No abstract

Methamphetamine (MA) and ethanol (EtOH) are two commonly abused drugs. Previous behavioral studies indicated that MA may synergistically alter EtOH responses. In the present study, we found that local application of MA did not potentiate ethanol-induced depressions of the spontaneous activity of Purkinje neurons in urethane-anesthetized rats. We and others previously found that, in cerebellar Purkinje neurons, EtOH and gamma-amino-butyric acid (GABA)-mediated depressions can be enhanced by norepinephrine (NE) acting via beta-adrenergic receptors while these responses are decreased by activation of alpha-adrenergic receptors. In the present experiment, after blocking alpha-adrenergic receptors with prazocin, MA significantly enhanced EtOH responses in most of neurons studied. It has been reported that MA may directly and indirectly enhance alpha-adrenergic and beta-adrenergic receptor-mediated responses. The present study may suggest that MA can negatively modulate (antagonize) the depressant effects of ethanol via the alpha-adrenergic receptor, which oppose the positive modulatory mechanism (potentiation of EtOH depression) via actions of the beta-adrenergic receptors. We found that lesioning NE neurons with N-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4), a selective noradrenergic neurotoxin, enhance the MA-facilitated ethanol responses, suggesting that this action of MA may not require NE. Since it has been reported that MA increases serotonin (5-HT) and catecholamine release from their nerve terminals, MA may potentiate EtOH depressions by facilitating the release of NE and 5-HT. Taken together, our data suggested that MA may modulate EtOH responses via catecholaminergic and serotonergic mechanisms in cerebellar Purkinje neurons.

Previous studies have indicated that gamma-aminobutyric acid (GABA)-induced electrophysiological responses can be enhanced by noradrenaline (NE) acting via beta-adrenergic receptors. Methamphetamine (MA) has been reported to be a noradrenergic releasing agent. In the present study, we examined the interaction of MA and GABA in cerebellar Purkinje neurons of urethane-anesthetized rats. We found that local application of MA did not potentiate GABA-induced electrophysiological depressions in Purkinje neurons. Since MA may act indirectly or directly on alpha or beta noradrenergic receptors, we further examined the interactions of MA with selective noradrenergic antagonists. We found that after blocking alpha-adrenergic receptors with prazocin, MA significantly facilitated GABA responses. On the other hand, co-administration of timolol with MA did not attenuate GABA-induced neuronal depressions. To examine further the interactions between alpha and beta receptors in modulating GABA response, we found that stimulation of alpha-adrenergic receptors in the absence of beta receptor activation, such as by application of the alpha-agonist phenylephrine alone, did not decrease GABA-induced inhibition. However, stimulation of alpha-adrenergic receptors in the presence of beta-receptor activation, such as by co-application of phenylephrine and the beta-agonist isoproterenol (ISO), attenuated ISO-facilitated GABA inhibition. Taken together, these data suggest that MA may activate two noradrenergic modulatory mechanisms: beta-adrenergic receptor-induced GABA potentiation and alpha-adrenergic inhibition, which attenuates beta-mediated modulation. In conclusion, our data suggest that MA may regulate GABA-induced electrophysiological response by altering both the alpha- and beta-noradrenergic inputs in cerebellar Purkinje neurons.

EtOH-induced electrophysiological responses in cerebellum can be facilitated by endogenous 5HT release by using a 5HT autoreceptor antagonist. Such actions are attenuated in aged rats perhaps through a presynaptic serotonergic mechanism.