A single high dose of methamphetamine increases cocaine self-administration by depletion of striatal dopamine in rats

Abstract

Psychostimulant addicts often take high doses of drugs, and high doses of psychostimulants such as methamphetamine (METH) are neurotoxic to striatal dopamine (DA) terminals. Yet, the effects of high doses of METH on drug-seeking and drug-taking behavior have not been examined. In the present study, we found that single high doses of METH in rats (10–20 mg/kg) dose-dependently increased cocaine self-administration under fixed-ratio 2 (FR2) reinforcement conditions, while higher doses (40 mg/kg×1 or 10 mg/kg/2 h×4) caused high mortality among rats maintained on daily cocaine self-administration. The increased cocaine self-administration appeared to be a compensatory response to reduced cocaine reward after METH, because the same doses of METH caused a dose-dependent reduction both in “breakpoint” levels for cocaine self-administration under progressive-ratio reinforcement and in nucleus accumbens DA response to acute cocaine. Further, METH (10–20 mg/kg) produced large DA release (4000%–6000% over baseline), followed by a significant reduction in striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) contents, but without significant changes in striatal DA transporter levels. These findings suggest that the present high doses of METH caused striatal DA depletion or hypofunction without severe damage in DA terminals, which may contribute to the increased cocaine-taking behavior observed in the present study. Provided that the present doses of METH may mimic METH overdose incidents in humans, the present findings suggest that METH-induced DA depletion or neurotoxicity may lead to an increase in subsequent drug-taking and drug-seeking behavior.

Environmental enrichment reduces methamphetamine cue-induced reinstatement but does not alter methamphetamine reward or VMAT2 function

“…However, EC rats pretreated with high doses of METH showed enhanced CPP compared to IC rats when conditioned with METH (0.3 mg/kg). The discrepancy between the previous study and the current study is likely attributed to pretreatment with repeated high doses of METH, as high dose METH pretreatment causes dopamine depletion [11, 23, 28, 29]. Although EC and IC rats showed a similar dopamine depletion with high dose METH pretreatment, metabolite levels were higher in EC rats [10], suggesting a differential effect on presynaptic dopamine function which may be related to the environment-induced alteration in METH CPP.…”

Dopamine D1 Receptors, Regulation of Gene Expression in the Brain, and Neurodegeneration

“…Moreover, blockade of intracellular calcium oscillation by IP 3 inhibitors inhibited SKF83959-induced increases in FGF-2 expression [136]. When taken together with previous observations, these data indicate a potentially significant role of D1-induced PI turnover in the regulation of gene expression and synaptic plasticity induced by drugs, such as the psychostimulants, that cause marked increases in DA levels in various brain regions [83,137,138]. These ideas remain to be investigated fully.…”

Genome-wide profiling identifies a subset of methamphetamine (METH)-induced genes associated with METH-induced increased H4K5Ac binding in the rat striatum

“…In animals, METH causes behavioral sensitization, is self-administered, and causes structural plasticity in the brain [3-6]. The acute behavioral effects of the drug are mediated by METH-induced increases in the amount of dopamine (DA) release in brain synapses [7,8] and by subsequent stimulation of DA receptors in various brain regions [9]. Activation of these receptors by direct or indirect agonists such as cocaine and amphetamine induces acute changes in the expression of several immediate early genes (IEGs) in the striatum [10,11].…”