Striatal dopamine depletion and behavioural sensitization induced by methamphetamine and 3-nitropropionic acid

The neurotoxic effects of methamphetamine (4 x 5 mg/kg i.p. at 2-h intervals) and 3-nitropropionic acid (20 mg/kg i.p. on days 1-4 and 6-9, saline on day 5), administered alone or in combination (3-nitropropionic acid as above and methamphetamine on day 5), were investigated in rats 1 week after the last injection. Neither methamphetamine nor 3-nitropropionic acid on their own altered brain dopamine levels, but in combination, they selectively lowered dopamine in the terminal regions of the corpus striatum and nucleus accumbens. Methamphetamine depleted 5-hydroxytryptamine (5-HT) in the striatum, while 3-nitropropionic acid depleted 5-HT in the accumbens and substantia nigra, but a combination of the two toxins failed to lower 5-HT in any of these brain regions. Measurements of aromatic L-amino acid decarboxylase activity disclosed no change in the capacity to decarboxylate L-3,4-dihydroxyphenylalanine in any region with any of the treatments, but a lowered capacity to decarboxylate 5-hydroxytryptophan in the nigra after all three treatments. Methamphetamine evoked characteristic hyperactivity and stereotypy in the animals, whereas 3-nitropropionic gave rise to early hypermotility followed by hypoactivity. At 1 week after treatment with 3-nitropropionic/methamphetamine, rats exhibited normal spontaneous motor behaviour, a poor response to dopamine D(1) receptor stimulation and an exaggerated response to dopamine D(2) receptor agonists. These results show that combined systemic treatment with methamphetamine and 3-nitropropionic acid partially depletes dopamine in the basal ganglia, rendering the animals supersensitive to dopamine D(2) receptor activation without altering their spontaneous locomotion.