Inactivation of the central nucleus of the amygdala reduces the effect of punishment on cocaine self‐administration in rats

Abstract

Continued cocaine use despite the negative consequences is a hallmark of cocaine addiction. One such consequence is punishment that is often used by society to curb cocaine use. Unfortunately, we know little about the mechanism involved in regulation by punishment of cocaine use. The fact that cocaine addicts continue cocaine use despite potential severe punishment suggests that the mechanism may be impaired. Such impairment is expected to critically contribute to compulsive cocaine use. This study aimed to test the hypothesis that the central nucleus of amygdala (CeN) plays a critical role in such regulation. To this end, rats were trained to press a lever to self-administer cocaine under a chained schedule: a response on one lever (cocaine-seeking lever) led to access to the other lever (cocaine-taking lever) on which a response was reinforced by cocaine and cues. Thereafter, responses on the seeking lever were punished by footshock with a probability of 0.5. Cocaine self-administration (SA) was significantly suppressed by punishment in an intensity-dependent manner. Interestingly, rats trained with daily 6-h (extended access) but not 2-h (limited access) sessions showed resistance to the lower intensity of punishment. Inactivation of the CeN induced a robust anti-punishment effect in both groups. These data provided evidence that the CeN is a critical neural substrate involved in regulation by punishment of cocaine SA. Rats with a history of extended cocaine SA appeared to be less sensitive to punishment. The decreased sensitivity could result from the neuroplastic changes induced by extended cocaine SA in the CeN.

Rodent models for compulsive alcohol intake

“…Also, only ~50% of rats exhibit footshock-resistant alcohol intake when 1 in 8 FR3 responses is paired with footshock (Seif et al, 2013), while all rats reduce responding when 1 in 3 FR3 responses are paired with footshock (S. J. Chung and F. W. Hopf, unpublished). This is similar to what is observed with footshock-resistant cocaine intake, where enough shocks c reduce responding in all rats (Xue, Steketee, & Sun, 2012), and even completely eliminate responding (i.e., a self-induced abstinence; Barnea-Ygael et al, 2012; Cooper, Barnea-Ygael, Levy, Shaham, & Zangen, 2007). In addition, after short-term intake, all rats show reduced cocaine intake by Pavlovian-conditioned aversive stimuli, while after long-term intake all rats are resistant to suppression of intake by these cues (Vanderschuren & Everitt, 2004).…”

“…A second possible explanation for CeA control over compulsive drug use may lie in the well-described CeA control of sensitivity to negative emotional stimuli and punishment (Ciocchi et al, 2010; Maren & Quirk, 2004; Phelps & LeDoux, 2005; Sehlmeyer et al, 2009). Indeed, CeA lesions reduce conditioned suppression, i.e., the suppression of ongoing operant behavior by a conditioned fear stimulus (Killcross, Robbins, & Everitt, 1997), and reduce direct suppression of behavior by footshocks (Xue et al, 2012). Taken together, there is ample reason to suggest the importance of the amygdala in both escalation of alcohol intake and the development of compulsive drug use.…”

Compulsive drug use and its neural substrates

“…With regard to the resistance to punishment discussed here, it has been shown that lesions of the CeA reduced conditioned suppression, i.e., the suppression of ongoing operant behavior by a conditioned fear stimulus (Killcross et al, 1997). A recent study extended these findings and showed that the CeA also contributes to the sensitivity to punishmentinduced suppression of cocaine self-administration (Xue et al, 2012). Taken together, there is substantial literature demonstrating the involvement of the amygdala in both the escalation of drug use and the development of compulsive drug use.…”

Deep Brain Stimulation in Treatment-Refractory Addiction

“…In humans, the reduction of amygdala volume has been related to increase in desire for alcohol and cocaine intake and greater tendency to relapse [56], while in rats its functional block leads to increase in compulsivity of cocaine intake and seeking and reduction of its anxiety-producing effect [57,58]. However, DBS of the amygdala does not find a clinical application in the treatment of addiction at present, even if it has been proposed by some authors [59].…”