Chronic methamphetamine exposure decreases high affinity uptake function in norepinephrine afferents in the cerebellar cortex: an electrophysiological and electrochemical study

It has been reported that chronic methamphetamine (MA) treatment decreases monoamine release in different brain regions. However, the clearance of nor epinephrine (NE) after chronic MA intake is not clear. In the present study , we administered MA to Sprague-Dawley rats for I month. The animals were l ater anesthetized with urethane for electrophysiological recording. Previou s studies have indicated that gamma-aminobutyric acid (GABA)-induced electr ophysiological responses are enhanced by norepinephrine (NE) acting via pos tsynaptic beta-adrenergic receptors. We found that local application of the NE high affinity uptake inhibitor desmethylimipramine (DMI) significantly potentiated GABA-induced electrophysiological depressions in cerebellar Pur kinje neurons in control rats. In contrast, DMI did not augment GABA respon ses in rats chronically treated with MA for 1 month, or in rats withdrawn f rom MA for 7-14 days after a I-month MA treatment. To further examine if DM I-induced GABA modulation is altered by post- or pre-synaptic mechanisms in chronic MA-treated rats, we examined the electrophysiological interaction of GABA and isoproterenol (ISO), a postsynaptic beta-adrenergic receptor ag onist, in Purkinje neurons. We found that GABA-induced inhibition is potent iated by local application of ISO in both control and chronic MA rats, sugg esting that the reduction in DMI/GABA interactions is probably not mediated through post-synaptic noradrenergic mechanisms. Presynaptic NE clearance w as further examined using in vivo chronoamperometric methods. Extracellular NE levels in the cerebellar cortex were measured using Nafion-coated carbo n fiber sensors. We found that local application of DMI inhibited NE cleara nce in control rats, but not in chronic MA animals, suggesting that presyna ptic NE clearance is reduced after chronic MA treatment. In addition, NE le vels in cerebellar tissue were measured using HPLC-ECD. The NE concentratio n was significantly decreased in chronic MA rats. Taken together, our data suggest that regulation of uptake by DMI at central noradrenergic nerve ter minals is abnormal after chronic MA exposure. Published by Elsevier Science Ltd.