Role of dopaminergic neurotransmission in locomotor stimulation by dexamphetamine and ethanol

Locomotor activity and brain tyrosine hydroxylation rate in vivo, assessed as dopa formation following dopa-decarboxylase inhibition by NSD 1015, was studied in mice. Dexamphetamine 91 mg/kg IP) induced increases in locomotor activity even from the high control baseline activity during the first 5 min in a motility meter. Inhibition of catecholamine synthesis by -methyl-p-tyrosine (250 mg/kg) alone, given 30 min before test, reduced this high baseline locomotor activity, but such pretreatment did not affect the amphetamine-induced locomotor increase. The inhibition of synthesis itself was slightly attenuated by amphetamine. Low doses of apomorphine (0.1 and 0.2 mg/kg) markedly antagonized the initial locomotor increase by amphetamine but only incompletely antagonized the amphetamine-induced stimulation 15–30 min after the start of the recording. After reserpine pretreatment, apomorphine did not antagonize the amphetamine-induced locomotor stimulation. The data suggest that the release of transmitter causing behavioural stimulation by amphetamine is brought about via two independent mechanisms: facilitation of release from intact granular stores which is not critically dependent on continued catecholamine synthesis but is sensitive to receptor-mediated regulation, and facilitation of the release of newly synthesized transmitter, insensitive to such regulation. Results with ethanol suggest greater dependence on intact dopamine (DA) neurotransmission for the stimulatory effect of this drug. Dexamphetamine (4 mg/kg) caused a greater increase in striatal than in mesolimbic dopa formation, and apomorphine (0.2 mg/kg) only incompletely antagonized the effect in the former region. It is suggested that this difference reflects a relatively greater component of extrinsic feedback regulation of nigrostriatal neurones, the operation of which may contribute to a more pronounced increase in tyrosine hydroxylation, less sensitive to inhibition by apomorphine than that occurring in the mesolimbic nerve endings.