Differential effects of acute and subacute HA-966 treatment on storage and release of striatal dopamine

Acute injections of HA-966 (100 mg/kg) into rats caused a rapid elevation of dopamine (DA) content in the striatum. 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels increased after a latency period of 0.5 h and 1 h respectively. Repeated ("subacute") HA-966 treatment produced a smaller DA increase than did single administration, while DOPAC and HVA rose at the same rate after both treatments. In HA-966-pretreated rats no tolerance for DA increase followed a lesion of the dopaminergic fibres. Acute as well as subacute HA-966 prevented the disappearance of DA after alpha-methyl-p-tyrosine for about 3 h. In both cases DOPAC and HVA levels dropped sharply after HA-966. HA-966 had no influence on the decline of DOPAC and HVA levels after monoamine oxidase inhibition. It is concluded that the rises of DOPAC and HVA after HA-966 did not occur because the capacity of the vesicular DA stores was exceeded. Instead, HA-966 affects the storage mechanism for newly formed DA. Possible explanations for the observed tolerance to DA accumulation after HA-966 are discussed.