[Changes in behavior and central monoaminergic systems in the rat after repeated methamphetamine pretreatment:...

We used various methods, including intracerebral dialysis, to investigate behavioral sensitization to methamphetamine (MAP) and neurochemical alterations of monoaminergic systems in rat striatum after repeated intermittent pretreatment with increased doses of MAP (2.5, 5, 7.5, 10 mg/kg sc x 2, every other day for a week) as an experimental model of MAP psychosis. MAP-pretreated rats showed an enhancement in MAP-stimulated striatal dopamine (DA) efflux from the neuron terminals into the synaptic cleft. The MAP-induced behavioral changes correlated significantly with the amount of DA efflux. The number of D2 receptors was not changed after the repeated MAP pretreatment. Therefore, as the possible explanations for the enhanced DA release. mechanism, it was suggested that the repeated exposure to abnormally high concentrations of DA produced by repeated MAP administration changed the presynaptic regulation mechanism as follows. (1) DA autoreceptor became subsensitive because low doses of (+/- ) apomorphine (25-50 micrograms/kg sc), a selective DA agonist, decreased striatal DA efflux below the predrug basal level in controls, but not in MAP-pretreated rats. It is recognized that low doses of apomorphine inhibit DA release via DA autoreceptor. (2) "Releasable DA pool" at the neuron terminals increased as shown by the enhanced DOPA accumulation 30 min after NSD1015 (100 mg/kg ip), an aromatic 1-amino acid decarboxylase inhibitor. (3) DA uptake decreased for the significantly more decreased DOPAC and HVA efflux after MAP challenge in MAP-pretreated rats. Serotonergic alteration was also indicated in MAP-pretreated rats, because of the significant decrease of 5-HIAA efflux after MAP challenge.