Drugs of abuse modulate dopaminergic neurotransmission : effects on exocytosis and neurotransmitter receptor function

Abstract

An extensive amount of literature is available on drugs of abuse. However, current knowledge on cellular and molecular mechanisms of actions is insufficient and hampers treatment of intoxicated patients. Drugs of abuse cause 100.000 hospital admissions yearly only in the US. Therefore, we investigated theeffects commonly used illicit drugs have on dopaminergic neurotransmission. Most tested drugs induced opposite effects, e.g., decreasing cholinergic input (possibly decreasing dopaminergic output) combined with decreasing GABA-ergic input (possibly increasing dopaminergic output). Predicting the ultimate effects in vivo is difficult and will depend on the investigated brain area, the drug concentration and other, not investigated, inputs on the dopaminergic system. In our studies, amphetamine did not induce changes in the basal intracellular calcium concentration ([Ca2+]i) or dopamine exocytosis. However, at a high amphetamine concentration, voltage-gated calcium channels (VGCCs) were inhibited, GABA-ergic input was increased and cholinergic input was decreased. All these mechanisms can contribute to reducing dopamine release following exposure to high concentrations of amphetamine. At a lower, recreational concentration, amphetamine increased cholinergic input, which could increase dopaminergic output. Methamphetamine inhibited VGCCs and cholinergic input at a high concentration, possibly reducing dopaminergic output. However, GABA-ergic input was either decreased or unaffected, which could respectively increase or not affect dopaminergic output. At a lower, recreational concentration, methamphetamine increased cholinergic input, possibly contributing to higher dopamine levels. We also observed 3,4-methylenedioxymethamphetamine (MDMA)- and 3,4-methylenedioxy-amphetamine (MDA)-induced inhibitions of VGCCs, depolarization-evoked dopamine release and cholinergic input at high concentrations. Metabolism could increase MDMAs neurotoxic effects since its metabolite MDA was more potent. Also, MDA potentiates GABA-ergic input (at high GABA receptor occupancy), further decreasing DA release. However, at low GABA receptor occupancy, both MDMA and MDA inhibit GABA-ergic input. This mechanism possibly contributes to drug-induced increases in extracellular dopamine levels. Meta-chlorophenylpiperazine (mCPP) has been suggested as a safe alternative to MDMA. However, of all tested drugs, mCPP induced the strongest effects on all endpoints measured in our studies. At a high concentration, mCPP almost completely inhibited depolarization-evoked and ACh-evoked increases in [Ca2+]i. Thus, mCPP inhibits VGCCs and cholinergic input. Furthermore, mCPP increased GABA-ergic input (at high receptor occupancy). All these mechanisms could contribute to a decrease in dopamine release. However, mCPP decreased GABA-ergic input at low receptor occupancy, which could enhance dopamine release. Overall, drugs of abuse can modulate the dopaminergic system. The degree of modulation depends on the type and concentration of the drug as well as on the concentration of the endogenous receptor ligands. Therefore, a spectrum of effects is expected, and reported, following in vivo exposure. Consequently, predicting the effects methamphetamine, amphetamine, MDMA, MDA and mCPP will induce in the in vivo situation is difficult. However, cholinergic and GABA-ergic receptors represent novel treatment targets as these systems provide a significant input on dopaminergic neurons and we have shown drug-induced effects on these inputs.