Beyond drug-induced alteration of glutamate homeostasis, astrocytes may contribute to dopamine-dependent intrastriatal functional shifts that underlie the development of drug addiction: A working hypothesis.

The transition from recreational drug use to compulsive drug-seeking habits, the hallmark of addiction, has been shown to depend on a shift in the locus of control over behaviour from the ventral to the dorsolateral striatum. This process has hitherto been considered to depend on the aberrant engagement of dopamine-dependent plasticity processes within neuronal networks. However, exposure to drugs of abuse also triggers cellular and molecular adaptations in astrocytes within the striatum which could potentially contribute to the intrastriatal transitions observed during the development of drug addiction. Pharmacological interventions aiming to restore the astrocytic mechanisms responsible for maintaining homeostatic glutamate concentrations in the nucleus accumbens, that are altered by chronic exposure to addictive drugs, abolish the propensity to relapse in both preclinical and, to a lesser extent, clinical studies. Exposure to drugs of abuse also alters the function of astrocytes in the dorsolateral striatum, wherein dopaminergic mechanisms control drug-seeking habits, associated compulsivity and relapse. This suggests that drug-induced alterations in the glutamatergic homeostasis maintained by astrocytes throughout the entire striatum may interact with dopaminergic mechanisms to promote aberrant plasticity processes that contribute to the maintenance of maladaptive drug-seeking habits. Capitalising on growing evidence that astrocytes play a fundamental regulatory role in glutamate and dopamine transmission in the striatum, we present an innovative model of a quadripartite synaptic microenvironment within which astrocytes channel functional interactions between the dopaminergic and glutamatergic systems that may represent the primary striatal functional unit that undergoes drug-induced adaptations eventually leading to addiction.