Novel Targets for Medication Development

GABA Modulators

GABA is an inhibitory amino acid neurotransmitter that acts by binding one of two broad classes of receptors, GABAA and GABAB. GABAA receptor antagonists and inverse agonists (drugs that bind to a receptor and produce effects opposite to those of an agonist; in the case of a GABA-gated ion channel, an inverse agonist would cause maximal closing of the ion channel; decrease alcohol self-administration. However, their therapeutic actions are limited by severe side effects that involve significant hyperexcitability of the central nervous system. In contrast, GABA agonists/modulators may block drug-seeking behavior by acting on reward, dependence, or both. GABA modulators that increase GABAergic activity directly or indirectly decrease cocaine, heroin, nicotine, and alcohol self-administration in non-dependent and dependent rats. GABA receptor agonists also block alcohol withdrawal in animals and humans and decrease drinking and certain components of craving in human individuals with alcoholism.

Another therapeutic approach is to explore GABA modulators that can indirectly facilitate GABA release. Gabapentin, an amino acid designed as a structural analog of GABA, is an anticonvulsant drug that came into clinical use as an adjunctive therapy in the treatment of human seizures and in the treatment of neuropathic pain disorders. Gabapentin selectively inhibits Ca2+ influx through voltage-operated Ca2+ channels. Gabapentin also increases GABA release. In animal models of alcohol dependence, gabapentin has strikingly different cellular and pharmacological effects in nondependent and alcohol-dependent rats. In nondependent rats, gabapentin facilitates GABAergic transmission in the central nucleus of the amygdala but does not affect alcohol intake. In dependent rats, in contrast, gabapentin decreases GABAergic transmission in the central nucleus of the amygdala and reduces excessive alcohol intake. Gabapentin also suppresses the anxiogenic-like effects of withdrawal from an acute alcohol injection. One hypothesis to explain these results is that during the development of alcohol dependence, neuroadaptive changes occur in the GABAergic system. Gabapentin has been shown to be effective in decreasing craving in human laboratory studies, reversing the physiological measures of protracted abstinence and reversing sleep deficits in protracted abstinence. It has also shown efficacy in human double-blind placebo-controlled trials, suggesting a key translation from animals to humans (for further reading, see Mason et al., 2012, 2014).

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