Drug addiction is a significant societal issue, with more than 20 million individuals being diagnosed with a substance use disorder (SUD) in the past year. While current treatments show some success, more than 50% of patients treated for SUD relapse within one year. Corticostriatal circuitry and plastic changes therein are involved in the transition from drug abuse to addiction. In particular, the dorsal lateral striatum (DLS) has emerged as a key brain region regulating habitual control over behavior, including that underlying addiction to stimulants. Astrocytes play fundamental roles in brain neuroplasticity through several mechanisms, including regulation of extracellular glutamate levels. Presently, nothing is known about functional changes in astrocytic networks in DLS of animals exhibiting habitual vs. goal-directed control over drug-seeking behavior.! The proposed experiments will therefore directly determine the function of astrocytes in DLS of rats exhibiting habitual vs. goal-directed control over cocaine seeking, and relative to yoked-saline controls.
In Aim 1 we will test the hypothesis that transition to habitual control over cocaine-seeking behavior is concomitant with a decrease in astrocytic glutamate transport via decreased GLT-1 expression and function in DLS. Recent data provide the first indication that expression of GLT1, the primary glutamate transporter in astrocytes, is significantly decreased in dorsal striatum following extended cocaine self-administration in rats. However, whether the function of glutamate transporters in astrocytes of the dorsal striatum changes in concert with the development of habitual control over cocaine seeking is completely unknown. Therefore, we will use patch clamp electrophysiology to record slow transporter currents in astrocytes (Aim 1a) and AAV-mediated expression of the iGluSnFR protein and 2-photon microscopy to measure the levels and dwell time of glutamate in the extrasynaptic space (Aim 1b) in DLS in brain slices prepared from rats trained to self- administer cocaine and exhibiting habitual vs. goal-directed control over cocaine seeking, as well as from yoked-saline controls.
In Aim 2, we will test the hypothesis that these changes in glutamate transport result in significantly altered extrasynaptic and synaptic NMDA receptor-mediated transmission in spiny efferent neurons in DLS. We will use whole-cell patch clamp to assess changes in extrasynaptic NMDA receptor-mediated currents by examining the amplitude of tonic NMDA receptor-mediated currents, as well as the amplitudes and decay kinetics of evoked NMDA receptor-mediated EPSCs in striatal efferent neurons in DLS. AMPA/NMDA ratios will also be determined. Completion of these aims will provide the first insights into whether the transition to habitual control over cocaine-seeking behavior occurs concomitant with changes in astrocyte function and structural connectivity in DLS and the effects of cocaine self-administration history on astrocyte modulation of excitatory afferents to striatal efferent neurons. Such insights will allow for targeting of approaches to diminish relapse in stimulant-addicted individuals.
Relapse to drug seeking is a significant health care issue, with more than 50% of patients treated for substance use disorder relapsing within one year. The dorsolateral striatum has emerged as a key brain region underlying stimulant-seeking behavior. While astrocytes play fundamental roles in brain neuroplasticity, nothing is presently known about functional changes in astrocytes in the dorsolateral striatum of animals exhibiting habitual control over drug-seeking behavior.! The proposed experiments will therefore directly determine the function of astrocytes in the dorsolateral striatum of rats exhibiting habitual vs. goal-directed control over cocaine seeking and the impact of such changes on the excitability of striatal efferent neurons. Completion of these studies will provide the first insights into changes in astrocyte function in the dorsolateral striatum of rats in which cocaine-seeking has become habitual. Such insights will allow for targeting of approaches to diminish relapse in stimulant-addicted individuals.
