Methampetamine (MA), a potent analog of amphetamine, has been found to induce release and inhibit metabolism of catecholamines in the central nervous system. Acute methamphetamine intoxication can produce neuronal excitation and thought disorders resembling schizophrenia, which have been attributed to an acute increase of catecholamines in the synape. On the other hand, chronic MA users often develop symptoms, such as depression, opposite to those caused by acute MA. It is thus possible that acute and chronic MA uses may alter release and clearance of catecholamines differentially. Previous studies have indicated that chronic MA diminishes DA content, TH immunoreactivity, and DA transporter function. Similarly, serotonergic functions, such as 5HT concentration, 5HT transport, and tryptophan hydroxyalse are reduced in chronic MA -treated animals. Although noradrenergic (NE) systems have also been implicated in psychiatric disorders, it is not clear if NE neurons are affected after chronic use of MA. In our study, we found that adult Sprague-Dawley rats, fed MA for one month at the dose of 3 mg/kg/day, showed a deficiency of norepinphrine clearance in the cerebellum. We found that the clearance of NE, as measured by in vivo voltammetry, can no longer be attenuated by locally applied desipramine, an NE uptake 1 inhibitor. Previous studies have indicated that gamma-aminobutyric acid (GABA) -induced electrophysiological responses are enhanced by NE acting via beta-adrenergic receptors. We found that local application of the NE uptake-1 blocker despiramine (DMI) significantly potentiated GABA -induced electrophysiological depressions in cerebellar Purkinje neurons in control rats. In contrast, DMI did not facilitate GABA responses in chronic MA -treated rats. To further determine if these electrophysiological responses are reversible, animals were withdrawn for 5-7 days after chronic MA treatment for one month. We found that DMI did not enhance GABA-induced depressions in these animals. These data suggest that chronic MA intake irreversibly damages NE clearance function at central noradrenergic nerve terminals. This work was presented in the CPPD meeting in Arizona, 1998. In addition, our institute and others recently reported that acute administration of MA induces free radical formation and upregulates p53 mRNA expression. Since various neuronal insults, such as brain ischemia, involve free radicles and p53, it is possible that MA may have an effect on stroke-induced brain damages. In our study, we found that MA (i.p. 10 mg/mg four times, two hrs apart) potentiates ischemic insults in mice. Animals pre-treated with MA showed greater motor difficiencies and cortical infarction after middle cerebral artery (MCA)ligation. The increase in infarction paralles the upregulation of p53 mRNA in the cortex.
