New medications for drug addiction hiding in glutamatergic neuroplasticity

Abstract

The repeated use of drugs that directly or indirectly stimulate dopamine transmission carry addiction liability and produce enduring pathological changes in the brain circuitry that normally regulates adaptive behavioral responding to a changing environment. This circuitry is rich in glutamatergic projections, and addiction-related behaviors in animal models have been linked to impairments in excitatory synaptic plasticity. Among the best-characterized glutamatergic projection in this circuit is the prefrontal efferent to the nucleus accumbens. A variety of molecular adaptations have been identified in the prefrontal glutamate synapses in the accumbens, many of which are induced by different classes of addictive drugs. Based largely on work with cocaine, we hypothesize that the drug-induced adaptations impair synaptic plasticity in the cortico-accumbens projection, and thereby dysregulate the ability of addicts to control their drug-taking habits. Accordingly, we go on to describe the literature implicating the drug-induced changes in protein content or function that impinge upon synaptic plasticity and have been targeted in preclinical models of relapse and, in some cases, in pilot clinical trials. Based upon modeling drug-induced impairments in neuroplasticity in the cortico-accumbens pathway, we argue for a concerted effort to clinically evaluate the hypothesis that targeting glial and neuronal proteins regulating excitatory synaptic plasticity may prove beneficial in treating addiction.

Figure 1

Model of the circuitry contributing to relapse in animal models and altered in neuroimaging studies in addicts, with emphasis on the key position of the cortico-accumbens glutamatergic projection, and the interconnected glutamatergic projections between allocortical and prefrontal cortical regions. This review focuses on drug-induced pathologies in the glutamatergic projections from prefrontal and allocortex into the nucleus accumbens. Glutamatergic pathologies are relatively less known for the cortico-cortical projections, but any glutamatergic-based pharmacological therapy will likely affect these projections in a manner either synergistic or countermanding the therapeutic effects on the cortico-accumbens pathologies. Arrows indicate direction of the projection and are color coded as follows: blue, dopamine; blue/red, dopamine/glutamate co-released; green, GABA/peptides co-released; red, glutamate. Abbreviations: BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; core- nucleus accumbens core; dorsal ACC, dorsal anterior cingulate cortex; Hipp, hippocampus; OFC, orbital frontal cortex; PPN, pedunculopontine nucleus; shell, nucleus accumbens shell; subgen ACC, subgenual anterior cingulate cortex; VTA, ventral tegmental area.

Figure 2

Canonical glutamatergic and dopaminergic synapse on a dendritic spine of a medium spiny cell illustrating proteins important for regulating excitatory synaptic plasticity and that can be readily targeted for treating addiction. The accompanying legend for specific proteins also indicates the category of drug that is hypothesized to be therapeutically useful based upon the type of glutamatergic neuropathologies produced in prefrontal-accumbens synapses that are described in the text. Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; Cys/Glu exchange, cystine/glutamate exchange; mGluR, metabotropic glutamate receptor; MSN, medium spiny neuron; NAM, negative allosteric modulator; NMDA, N-methyl d-aspartate; NR2B, N-methyl d-aspartate receptor subtype 2B; VTA, ventral tegmental area.