Methamphetamine modulates GABA-induced electrophysiological depression by alternating noradrenergic actions 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.
Jeng
C H
CH
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
Wang
Y
Y
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D018663:Adrenergic Agents; D000697:Central Nervous System Stimulants; D011941:Receptors, Adrenergic; D008694:Methamphetamine; D005680:gamma-Aminobutyric Acid