Deep brain stimulation of the nucleus accumbens shell attenuates cocaine reinstatement through local and antidromic activation

Abstract

Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. Here, we demonstrate that DBS in the nucleus accumbens shell, but not the core, attenuates cocaine priming-induced reinstatement of drug seeking, an animal model of relapse, in male Sprague Dawley rats. Next, we compared DBS of the shell with pharmacological inactivation. Results indicated that inactivation using reagents that influenced (lidocaine) or spared (GABA receptor agonists) fibers of passage blocked cocaine reinstatement when administered into the core but not the shell. It seems unlikely, therefore, that intrashell DBS influences cocaine reinstatement by inactivating this nucleus or the fibers coursing through it. To examine potential circuit-wide changes, c-Fos immunohistochemistry was used to examine neuronal activation following DBS of the nucleus accumbens shell. Intrashell DBS increased c-Fos induction at the site of stimulation as well as in the infralimbic cortex, but had no effect on the dorsal striatum, prelimbic cortex, or ventral pallidum. Recent evidence indicates that accumbens DBS antidromically stimulates axon terminals, which ultimately activates GABAergic interneurons in cortical areas that send afferents to the shell. To test this hypothesis, GABA receptor agonists (baclofen/muscimol) were microinjected into the anterior cingulate, and prelimbic or infralimbic cortices before cocaine reinstatement. Pharmacological inactivation of all three medial prefrontal cortical subregions attenuated the reinstatement of cocaine seeking. These results are consistent with DBS of the accumbens shell attenuating cocaine reinstatement via local activation and/or activation of GABAergic interneurons in the medial prefrontal cortex via antidromic stimulation of cortico-accumbal afferents.

Figure 1.

Deep brain stimulation of the nucleus accumbens shell, but not core, attenuates cocaine priming-induced reinstatement. A, C, Mean (±SEM) active and inactive lever responses from reinstatement sessions with 0 or 150 μA of stimulation aimed at the shell (A) or core (C). DBS began immediately following administration of 10 mg/kg (i.p.) cocaine and continued throughout the 2 h reinstatement session. B, Time course of active lever responding from 0 or 150 μA stimulation of the accumbens shell. D, Electrode placements from both the shell (closed circles) and core (open circles). The values are in millimeters, relative to bregma. *p < 0.05 0 μamps compared with 150 μamps. There were five to eight animals per group.

Figure 2.

Baclofen-muscimol or lidocaine microinjected into the core but not the shell of the nucleus accumbens attenuated cocaine priming-induced reinstatement. A–D, Mean (±SEM) active and inactive lever responses from reinstatement sessions with saline or baclofen and muscimol microinjected into the nucleus accumbens shell (A) or core (B) and lidocaine microinjected into the shell (C) or core (D). Cocaine (10 mg/kg, i.p.) was administered 10 min following the baclofen and muscimol microinjection or immediately following the lidocaine injection. *p < 0.05 compared to saline microinjections. There were 7–12 animals per group.

Figure 3.

DBS of the nucleus accumbens shell induces c-Fos expression in the nucleus accumbens shell and the infralimbic prefrontal cortex. All animals received bilateral nucleus accumbens shell DBS (0 or 150 μA) for 30 min. Animals were perfused 70 min from the start of stimulation, and c-Fos immunoreactivity was measured to assess neuronal activation following accumbens DBS. Figure 3 shows a representative cartoon depicting the area of c-Fos staining quantification from the five brain regions where c-Fos was counted (nucleus accumbens shell, dorsal striatum, prelimbic cortex, infralimbic cortex, and ventral pallidum), a representative image from both the 0 and 150 μA condition, and the quantification (mean ± SEM c-Fos-positive cells per square millimeter). *p < 0.05 0 μamps compared with 150 μamps. There were five animals per group.

Figure 4.

Baclofen and muscimol microinjected into the infralimbic, prelimbic, and cingulate cortex attenuates cocaine priming-induced reinstatement. A–C, Mean (±SEM) active and inactive lever responding from a reinstatement session in which baclofen and muscimol or saline was microinjected 10 min before a 10 mg/kg cocaine priming injection into the cingulate cortex (A), the prelimbic cortex (B), or the infralimbic cortex (C). D, Cannulae placements from infrlimbic (open circles), prelimbic (gray circles), and cingulate (black circles). The values are in mm relative to bregma. *p < 0.05 Baclofen and muscimol compared to saline microinjections. There were 9–11 animals per group.