The Interaction of Naloxone with Striatal Dopaminergic Mechanisms

Abstract

An analysis was made of the interaction between naloxone (NX) and striatal dopaminergic (DA) mechanisms in an attempt to elucidate the complex action of this drug on behavior. In doses ranging from 0.20–0.80 mg/kg, NX inhibited the stereotyped behavior induced by the directly acting DA agonist apomorphine (AISB), in a dose-dependent manner. NX (0.40 mg/kg) also produced a sigmoidal inhibition of the stereotypy induced by successive low doses of apomorphine (0.10–0.25 mg/kg). Since the effect of NX on behavior has been shown to be species dependent, an identical study was also undertaken in the guinea pig. Though NX exerted similar effects on AISB in both the rat and guinea pig and the stereotypy curves plotted for both species were of nearly identical configuration, low doses of apomorphine produced considerably more stereotypy in the guinea pig than did identical doses in the rat. The concomitant administration of the indirect DA agonist d-amphetamine (0.50–5.0 mg/kg) resulted in an effect opposite to that seen with NX and apomorphine. NX potentiated amphetamine induced stereotypy (AmISB) with the amphetamine + NX curve significantly above and virtually parallel to the amphetamine + saline curve. To test the hypothesis that these effects were the result of an action exerted by NX on the release of striatal DA, the effect of NX on AISB was assessed in the presence and absence of drugs that inhibit DA release non-specifically (MPT) and specifically (-hydroxybutyric acid). Pretreatment with either drug significantly reversed the inhibitory effect of NX on AISB relative to saline pretreated animals. This was consistant with previous observations that drugs enhancing striatal DA levels also inhibit AISB in a dose-dependent manner, and potentiate AmISB. These results are also in agreement with our recent findings that NX (10-6 M) can significantly enhance the release of 3H-DA stimulated by d-amphet amine (10-6 M) in rat striatal slices in vitro. NX appears to enhance striatal DA levels only if the nigrostriatal pathway is in a state of arousal (e.g. by amphetamine). This effect is probably not mediated by a direct action of NX on presynaptic DA receptors, but rather appears to be produced indirect by an action presynaptic opioid receptors localized on striatal DA nerve terminals.