Behavioural interactions between 5‐hydroxytryptophan, neuroleptic agents and 5‐HT receptor antagonists in modifying rodent responding to aversive situations

Abstract

1 The ability of 5-hydroxytryptophan, 5-HT2 receptor antagonists and typical and atypical neuroleptic agents to modify behavioural responding to aversive situations was investigated in the mouse light/dark test and rat social interaction. 2 The administration of 5-hydroxytryptophan inhibited rat social interaction and the exploratory behaviour of mice in the light/dark test.3 The 5-HT2 receptor antagonists, ketanserin, ritanserin, MDL11939, methysergide and RP62203, the neuroleptic agents, spiperone, haloperidol and benperidol, and the atypical neuroleptic agent, clozapine, when administered alone failed to modify mouse or rat behaviour. In contrast, when administered alone, sulpiride in rats and mice and thioridazine in rats disinhibited behaviour. 4 Methysergide, RP62203, ketanserin, ritanserin and MDL11939 antagonized the inhibitory effects of 5-hydroxytryptophan or reversed the inhibitory effects to one of disinhibition. 5 Low doses of spiperone (but not haloperidol or benperidol) also antagonized the inhibitory effects of 5-hydroxytryptophan in the rat but not the mouse. Higher doses of the three neuroleptic agents caused locomotor depression in both rats and mice which obscured any specific changes in behavioural responding to the aversive situations. 6 The disinhibitory profile of sulpiride in both mice and rats and thioridazine in rats was evident during their interaction with 5-hydroxytryptophan. Thioridazine in the mouse and clozapine in rats and mice also reversed the inhibitory effects of 5-hydroxytryptophan to one of disinhibition. 7 In summary, we present evidence that the atypical neuroleptic agents, thioridazine and clozapine, with their known affinity for the 5-HT2 receptors, can mimic the actions of reference 5-HT2 receptor antagonists to antagonize the inhibitory effects of 5-hydroxytryptophan in rodent models of anxiety. The results are intepreted in terms of drug action on different 5-HT2 and other 5-HT receptor subtypes. In addition, thioridazine and sulpiride have disinhibitory effects in their own right which remain to be explained.

Endogenous 5-HT Tonically Inhibits Spontaneous Firing Activity of Dorsal Hippocampus CA1 Pyramidal Neurons Through Stimulation of 5-HT1A Receptors in Quiet Awake Rats In Vivo Electrophysiological Evidence

“…(Leysen et al 1985) did not modify the increasing effect of WAY-100635 ( Figure 5). This is a supra-sufficient dose of ritanserin to block a 5-HT 2A receptor-mediated behavior of rats (Costall and Naylor 1995;Imeri et al 1999). Thus, the involvement of 5-HT 2A receptors could be ruled out whichever this excitatory 5-HT receptor facilitates or diminishes the excitability of the pyramidal neurons.…”

Antagonist Functional Selectivity: 5-HT2A Serotonin Receptor Antagonists Differentially Regulate 5-HT2A Receptor Protein Level In Vivo

“…The dosage of each drug used in this study was decided on the basis of literature doses to induce a regulatory adaptation of 5-HT 2A receptors or the maximal tolerated doses that are in excess of those shown previously to induce antipsychotic-like activity. Thus, the doses of M100907 and M11939 chosen (5 mg/kg) exceed the maximal effective doses used in behavioral studies (0.1 mg/kg for M100907 and M11939) (Costall and Naylor, 1995;Martin et al, 1997). Likewise, for ketanserin, the dose chosen (10 mg/kg) exceeds the effective dose for normalization of MK801-induced hyperactivity (0.12 mg/kg) (O'Neill et al, 1998) and was the maximal tolerated dose for this drug.…”

Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model

“…The 5HT and/or DA compound administration started ;4-10 h before the viral injection (taking into consideration the ;8 h required for viral expression of recombinant proteins) (Qin et al 2005;Kielland et al 2009) and ;16-20 h before behavioral tests. 5HT and DA compounds were dissolved in saline, and saline alone was tested as controls, and their dosages were estimated based on the published data (Puglisi- Allegra and Cabib 1988;Costall and Naylor 1995;Kennett et al 1997;O'Dell et al 2000;Usiello et al 2000;Wang et al 2008) and dose response curves (cf. Supplemental Fig.…”