PHARMACOLOGICAL STUDY OF TA-0910, A NEW THYROTROPIN-RELEASING-HORMONE (TRH) ANALOG (II) - INVOLVEMENT OF THE DA SYSTEM IN THE LOCOMOTOR STIMULATING ACTION OF TA-0910

The mechanism of the locomotor stimulating action of a new thyrotropin-releasing hormone (TRH) analog, TA-0910, was studied in rats. The locomotor stimulating action of TA-0910 (3 mg/kg) was inhibited by haloperidol or alpha-methyl-p-tyrosine (alpha-MT); slightly inhibited by phenoxybenzamine, prazosin, clonidine, or naloxone; not affected by propranolol, metergoline, or a low dose of scopolamine; and was enhanced by a high dose of scopolamine. The locomotor activity was increased by TA-0910 (0.3 mg/kg) in combination with methamphetamine, apomorphine, or L-DOPA under pretreatment with pargyline. A low dose of apomorphine inhibited the increase in locomotor activity induced by TA-0910 (3 mg/kg). The increase in locomotion was most notable and dose-dependent with the injection of 20 ng or more in the nucleus accumbens. The intravenous administration of TA-0910 produced dose-dependent and significant hyperlocomotion at 1 mg/kg or more. In the rats lesioned unilaterally in the nigrostriatal dopamine (DA) pathway by 6-hydroxydopamine, TA-0910 induced ipsilateral circling behavior at 3 mg/kg or more. This circling behavior was inhibited by haloperidol or alpha-MT. These results suggest that the locomotor stimulating action of TA-0910 is mediated primarily via the dopaminergic neuron, especially the nucleus accumbens of the mesolimbic DA system. Other possible mechanisms are also discussed.