The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior

Abstract

The role of limbic-striato-pallidal circuitry in cocaine-induced reinstatement was evaluated. The transient inhibition of brain nuclei associated with motor systems [including the ventral tegmental area (VTA), dorsal prefrontal cortex (dPFC), core of the nucleus accumbens (NAcore), and ventral pallidum (VP)] prevented cocaine-induced reinstatement. However, only the VP proved to be necessary for food reinstatement, suggesting that the identified circuit is specific to drug-related reinstatement. Supporting the possibility that the VTA-dPFC-NAcore-VP is a series circuit mediating reinstatement, simultaneous unilateral microinjection of GABA agonists into the dPFC in one hemisphere and into the VP in the contralateral hemisphere abolished cocaine reinstatement. Although dopamine projections from the VTA innervate all three forebrain nuclei, the blockade of dopamine receptors only in the dPFC antagonized cocaine-induced reinstatement. Furthermore, DA administration into the dPFC was sufficient to elicit a reinstatement in drug-related responding. These data demonstrate that dopamine release in the dPFC initiates a dPFC-NAcore-VP series circuit that mediates cocaine-induced drug-seeking behavior.

Figures

Fig. 1.

GABA receptor activation prevented cocaine-induced reinstatement. Pretreatment with combinations of the GABAB and GABAA receptor agonists bac–mus into the dPFC (A), ) NAcore (B), VTA (C), and VP (D) blocked the reinstatement elicited by cocaine administration (n = 6–8 for each dose in each nucleus). Subjects pretreated with a screening dose (0.3 and 0.03 nmol/side, respectively) into any of these areas showed no change in active lever presses compared with extinction (EXT) responding, suggesting that neural activation of these areas is critical for the ability of cocaine to elicit reinstatement. Note that, when pretreated with saline vehicle (SAL), all subjects exhibited a robust return to drug seeking. Data depicted as mean + SEM active lever presses. Dose combinations of baclofen and muscimol were 0.3 and 0.03, 0.1 and 0.01, 0.03 and 0.003, and 0.01 and 0.001 nmol/side, respectively. x-Axis labels are designated using the baclofen dose. *p < 0.001, increase in active lever presses compared with EXT. #p< 0.05, responding that was greater than EXT and less than SAL.

Fig. 2.

Inactivation of some brain regions tested was ineffective in altering cocaine-induced reinstatement. Subjects pretreated with a high screening dose of bac–mus (0.3 and 0.03 nmol/side, respectively) into the vPFC, NAshell, SN, CN, BLA, or MD (n = 6–8) displayed robust lever-press responding on reinstatement testing equivalent to that seen after saline (SAL) pretreatment. *p < 0.05, comparing cocaine-induced active lever pressing with extinction (EXT) responding.

Fig. 3.

Reinstatement of food-seeking behavior is blocked by inhibition of the VP but not the dPFC or NAcore. Pretreatment with the screening dose of bac–mus (0.3 and 0.03 nmol/side, respectively) into the VP inhibited lever-press responding elicited by noncontingent food presentation, whereas infusion of bac–mus into the NAcore or PFC (0.3 and 0.03 nmol/side, respectively) resulted in response rates indistinguishable from saline (SAL) pretreatment (i.e., a robust reinstatement). *p < 0.001, comparing food reinstatement responding with extinction (EXT) responding.

Fig. 4.

A series, rather than parallel, circuit is involved in cocaine-primed reinstatement. A, Circuits can be organized in either parallel or series. Parallel circuits would suggest that information could flow simultaneously along multiple pathways, whereas a series circuit would suggest that information flows sequentially from one nucleus to the next. B, Subjects receiving bac–mus (0.3 and 0.03 nmol/side, respectively) infusion into the dPFC and VP on the same side (ipsilateral;n = 5) of the brain displayed vigorous active lever-press responding after cocaine challenge. However, when subjects received bac–mus treatment into one dPFC and the contralateral VP (contralateral; n = 6), responding on the active lever did not differ from extinction (EXT) responding, suggesting these brain regions are in series circuit essential for the ability of cocaine to elicit a reinstatement of drug-seeking behavior. *p < 0.001, comparing ipsilateral with extinction (EXT) responding.

Fig. 5.

Role of dopamine in the dPFC in cocaine reinstatement. A, Fluphenazine (FLU) infusion into the dPFC, but not the NAcore or VP (n = 6 in each condition), before reinstatement testing abolished the increase in active lever pressing observed after pretreatment with saline vehicle (SAL).B, After bac–mus (0.3 and 0.03 nmol/side, respectively) activation of the VTA, subjects received either saline (0 nmol;n = 5) or dopamine (30 nmol/side;n = 7) infusions into the dPFC before a cocaine (COC) reinstatement challenge. When no dopamine was infused into the dPFC, subjects exhibited the expected blockade of cocaine-induced reinstatement, similar to that seen after inactivation of the VTA in Figure 1. However, dopamine replacement into the dPFC resulted in a highly significant reinstatement of self-administration behavior. Similarly, dopamine alone into the dPFC was sufficient to induce robust responding. *p < 0.001, comparing extinction (EXT) responding with other treatments.

Fig. 6.

Locomotor activity. Mean ± SEM photocell counts are shown for the 2 hr test sessions for both spontaneous and cocaine-induced motor activity studies. A, Subjects received two treatments before each test: an intracranial infusion of saline (sal) or bac–mus followed by an intraperitoneal injection of either saline (sal) or cocaine (coc) (10 mg/kg; n = 8 in each condition). bac–mus pretreatment did not block either spontaneous or cocaine-induced locomotor activity when infused into the dPFC, NAcore, VTA, or VP. B, Fluphenazine (flu), when infused into the VP or NAcore but not the dPFC, produced a significant reduction in cocaine-induced locomotor activity. *p < 0.01, comparing bac–mus or fluphenazine with saline.

Fig. 7.

Location of microinjection cannula tips. This figure depicts the location of the microinjection cannula tips in coronal section based on the atlas of Paxinos and Watson (1998).A, Dorsal (●) and ventral (▪) PFC; B, NAcore (●) and NAshell (▪); C, ventral pallidum (●); D, basolateral amygdala (▴), central nucleus of the amygdala (✚), and mediodorsal nucleus of the thalamus (▪);E, VTA (●) and substantia nigra (▪). Note that the ● was used in brain regions critical for the normal production of cocaine-induced reinstatement in the inactivation studies. Numbers indicate the distance from bregma in the anteroposterior plane.

Fig. 8.

Circuit containing the nuclei injected with GABA agonists. The circuit illustrates the connectivity of the limbic and motor regions that have been implicated in the production of goal-directed behavior. The limbic subcircuit is more closely associated with limbic structures, and the motor subcircuit is more intimately connected with motor structures (Heimer et al., 1991; Zahm and Brog, 1992). Arrowheads indicate the direction of the projection, and bidirectional arrowsindicate reciprocal connections. Larger circles andarrows indicate nuclei identified as critical for drug-seeking behavior.