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Our previous studies have suggested a strong involvement of serotonergic innervations in epileptogenesis and associated memory impairment. Several studies have suggested that the modulation of 5-HT 3 receptors could serve as a promising tool for the management of epilepsy and memory deficit. The present study was envisaged to confirm this hypothesis. In this study, kindling was induced in male Swiss Albino mice using a subconvulsive dose of pentylenetetrazole (PTZ) (35 mg/kg at 48 ± 2 h). Once the animals were kindled, they were treated with a vehicle, ondansetron (0.1, 0.5, 1 mg/kg/day; i.p.), m-chlorophenylbiguanide (m-CPBG) (1 mg/kg/day; i.p.), and ondansetron + m-CPBG for 20 days. On days 5, 10, 15, and 20, they were administered a PTZ challenging dose (35 mg/kg) to assess the seizure severity score; thereafter, memory was evaluated. After behavioral assessment on day 20, the animals were sacrificed and their brains were isolated to estimate cortical and hippocampal neurotransmitter levels (glutamate and gamma aminobutyric acid (GABA) by the high-performance liquid chromatography with the fluorescence detection method, and the nitrite level and acetylcholinesterase (AChE) activity by the microplate reader method). Ondansetron treatment significantly reduced the seizure severity and improved the acquisition performance in a dose-dependent manner. Neurochemical analysis suggested that ondansetron treatment significantly reduced the nitrite level and AChE activity in the cortex as well as in the hippocampus. The outcome of this study suggests the reduction in AChE activity and the nitrite level could be considered as protective mechanisms of ondansetron for amelioration of PTZ kindling and associated memory deficit. [ABSTRACT FROM AUTHOR]

The serotonergic system has often been defined as a neuromodulator system, and is specifically involved in learning and memory via its various receptors. Serotonin is involved in many of the same processes affected by cannabinoids. The present study investigated the influence of bilateral post-training intra-prelimbic (PL) administrations of serotonergic 5-hydroxytryptamine type-3 (5-HT3) receptor agents on arachidonylcyclopropylamide (ACPA) (cannabinoid CB1 receptor agonist)-induced amnesia, using the step-through inhibitory avoidance (IA) task to assess memory in adult male Sprague–Dawley rats. The results indicated that sole intra-PL microinjection of ACPA (0.1 and 0.5 μg/rat) and 5-HT3 serotonin receptor agonist (m-Chlorophenylbiguanide hydrochloride, m-CPBG; 0.001, 0.01 and 0.1 μg/rat) impaired, whereas Y-25130 (a selective 5-HT3 serotonin receptor antagonist; 0.001 and 0.01 and 0.1 μg/rat) did not alter IA memory consolidation, by itself. Moreover, intra-PL administration of subthreshold dose of m-CPBG (0.0005 μg/rat) potentiated, while Y-25130 (0. 1 μg/rat) restored ACPA-induced memory consolidation deficit. The isobologram analysis showed that there is a synergistic effect between ACPA and m-CPBG on memory consolidation deficit. These findings suggest that 5-HT3 receptor mechanism(s), at least partly, play(s) a role in modulating the effect of ACPA on memory consolidation in the PL area. [ABSTRACT FROM AUTHOR]

Abstract: In the present study the role of 5-HT3 receptors located at the medial septum/vertical limb of the diagonal band complex (MS/vDB) in the control of blood pressure in unanaesthetized rats was investigated. Microinjections of ondansetron, a selective 5-HT3 receptor antagonist, into this area caused a dose-dependent increase in blood pressure. This rise was attenuated by the blockade of alpha-adrenoceptors with i.v. prazosin and blunted by the prior microinjection of losartan, an AT1 antagonist, into this brain area. Microinjections of the 5-HT3 agonist m-CPBG into this area failed to have any effect on blood pressure in non-stressed rats but significantly reduced the stress-induced hypertensive response. The reflex bradycardia evoked by i.v. phenylephrine was significantly increased after microinjections of ondansetron into this brain area but not the tachycardia evoked by i.v. sodium nitroprusside, suggesting that the pressor part of baroreflex has been enhanced. The data suggest that 5-HT3 receptors at this brain level exert a tonic sympathoinhibitory action that is mediated via the local release of angiotensin in the MS/vDB. This tonic 5-HT3 receptor drive also exerts an inhibitory action on the pressor component of the baroreflex. Also, the present data show that 5-HT3 receptors located in the MS/vDB participate in the regulation of stress-induced hypertensive response. [ABSTRACT FROM AUTHOR]

We examined the properties of the drug interaction between morphine and 5-HT3 receptor antagonist at the spinal level. The nociceptive state was induced by subcutaneously injecting formalin solution (5%, 50 μl) into the hindpaw of the rats. Intrathecal morphine and m-CPBG (5-HT3 receptor agonist) dose-dependently decreased the flinching response during phase 1 and phase 2 in the formalin test. Intrathecal 5-HT3 receptor antagonists (LY-278,584 and ondansetron) did not reverse the antinociceptive effect of intrathecal morphine. Intrathecal naloxone had little effect on attenuation of the antinociception of intrathecal m-CPBG. Taken together, no reciprocal interaction was noted between 5-HT3 receptor and opioid receptors at the spinal level. Thus, the 5-HT3 receptor antagonist may be useful to manage opioid-induced emesis at the spinal level. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: In the present study, we investigated the role of 5-HT3 and 5-HT2C receptors located within the medial amygdala (MeA) in the control of water and salt intake in sodium-depleted rats. Pharmacological activation of 5-HT3 receptors located in the medial amygdala by the selective 5-HT3 receptor agonist m-CPBG significantly reduced salt intake in sodium-depleted rats, an effect that is reverted by pretreatment with the selective 5-HT3 receptor antagonist ondansetron. In addition, the injection of ondansetron alone into the medial amygdala had no effect on salt intake in sodium-depleted and in sodium-repleted rats. Pharmacological stimulation of 5-HT2C receptors located in the medial amygdala by the selective 5-HT2C receptor agonist m-CPP failed to modify salt intake in sodium-depleted rats, whereas the blockade of these receptors by the selective 5-HT2C receptor antagonist SDZ SER 082 significantly reduced salt intake in this same group of animals. These results lead to the conclusion that the pharmacological activation of 5-HT3 receptors located within the MeA inhibits salt intake in sodium-depleted rats and that, in this same brain region, the functional integrity of 5-HT2C receptors is required to achieve the full expression of sodium appetite in sodium-depleted rats. [Copyright &y& Elsevier]

Rationale: Temporal differentiation refers to animals' ability to regulate their behaviour during an ongoing interval. Striatal dopaminergic mechanisms are purported to be involved in temporal differentiation, and recent evidence also implicates 5-hydroxytryptaminergic (5-HTergic) mechanisms, possibly mediated by 5-HT2A receptors. There is evidence that 5-HT3 receptors contribute to the regulation of dopamine release in the basal ganglia; however, it is not known whether 5-HT3 receptor stimulation can influence temporal differentiation. Objective: We examined the effects of a selective 5-HT3 receptor agonist m-CPBG, a mixed 5-HT2A/3 receptor agonist quipazine, and selective 5-HT3 and 5-HT2A receptor antagonists (MDL- 72222 and ketanserin, respectively) on temporal differentiation in a free-operant psychophysical procedure. Methods: Twenty-four rats were trained to respond on two levers (A and B) under a free-operant psychophysical schedule, in which sucrose reinforcement (0.6 M, 50 µl) was provided intermittently for responding on A during the first half and on B during the second half of 50-s trials. Logistic psychometric functions were fitted to the relative response rate data [percent responding on B (%B) vs time from trial onset (t)], and quantitative indices of timing performance [T50 (value of t corresponding to %B=50), Weber fraction, and mean time of switching from A to B, S50] were derived. Results: Quipazine (0.5, 1, and 2 mg kg-1) altered timing performance, dose-dependently reducing T50 and S50; m-CPBG (2.5, 5, and 10 mg kg-1) had no significant effect. The effect of quipazine was antagonized by ketanserin (2 mg kg-1), but not by MDL-72222 (1 mg kg-1). Conclusions: The present results provide no evidence for the involvement of 5- HT3 receptors in temporal differentiation and indicate that the effect of quipazine on performance was mediated by 5-HT2A receptor stimulation. The results are consistent with previous evidence for the involvement of 5-HT2A receptors in interval timing behaviour. [ABSTRACT FROM AUTHOR]

In the present paper, we studied in rats the effect of third ventricle administration of m-chlorophenylbiguanide hydrochloride (1-(3-chlorophenyl)biguanide (m-CPBG), a selective 5-HT3 agonist, on water intake induced by three different physiological stimuli: water deprivation, acute salt load and hypovolemia. Central acute m-CPBG injections in the doses of 80 and 160 nmol significantly reduced water intake elicited by an acute salt load. Third ventricle injections of m-CPBG in the dose of 160 nmol significantly inhibited water intake in hypovolemic animals, whereas third ventricle injections of m-CPBG in a higher dose (320 nmol) were necessary to decrease water intake in water-deprived rats. Pretreatment with 1-methyl-N-[8-methyl-8-azabicyclo(3.2.1)-oct-3-yl]-1H-indazole-3-carboxamide (LY-278,584), a selective 5-HT3 antagonist, abolished the inhibitory effect on water intake seen after central administration of m-CPBG in all groups studied. The central administration of m-CPBG was also able to inhibit water intake induced by pharmacological activation of central cholinergic and angiotensinergic pathways. Third ventricle injections of m-CPBG in the highest dose employed in this study (320 nmol) were unable to modify food intake in food-deprived rats. An aversion test has shown that acute third ventricle injections of m-CPBG do not induce illness-like effects that could explain the water intake inhibition here observed. Also, central administration of m-CPBG did not modify the intake of a “dessert” meal consisting of diluted condensed milk. It is concluded that central 5-HT3 receptor activation exerts a specific inhibitory effect on water intake. [Copyright &y& Elsevier]