title: Chronic methamphetamine exposure decreases high affinity uptake function in norepinephrine afferents in the cerebellar cortex: an electrophysiological and electrochemical study.
abstract: It has been reported that chronic methamphetamine (MA) treatment decreases monoamine release in different brain regions. However, the clearance of norepinephrine (NE) after chronic MA intake is not clear. In the present study, we administered MA to Sprague-Dawley rats for 1 month. The animals were later anesthetized with urethane for electrophysiological recording. Previous studies have indicated that gamma-aminobutyric acid (GABA)-induced electrophysiological responses are enhanced by norepinephrine (NE) acting via postsynaptic 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 Purkinje neurons in control rats. In contrast, DMI did not augment GABA responses in rats chronically treated with MA for 1 month, or in rats withdrawn from MA for 7-14 days after a 1-month MA treatment. To further examine if DMI-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 agonist, in Purkinje neurons. We found that GABA-induced inhibition is potentiated by local application of ISO in both control and chronic MA rats, suggesting that the reduction in DMI/GABA interactions is probably not mediated through post-synaptic noradrenergic mechanisms. Presynaptic NE clearance was further examined using in vivo chronoamperometric methods. Extracellular NE levels in the cerebellar cortex were measured using Nafion-coated carbon fiber sensors. We found that local application of DMI inhibited NE clearance in control rats, but not in chronic MA animals, suggesting that presynaptic NE clearance is reduced after chronic MA treatment. In addition, NE levels in cerebellar tissue were measured using HPLC-ECD. The NE concentration was significantly decreased in chronic MA rats. Taken together, our data suggest that regulation of uptake by DMI at central noradrenergic nerve terminals is abnormal after chronic MA exposure.
authors.affiliation: National Institute on Drug Abuse, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. ywang@intra.nida.nih.gov
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Chou
authors.forename: C H
authors.initials: CH
authors.lastname: Jeng
authors.forename: M
authors.initials: M
authors.lastname: Morales
authors.forename: J Y
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002525:Cerebellar Cortex / Q000187:drug effects / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D011689:Purkinje Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000187:drug effects* / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000318:Adrenergic beta-Agonists; D008694:Methamphetamine; D005680:gamma-Aminobutyric Acid; D007545:Isoproterenol; D003891:Desipramine; D009638:Norepinephrine