Molecular targets for the treatment of alcohol and drug dependence.

Drugs of abuse alter brain function through interactions with multiple neurotransmitter and neuromodulator systems. These interactions mediate the reinforcing effects of drugs of abuse, including alcohol, cocaine, methamphetamine, nicotine and opiates. The present Research Topic provides a primer on the neurobiology of these addictions and novel molecular targets for the treatment of these addictions. Neural adaptations of the glutamatergic system play a key role in drug abuse associated with tolerance, dependence and withdrawal. Activation of glutamate transporter 1 (GLT1), its human homolog is excitatory amino acid transporter 2 (EAAT2), attenuates a conditioned place preference induced by morphine, methamphetamine and cocaine. It has also been shown that up-regulation of GLT1 levels within the mesocorticolimbic system is inversely associated with alcohol consumption and relapse-like behavior. Polyamine modulation of NMDA receptor activity not only reduces alcohol intake but also ameliorates the alcohol-withdrawal syndrome. In addition, adenosine A2A receptor modulation of alcohol intake is mediated in part through NMDA receptor activity. Moreover, adenosine activity, through several adenosine receptors, regulates glutamate levels in the brain. Allosteric modulators of the purinergic P2X4 receptor reduce alcohol consumption, and this effect may be mediated, in part, by modulation of GABA, glutamate and glycine in the ventral tegmental area. Multiple muscarinic receptor subtypes, and pathways from the pedunculopontine and laterodorsal tegmental nuclei, play key roles in integrating cholinergic, dopaminergic and opioid signaling in the midbrain. Thus, these receptors are important putative targets for treating opiate and cocaine abuse. Multiple peptidergic systems regulate alcohol and drug abuse as well as the development of dependence. Enkephalinergic, ghrelinergic, neurotensin and neuropeptide Y modulate cholinergic, dopaminergic, GABAergic, glutamatergic and serotonergic systems within the mesocorticolimbic neurocircuit. This neurocircuit, along with the extended amygdala mediates both the positive and negative reinforcing aspects of alcohol and drugs of abuse. Neuropeptide Y and corticotrophin releasing factor are key neuromodulators of activity in the amygdala and its subsequent projections to the mesocorticolimbic neurocircuitry. As pharmacological agents continue to be tested for treating alcohol as well as drug abuse and dependence, it is becoming clear that not all treatments are effective in all subjects implicating the important role of genetics. Thus, pharmacogenetics a burgeoning field of study that matches an individual’s genetic make-up with possible pharmacotherapies will be discussed as well. In this Research Topic, we will review the literature and findings of the existing target systems for the treatment of alcohol and drug dependence.