Behavioural interactions between 5-hydroxytryptophan, neuroleptic agents and 5-HT receptor antagonists in modifying rodent responding to aversive situations.
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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. (+info)
In vivo kinetics of [18F](N-methyl)benperidol: a novel PET tracer for assessment of dopaminergic D2-like receptor binding.
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A novel D2-like receptor-binding radioligand, [18F](N-methyl)benperidol ([18F]NMB), was evaluated via positron emission tomographic (PET) imaging studies of baboons. [18F]NMB rapidly localized in vivo within dopaminergic receptor-rich cerebral tissues, and striatum-to-cerebellum ratios as high as 35 were achieved after 3 hours. Pretreatment of an animal with unlabeled receptor-specific antagonists before injection of [18F]NMB confirmed that the radioligand bound specifically to central D2-like receptors in vivo, and not to S2- or D1-like receptors. Unlabeled eticlopride displaced striatal [18F]NMB in vivo, showing that D2-like binding is reversible. Receptor-binding by the radioligand was resistant to competitive displacement by synaptic dopamine, as illustrated by the lack of effect of intravenous d-amphetamine on the in vivo localization of [18F]NMB. Studies involving sequential intravenous administration of [18F]NMB, d-amphetamine, and eticlopride show that the radioligand does not undergo agonist-mediated internalization with subsequent trapping. The feasibility of applying a three-compartment non-steady state model for quantification of [18F]NMB receptor binding was demonstrated. These in vivo characteristics give [18F]NMB distinct advantages over the PET radiopharmaceuticals currently used for clinical investigation of D2-like receptor binding. (+info)