Novel Targets for Medication Development

Glutamate Modulators

Glutamate plays multiple roles in the neurobiology of addiction, many of which provide potential targets for medications development. Glutamate is associated with the neuroplasticity that is important for the incentive salience of cues paired with repeated drug administration, particularly psychostimulants. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors move to the post-synaptic membrane with repeated cocaine administration and play a key role in facilitating drug seeking, particularly after long periods of abstinence. Another prominent hypothesis is that repeated self-administration of psychostimulants decreases the release of glutamate in key brain circuits associated with the preoccupation/anticipation stage of the addiction cycle. Strong evidence suggests that repeated psychostimulant administration in animals decreases the extracellular nonsynaptic glutamate pool in the NAc, removing glutamate tone that normally functions to limit glutamate release. As a result of this decrease in glutamate tone, a challenge injection of a psychostimulant is able to increase nucleus accumbens glutamate levels back to the levels observed in controls. Such an exaggerated response of glutamate to activity in these circuits could convey sensitivity to relapse. For example, the drug-induced reinstatement of drug seeking appears to be mediated by a prefrontal cortex glutamatergic projection to the nucleus accumbens. Cue-induced reinstatement involves glutamatergic projections to the nucleus accumbens from the frontal cortex, basolateral amygdala, and ventral subiculum. Pharmacological agents that modulate glutamate function may play a role in glutamate hypo- or hyperexcitability during protracted abstinence, depending on the drug, and may decrease drug- and cue-induced reinstatement. Various glutamatergic modulators, all of which decrease glutamatergic neurotransmission, including AMPA receptor antagonists, NMDA receptor antagonists, metabotropic glutamate-2/3 receptor agonists, and metabotropic glutamate-5 receptor antagonists, have been shown to block cue-induced reinstatement (for further reading, see Wolf, 2010).

Additional evidence for a potential AMPA/kainate glutamate target in addiction comes from studies of topiramate, an anticonvulsant that blocks AMPA/kainate receptors and allosterically modulates ion channel conductance. Controlled clinical trials have reported decreases in drinking behavior in alcohol dependence and improvements in quality of life, but with significant adverse effects on memory and concentration. Given the side effects associated with direct glutamate receptor antagonists, drugs that indirectly modulate the system may be more logical candidates for medications development.

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