A PHARMACOLOGICAL ANALYSIS OF THE HYPERACTIVITY SYNDROME INDUCED BY β‐PHENYLETHYLAMINE IN THE MOUSE

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Abstract
The effects of the putative 5‐hydroxytryptamine (5‐HT) receptor antagonists, methysergide, mianserin and methergoline, the dopamine receptor antagonists, haloperidol, thioridazine and clozapine, and the noradrenaline (NA) receptor antagonists, phentolamine, phenoxybenzamine and propranolol on the behavioural responses of mice to β‐phenylethylamine (PEA, 75 mg/kg) have been examined. PEA produced a syndrome consisting of three distinct phases. The brief initial phase (0–5 min after injection) which consisted of forward walking, sniffing and headweaving, was succeeded by a locomotor depressant phase (5–20 min after injection) which consisted of abortive grooming, headweaving, splayed hindlimbs, forepaw padding, sniffing and hyperreactivity, and a late locomotor stimulant phase (20–35 min after injection), which was characterized by forward walking, sniffing, hyperreactivity, rearing and licking. Methysergide, mianserin, methergoline, clozapine and propranolol inhibited headweaving and splayed hindlimbs, whereas haloperidol, thioridazine, phentolamine and phenoxybenzamine had no effect on these responses. Forepaw padding was strongly inhibited by methergoline and a high dose of mianserin, and weakly antagonized by methysergide, clozapine, haloperidol and thioridazine. In contrast, padding was mildly potentiated by phenoxybenzamine and phentolamine but strongly potentiated by propranolol. It is proposed that headweaving and splayed hindlimbs are 5‐HT‐mediated responses whereas forepaw padding also involves 5‐HT mechanisms but may be partially due to release of tryptamine. Rearing and licking were inhibited by haloperidol (most strongly), thioridazine and clozapine but potentiated by mianserin, methysergide, propranolol, phenoxybenzamine or phentolamine. Methergoline inhibited licking without affecting rearing. It is suggested that PEA‐induced rearing and licking are produced by activation of dopaminergic neurones and inhibited by 5‐HT or NA stimulation. Phenoxybenzamine inhibited sniffing and produced backward walking when administered prior to PEA, suggesting mediation by NA of sniffing and an inhibitory influence of NA on backward walking. Clozapine and thioridazine were the most effective antagonists of hyperreactivity and it is proposed that this response is dopamine‐mediated. Forward walking was inhibited by high doses of haloperidol or clozapine and potentiated by methergoline, mianserin or methysergide, suggesting that hyperactivity may also be mediated by dopamine but subject to 5‐HT inhibition. Abortive grooming was the dominant behavioural component observed after PEA administration and was prevented by all of the antagonists tested which suggests that catecholamine and 5‐HT mechanisms may be involved in the expression of this response. Since PEA is an endogenous compound in animals and man, and has been claimed to be present in abnormal amounts in some schizophrenics, PEA‐induced behavioural stimulation in mice (which includes the postulated hallucinogenic responses of abortive grooming and backward walking) may be a useful animal model of psychosis.