Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine

Abstract

1 Administration to rats of methamphetamine (15 mg kg-1, i.p.) every 2 h to a total of 4 doses resulted in a neurotoxic loss of striatal dopamine of 36% and of 5-hydroxytryptamine (5-HT) in the cortex (43%) and hippocampus (47%) 3 days later. 2 Administration of chlormethiazole (50mgkg-', i.p.) 15min before each dose of methamphetamine provided complete protection against the neurotoxic loss of monoamines while administration of dizocilpine (1 mg kg-', i.p.) using the same dose schedule provided substantial protection. 3 Measurement of dopamine release in the striatum by in vivo microdialysis revealed that methamphetamine produced an approximate 7000% increase in dopamine release after the first injection. The enhanced release response was somewhat diminished after the third injection but still around 4000% above baseline. Dizocilpine (1 mg kg-', i.p.) did not alter this response but chlormethiazole (50 mg kg-', i.p.) attenuated the methamphetamine-induced release by approximately 40%. 4 Dizocilpine pretreatment did not influence the decrease in the dialysate concentration of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) produced by administration of methamphetamine while chlormethiazole pretreatment decreased the dialysate concentration of these metabolites still further. 5 The concentration of dopamine in the dialysate during basal conditions increased modestly during the course of the experiment. This increase did not occur in chlormethiazole-treated rats. HVA concentrations were unaltered by chlormethiazole administration. 6 Chlormethiazole (100-1000IM) did not alter methamphetamine (100 tM) or K+ (35 mM)-evoked release of endogenous dopamine from striatal prisms in vitro. 7 Several NMDA antagonists prevent methamphetamine-induced neurotoxicity; however chlormethiazole is not an NMDA antagonist. Inhibition of striatal dopamine function prevents methamphetamine-induced toxicity of both dopamine and 5-HT pathways. Therefore the attenuation of the enhanced dopamine release which occurs in animals given chlormethiazole may be associated with the protective action of this drug against methamphetamine-induced neurotoxicity.

Mice with Decreased Cerebral Dopamine Function following a Neurotoxic Dose of MDMA (3,4-Methylenedioxymethamphetamine, “Ecstasy”) Exhibit Increased Ethanol Consumption and Preference

“…The MDMA-induced loss in the dopaminergic markers of mice presumably reflects a neurotoxic degeneration of dopamine nerve terminals similar to that seen following methamphetamine administration to both rats and mice (Baldwin et al, 1993). The current study extends these findings by showing that the reduction of striatal dopamine concentration and dopamine transporters induced by MDMA persists for at least 5 weeks after injection.…”

Studies on the role of dopamine in the degeneration of 5‐HT nerve endings in the brain of Dark Agouti rats following 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) administration

“…Interestingly the size of the increase in extracellular dopamine in the striatum following MDMA seen in vivo was similar in magnitude to that seen after a high dose of methamphetamine (Baldwin et al, 1993) which raises questions as to why the locomotor and behavioural activity seen after MDMA administration appears to be 5-HT rather than dopamine receptor mediated, having a di erent pro®le to that seen after amphetamine (Callaway et al, 1990;Callaway & Geyer, 1992). It could be that the serotonin-mediated behaviours predominate over any dopamine-mediated e ects.…”

“…Previously in an in vivo study we found that clomethiazole inhibited both the increase in dopamine and reduction in HVA and DOPAC which followed an injection of methamphetamine (Baldwin et al, 1993). In contrast, clomethiazole appeared to have no e ect on MDMA-induced changes in dopamine metabolism.…”

“…The question arises as to the mechanisms involved in this selectivity. It is noteworthy that methamphetamine which also increases extracellular 5-HT and dopamine (see for example Baldwin et al, 1993) and also increases free radical formation (Giovanni et al, 1995) produces neurotoxic degeneration of both 5-HT and dopamine neurones (Gibb et al, 1990;Green et al., 1992; Baldwin et al, 1993). If we are correct and the extracellular dopamine increase does not re¯ect carriermediated exchange then relatively little MDMA may be entering the dopamine nerve ending and being metabolised to the neurotoxic metabolites which are then auto-oxidised thereby producing free radicals (see Colado et al, 1997b).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…MK-801-induced behavioral sensitization was associated with changes in the kinetics of DA release characterized by a delayed (after 2 hour) release in the PFC . But MK-801 failed to alter the striatal DA release caused by METH (Baldwin et al, 1993), and a few other reports showed that MK-801 had a weak or no effect on 948 pallidal, accumbal, or prefrontal cortical DA release (Wedzony et al, 1993;Saulskaya and Marsden, 1995;Wheeler et al, 1995;Druhan et al, 1996;Takahashi et al, 1996;Anagnostakis et al, 1998;Callado et al, 2000). MK-801 treatment reversed the decrease in striatal DA, DOPAC (3,4-dihydroxyphenylacetic acid), and HVA (homovanillic acid) caused by METH (Boireau et al, 1995), and d-AMPH pretreatment prevented MK-801-induced striatal DA release (Nash and Yamamoto, 1993).…”