The current results indicate that i) DBS of the nucleus accumbens shell attenuated the reinstatement of cocaine seeking; ii) DBS of the dorsal striatum had no influence on cocaine reinstatement; iii) DBS of the nucleus accumbens shell did not affect the reinstatement of food seeking; and iv) DBS of the accumbens shell in the absence of a cocaine priming injection did not promote the reinstatement of cocaine seeking. Collectively, these results demonstrate that DBS of the nucleus accumbens shell attenuates the reinstatement of cocaine seeking in an anatomically and reinforcer-specific manner.
In studies of parkinsonism, depression and anxiety disorders, clinical measurements are made during DBS and compared to measurements when the stimulation is off. The stimulation is constant and the effects are completely reversed when the stimulation is turned off. For example, the anti-depressant effect of continuous DBS was immediate, bi-directional and reversible (Schlaepfer et al., 2007
). That is, when the stimulator was turned on depression ratings immediately improved and when it was turned off depression ratings worsened (Schlaepfer et al., 2007
). Similar to clinical studies, DBS was administered continuously during the reinstatement session in the current experiments.
The clinical effect of DBS at high frequencies is due at least in part to the suppression of neuronal activity via the activation of inhibitory interneurons and/or depolarization inactivation (Benabid et al., 1991
; Blond et al., 1992
). Consistent with the view that DBS produces its effects by reversible neuronal inactivation, intra-accumbal administration of an AMPA receptor antagonist, which blocks excitatory neurotransmission, attenuates cocaine priming-induced reinstatement of cocaine seeking (Cornish et al., 1999
; Cornish and Kalivas, 2000
; Park et al., 2002
). In contrast, activation of the nucleus accumbens with an AMPA microinjection promotes the reinstatement of cocaine seeking (Cornish et al., 1999
; Cornish and Kalivas, 2000
). However, there also is evidence that DBS inactivates cell bodies but activates axons in the stimulated area (Vitek, 2002
; McIntyre et al., 2004
). Consonant with this notion, DBS of the nucleus accumbens core suppressed neuronal activity in the orbitofrontal cortex apparently via antidromic stimulation of cortico-accumbal afferents and the subsequent activation of inhibitory cortical interneurons (McCracken and Grace, 2007
). Potential DBS-induced inactivation of accumbal afferents is particularly significant given mounting evidence that activation of excitatory medial prefrontal cortical and orbitofrontal cortical afferents to the nucleus accumbens promotes the reinstatement of cocaine seeking (Park et al., 2002
; McFarland et al., 2003
; Fuchs et al., 2004
). Taken together, these results suggest that DBS of the nucleus accumbens shell attenuates cocaine seeking by inhibiting neuronal activity in accumbal output neurons and/or inactivation of accumbal afferents.
It is well known that animals will self-stimulate various brain areas, including the nucleus accumbens (Mogenson et al., 1979
; West and Wise, 1988
). The electrical impulses that rats learn to self stimulate are brief (usually lasting less than one second) and stimulate neuronal activity (Wise et al., 1992
). Previous evidence indicates that only the initial onset of brain stimulation is reinforcing (Pollock and Kornetsky, 1990
). In contrast, in the present experiments high frequency DBS was administered continuously throughout the reinstatement session in order to suppress neuronal activity. It has been shown that non-contingent stimulation can be aversive, even when the stimulation is identical to the self-administered pattern (Steiner et al., 1969
). Importantly, clinical studies report that prolonged and continuous DBS of the nucleus accumbens is neither reinforcing nor aversive (Sturm et al., 2003
; Kuhn et al., 2007a
; Okun et al., 2007
; Schlaepfer et al., 2007
). The present results support this clinical observation. DBS of the nucleus accumbens shell in the absence of a cocaine priming injection failed to promote drug seeking, which suggests that DBS is unlikely to promote drug craving. It is also notable that DBS of the nucleus accumbens shell did not attenuate food-seeking behavior in rats, which indicates that DBS does not produce a generalized disruption of normal behavior. Although it is unclear exactly why DBS of the nucleus accumbens shell produced reinforcer specific effects in the current study, it is likely because the neuronal circuits subserving cocaine and food seeking behaviors are at least partially segregated (Carelli et al., 2000
; Horvath and Diano, 2004
In conclusion, the present results indicated that DBS of the nucleus accumbens shell blunts the reinstatement of drug seeking produced by re-exposure to cocaine. This effect was anatomically specific in that DBS of the dorsal striatum did not influence cocaine reinstatement. In addition, DBS of the accumbens shell failed to influence the reinstatement of food seeking, which indicates that the DBS effect was selective to cocaine and not due to a generalized disruption in motivated behavior. Taken together, these results indicate that DBS of the nucleus accumbens shell may represent a novel therapeutic modality for the treatment of severe cocaine addiction.