-Myristate 13-acetate diester (PMA), a protein kinase C (PKC) activator, had only a weak inhibitory effect on I_5-HT, and staurosporine, a PKC inhibitor, failed to significantly occlude I_5-HT. Therefore, the K⁺ conductance activated via the 5-HT_1A receptor of dorsal raphe neurons was thus characterized by the sensitivity to such K⁺ channel blockers as quinine, Ba²⁺ and 4-aminopyridine. Moreover, G protein, which is NEM-sensitive and can couple to the 5-HT_1A receptor, is thus considered to activate the inwardly rectifying K⁺ conductance without being mediated by such second messengers as Ca²⁺ and PKC.     

Role of cortical and striatal 5-HT1A receptors in alleviating antipsychotic-induced extrapyramidal disorders

Previous studies have revealed that 5-HT_1A agonists ameliorate antipsychotic-induced extrapyramidal symptoms (EPS) through postsynaptic 5-HT_1A receptors. Here, we conducted an intracerebral microinjection study of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin ((±)8-OH-DPAT) to determine the action site of the 5-HT_1A agonist in alleviating EPS. Bilateral microinjection of(±)8-OH-DPAT (5 µg/1 µL per side) either into the primary motor cortex (MC) or the dorsolateral striatum (dlST) significantly attenuated haloperidol-induced catalepsy in rats. The anticataleptic action of (±)8-OH-DPAT was more prominent with the MC injection than with the dlST injection. WAY-100135 (a selective 5-HT_1A antagonist) completely antagonized the reversal of haloperidol-induced catalepsy both by intracortical and intrastriatal (±)8-OH-DPAT. Furthermore, lesioning of dopamine neurons with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (30 mg/kg/day, i.p., for 4 days) did not alter the anti-EPS actions of (±)8-OH-DPAT in a mouse pole test. The present results strongly suggest that 5-HT_1A agonist alleviates antipsychotic-induced EPS by activating postsynaptic 5-HT_1A receptors in the MC and dlST, probably through non-dopaminergic mechanisms.     

Stimulation of 5-HT2A receptors in the paraventricular hypothalamus attenuates neuropeptide Y-induced hyperphagia through activation of corticotropin releasing factor

The effect of 5-HT₁ and 5-HT₂ receptor agonists administered into the paraventricular hypothalamus was studied on the hyperphagia caused by neuropeptide Y (NPY) injected into the same area. The 5-HT_2A/2C receptor agonist DOI (10–20 nmol/0.5 μl) significantly reduced NPY overeating while the 5-HT_1A/1B receptor agonist RU 24969 (3.5–14 nmol/0.5 μl) and the 5-HT_1B/2C receptor agonist mCPP (5–20 nmol/0.5 μl) had no such effect. The 5-HT_2A receptor antagonist spiperone (5 μg/0.5 μl) and the corticotropin releasing factor antagonist α-helical-CRF^9–41 (0.5–1 μg/0.5 μl completely antagonized the effect of 10 nmol DOI.     

Stimulation of 5-HT1A receptors reduces apoptosis after transient forebrain ischemia in the rat

It has recently been shown that 5-HT_1A receptor stimulation reduced the infarct volume after occlusion of the middle cerebral artery in rats. Since there is increasing evidence that apoptosis is involved in neurodegenerative diseases and stroke, we investigated whether the 5-HT_1A agonist Bay x 3702 could protect neurons against apoptotic damage in a rat model of transient forebrain cerebral ischemia. Bay x 3702 (4 μg/kg i.v.) caused a 10% reduction of neuronal damage in the hippocampal CA1 subfield. Higher doses of Bay x 3702 (40 and 12 μg/kg i.v.) did not cause any neuroprotective effect, most likely because of the strong reduction of mean arterial blood pressure during the period of Bay x 3702 infusion. Bay x 3702 (4 μg/kg i.v.) diminished DNA laddering in the hippocampus and striatum 4 days after 10 min forebrain ischemia. These results were confirmed by TUNEL-staining. The anti-apoptotic effect was abolished by additional treatment with the 5-HT_1A receptor antagonist WAY 100635 (1 mg/kg). Taken together, the results suggest that Bay x 3702 can rescue hippocampal as well as striatal neurons from apoptotic cell death in vivo via stimulation of 5-HT_1A receptors.     

Increased binding at 5-HT1A, 5-HT1B, and 5-HT2A receptors and 5-HT transporters in diet-induced obese rats

5-Hydroxytryptamine (5-HT, serotonin), synthesized in midbrain raphe nuclei and released in various hypothalamic sites, decreases food intake but the specific 5-HT receptor subtypes involved are controversial. Here, we have studied changes in the regional density of binding to 5-HT receptors and transporters and the levels of tryptophan hydroxylase, in rats with obesity induced by feeding a palatable high-energy diet for 7 weeks. We mapped binding at 5-HT receptor subtypes and transporters using quantitative autoradiography and determined tryptophan hydroxylase protein levels by Western blotting. In diet-induced obese (DiO) rats, specific binding to 5-HT_1A receptors ([³H]8-OH-DPAT) was significantly increased in the dorsal and median raphe by 90% (P<0.01) and 132% (P<0.05), respectively, compared with chow-fed controls. 5-HT_1B receptor binding sites ([¹²⁵I]cyanopindolol) were significantly increased in the hypothalamic arcuate nucleus (ARC) of DiO rats (58%; P<0.05), as were 5-HT_2A receptor binding sites ([³H]ketanserin) in both the ARC (44%; P<0.05) and lateral hypothalamic area (LHA) (121%; P<0.05). However, binding to 5-HT_2C receptors ([³H]mesulgergine) in DiO rats was not significantly different from that in controls in any hypothalamic region. Binding to 5-HT transporters ([³H]paroxetine) was significantly increased (P<0.05) in both dorsal and median raphe, paraventricular nuclei (PVN), ventromedial nuclei (VMH), anterior hypothalamic area (AHA) and LHA of DiO rats, by 47%–165%. Tryptophan hydroxylase protein levels in the raphe nuclei were not significantly different between controls and DiO rats. In conclusion, we have demonstrated regionally specific changes in binding to certain 5-HT receptor subtypes in obesity induced by voluntary overeating of a palatable diet. Overall, these changes are consistent with reduced 5-HT release and decreased activity of the 5-HT neurons. Reduction in the hypophagic action of 5-HT, possibly acting at 5-HT_1A, 5-HT_1B and 5-HT_2A receptors, may contribute to increased appetite in rats presented with highly palatable diet.     

Effects of 8-OH-DPAT, a 5-HT1A receptor agonist, and DOI, a 5-HT2A/2C agonist, on monosynaptic transmission in spinalized rats

We investigated the effect of the 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) and the 5-HT_2A/2C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on monosynaptic transmission in spinalized rats. 8-OH-DPAT significantly inhibited the excitation of α-motoneurons evoked by monosynaptic transmission without a direct effect on α-motoneuron excitation. DOI potentiated the excitation of α-motoneurons by both direct stimulation and monosynaptic transmission. These results indicate that activation of 5-HT_1A receptors inhibits monosynaptic transmission, whereas activation of 5-HT_2A/2C receptors enhances it.     

Quantitative autoradiography of 5-HT1D and 5-HT1E binding sites labelled by [H]5-HT, in frontal cortex and the hippocampal region of the human brain

In human cortex and hippocampus area, [³H]5-HT (5 nM) labels 5-HT_1A, 5-HT_1D and 5-HT_1E sites. After masking 5-HT_1A receptors by 0.1 μM 8-OH-DPAT, the binding displaced by 0.1 μM 5-CT presumably represented 5-HT_1D sites and the remaining binding 5-HT_1E sites. In frontal cortex, 5-HT_1A receptors represented the main binding in layers II and VI and a lower fraction on other layers. 5-HT_1D and 5-HT_1E sites, were more homogeneously distributed in layers II to VI (21–34% of specific [³H]5-HT binding). 5-HT_1E sites were of similar affinities (K_D close to 6–8 nM) in the cortical layers II to VI. In CA1 field of hippocampus, (pyramidal layer, stratum radiatum, molecular layer), CA2 and dentate gyrus, 5-HT_1A receptors represented the major fraction, 5-HT_1D sites a significant fraction and 5-HT_1E a minor fraction of the specific [³H]5-HT binding. In CA3–CA4 fields, 5-HT_1A receptors were less densely present, 5-HT_1D sites were predominant and 5-HT_1E sites represented a significant fraction (27%). The highest densities of 5-HT_1E sites have been measured in subiculum, where 5-HT_1A, 5-HT_1D, and 5-HT_1E binding sites were equally represented and in entorhinal cortex where 5-HT_1E sites represented the major binding in layer III. They were also present in layers II and IV (29 and 24%) and, to a lesser extent, in layers V and VI. 5-HT_1A sites were predominant in layer VI, II and V and were less abundant in other layers. 5-HT_1D were homogeneously present in layers II, III, IV and were present in low amounts in other layers. No 5-HT_1E were detected in choroid plexus, where [³H]5-HT was dramatically reduced by mesulergine (5-HT_2C receptors). No significant displacement of [³H]5-HT by mesulergine was measured in other structures.     

Sleep/waking effects following intrathecal administration of the 5-HT1A agonist 8-OH-DPAT alone and in combination with the putative 5-HT1A antagonist NAN-190 in rats

Sleep, waking, and EEG power spectra were investigated in rats after intrathecal (IT) administration of a 5-HT_1A agonist and a 5-HT_1A antagonist. Total slow wave sleep (TSWS) was increased and waking was decreased over the 8-h recording period after the 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (38 nmol). Within TSWS, SWS1 was unchanged while SWS-2 tended to be increased. The 5-HT_1A antagonist 1-[2-Methoxyphenyl)-4-(4-(2-phthalimido)-butyl]piperazine hydrobomide (NAN-190) did not change and sleep/waking stages. Combined treatment with 8-OH-DPAT and NAN-190 increased variance. Following the combination, sleep and waking were not significantly different from control. SWS-2 tended to be reduced compared to the effect of 8-OH-DPAT alone. There were no systematic changes in neither waking nor TSWS fronto-frontal or fronto-parietal EEG power spectrum after any of the treatments, indicating that sleep quality was not changed. The results confirm earlier data suggesting that in the spinal cord, stimulation of 5-HT1A receptors have a dampening effect on transmission of sensory information, leading to deactivation and thereby increased sleep tendency. The reason why the 8-OH-DPAT effect was not clearly antagonized by the putative 5-HT1A antagonist NAN-190, may be due to the generally weak antagonistic and also partial agonistic effect of NAN-190 as reported in the literature.     

Enhanced accumbal dopamine release following 5-HT2A receptor stimulation in rats pretreated with intermittent cocaine

This study was conducted to determine whether dopamine (DA) release in the nucleus accumbens (NACC) following 5-HT_2A receptor stimulation is potentiated by intermittent cocaine. Rats received daily injections of either saline or cocaine (30 mg/kg, s.c.) for 14 days. At the 7th day after withdrawal, microdialysis was performed in the NACC. Infusion of (±)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI, 50 μM), a 5-HT₂ receptor agonist, into the NACC produced greater and longer-lasting increases in extracellular DA in the rats pretreated with cocaine than in the rats pretreated with saline. The DOI-induced increases in NACC DA were attenuated by co-perfusion with ketanserin (50 μM), a 5-HT_2A receptor antagonist. The results are consistent with the concept that intermittent cocaine may cause enhanced sensitivity of 5-HT_2A receptors within the NACC.     

Anxiolytic effect of the 5-HT1A compounds 8-hydroxy-2-(di-n-propylamino) tetralin and ipsapirone in the social interaction paradigm: Evidence of a presynaptic action

This study analyses at which site, pre- or postsynaptic, the 5-HT_1A ligands—8-hydroxy-2(dl-n-propyilamino)tetralin (8-OH-DPAT) and ipsapirone—induce their amdoytic action. The experimental anxiety was assessed in the social interaction test. An anxioyfic action was observed after the systemic administration of 8-OH-DPAT (025 and 0.5 mg/kg and ipsapirone (5 but not 10 mg/kg). In 5,7-dihydroxytrpytamine (5,7-DHT, 150 μg/10 μl) lesioned rats the arodoytie effect of 8-OH-DPAT and ipsapirone was not observed, suggesting a presynaptic action of these drugs.dnVs. When directly injected into the dorsal raphe nucleus 8-OH-DPAT (0.1 μgμl) and ipsapirone (0.2 μg/μl), both compounds produce an)dolytic effects. At same doses, these drugs lacked an effect after their intrahippocampal infusion. All data strongly suggest that both drugs act presynaptically to reduce the anxiety levels in the social interaction paradigm.     

Effects of triiodothyronine and fluoxetine on 5-HT1A and 5-HT1B autoreceptor activity in rat brain: regional differences

The thyroid hormone triiodothyronine (T3) augments and accelerates the effects of antidepressant drugs. Although the majority of studies showing this have used tricyclics, a few studies have shown similar effects with the selective serotonin re-uptake inhibitor (SSRI) fluoxetine. In this study we investigated the effects of fluoxetine (5 mg/kg), T3 (20 μg/kg) and the combination of these drugs, each administered daily for 7 days, on serotonergic function in the rat brain, using in vivo microdialysis. Fluoxetine alone induced a trend towards desensitization of 5-HT_1A autoreceptors as shown by a reduction in the effect of 8-OH-DPAT to lower 5-HT levels in frontal cortex, and desensitized 5-HT_1B autoreceptors in frontal cortex. The combination of fluoxetine and T3 induced desensitization of 5-HT_1B autoreceptors in hypothalamus. Since there is evidence linking hypothalamic function and depression, we suggest that this effect may partly account for the therapeutic efficacy of the combination of an SSRI and T3.     

5-HT1A and 5-HT2 receptors differentially regulate the excitability of 5-HT-containing neurones of the guinea pig dorsal raphe nucleus in vitro

We have used intracellular recording techniques to examine the effects of 5-hydroxytryptamine (5-HT, serotonin) on 5-HT-containing neurones of the guinea pig dorsal raphe nucleus in vitro. Bath-applied 5-HT (30–300 μM) had two opposing effects on the membrane excitability of these cells, reflecting the activation of distinct 5-HT receptor subtypes. As demonstrated previously in the rat, 5-HT evoked a hyperpolarization and inhibition of 5-HT neurones, which appeared to involve the activation of an inwardly rectifying K⁺ conductance. This hyperpolarizing response was blocked by the 5-HT_1A receptor-selective antagonist WAY-100635 (30–100 nM). In the presence of WAY-100635, 5-HT induced a previously unreported depolarizing, excitatory response of these cells, which was often associated with an increase in the apparent input resistance of the neurone, likely due to the suppression of a K⁺ conductance. Like the hyperpolarizing response to 5-HT, this depolarization could be recorded in the presence of the Na⁺ channel blocker tetrodotoxin. In addition, the response was not significantly attenuated by the α₁-adrenoceptor antagonist prazosin (500 nM), indicating that it is not due to the release of noradrenaline, or to the direct activation of α₁-adrenoceptors by 5-HT. The 5-HT₃ receptor antagonist granisetron (1 μM) and the 5-HT₄ receptor antagonist SB 204070 (100 nM) failed to reduce the depolarizing response to 5-HT; however, ketanserin (100 nM), mesulergine (100 nM) and lysergic acid diethylamide (1 μM) significantly reduced or abolished the depolarization, indicating that this effect of 5-HT is mediated by 5-HT₂ receptors.     

DOI disrupts prepulse inhibition of startle in rats via 5-HT2A receptors in the ventral pallidum

Serotonin (5-HT)_2A receptors are known to be involved in prepulse inhibition of the startle response (PPI), a measure of sensorimotor inhibition that is deficient in schizophrenia, Huntington's disease, and obsessive compulsive disorder. In the present studies, the localization of the 5-HT_2A receptors responsible for modulating PPI was investigated using central injections of the hallucinogenic 5-HT₂ agonist DOI and the novel 5-HT_2A antagonist MDL 100,907. 5-HT_2A receptors are densely localized in the nucleus accumbens (NAC) and the ventral pallidum (VP), areas known to be important components of neural circuitry that mediates the ventral forebrain modulation of PPI. In the present studies, it was found that the infusion of DOI (0.0–5.0 μg/0.5 μl) into the VP disrupted PPI without having effects on startle reactivity. In contrast, similar infusions into the NAC had no effect on PPI or startle reactivity. The infusion of MDL 100,907 into the VP was found to increase PPI by itself and to attenuate the PPI-disruptive effects of systemically administered DOI. It is concluded that 5-HT_2A receptors within the VP are important for the modulation of PPI, presumably through interactions at intrinsic GABAergic or cholinergic interneurons.     

Melatonin reversal of DOI-induced hypophagia in rats; possible mechanism by suppressing 5-HT2A receptor-mediated activation of HPA axis

Serotonin type 2A (5-HT_2A) receptor-mediated neurotransmitter is known to activate hypothalamic–pituitary–adrenal (HPA) axis, regulate sleep–awake cycle, induce anorexia and hyperthermia. Interaction between melatonin and 5-HT_2A receptors in the regulation of the sleep–awake cycle and head-twitch response in rat have been reported. Previous studies have shown that melatonin has suppressant effect on HPA axis activation, decreases core body temperature and induces hyperphagia in animals. However, melatonin interaction with 5-HT_2A receptors in mediation of these actions is not yet reported. We have studied the acute effect of melatonin and its antagonist, luzindole on centrally administered (±)-1-(2,5-dimethoxy-4-iodophenyl) 2-amino propane (DOI; a 5-HT_2A/2C agonist)-induced activation of HPA axis, hypophagia and hyperthermia in 24-h food-deprived rats. Like ritanserin [(1 mg/kg, i.p.) 5-HT_2A/2C antagonist], peripherally administered melatonin (1.5 and 3 mg/kg, i.p.) did not affect the food intake, rectal temperature or basal adrenal ascorbic acid level. However, pretreatment of rats with it significantly reversed DOI (10 μg, intraventricular)-induced anorexia and activation of HPA axis. But the hyperthermia induced by DOI was not sensitive to reversal by melatonin. Mel₁ receptor subtype antagonist luzindole (5 μg, intraventricular) did not modulate the DOI effect but antagonized the melatonin (3 mg/kg, i.p.) reversal of 5-HT_2A agonist response. The present data suggest that melatonin reversal of DOI-induced hypophagia could be due to suppression of 5-HT_2A mediated activation of HPA axis.     

Effect of a 5-HT1A receptor agonist, flesinoxan, on the extracellular noradrenaline level in the hippocampus and on the locomotor activity of rats

We have studied effects of 5-hydroxytryptamine 1A (5-HT_1A) receptor-selective compounds on the extracellular noradrenaline (NA) level in the hippocampus of rats using microdialysis and on their locomotor activity. A selective 5-HT_1A receptor agonist, flesinoxan (5 mg/kg, i.p.) increased the extracellular NA level in the hippocampus, and increased the locomotor activity. Both responses were blocked by pretreatment with a 5-HT_1A receptor antagonist, WAY100635 (1 mg/kg, i.p.) and an α₂ adrenoceptor agonist, clonidine (50 μg/kg, i.p.). Bilateral intrahippocampal injection of flesinoxan (200 nmol in 2 μl, respectively) increased the locomotor activity of rats and the intrahippocampal perfusion of flesinoxan (1 mM, 2 μl/min) increased the extracellular NA level in the hippocampus. Bilateral intrahippocampal injections of a small amount of WAY100635 (0.1 nmol in 2 μl, respectively) blocked the flesinoxan (5 mg/kg, i.p.)-induced hyperactivity. Flesinoxan (5 mg/kg, i.p.) did not significantly influence the level of serotonin or its major metabolite in the hippocampus, or dopamine or its metabolites in the striatum. In conclusion, these behavioral as well as pharmacological results indicate that postsynaptic 5-HT_1A receptor activation by flesinoxan increase the extracellular NA level in the hippocampus, which may be the cause of the increase of the locomotor activity.