Different Neural Substrates Mediate Cocaine Seeking after Abstinence versus Extinction Training: A Critical Role for the Dorsolateral Caudate–Putamen

Abstract

Cue-induced reinstatement of extinguished drug seeking is a preclinical model of relapse. However, relapse typically occurs after abstinence rather than explicit extinction training. We show that inactivation of the dorsolateral caudate-putamen, but not other structures previously implicated in reinstatement, attenuates cocaine seeking after abstinence. This suggests that there is limited overlap in the substrates of cocaine seeking after abstinence versus extinction, and that habit learning exerts greater control over drug seeking than regions implicated in stimulus-reward associations.

Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats

“…The mean number of inactive lever presses during the 1-h test period for cocaine and yoked-saline animals was 28.6±6.9 and 7.8±2.5, respectively (F (1,8) =7.84, p=0.023). As described in previous reports (Berglind et al 2007;Fuchs et al 2006), this increase in inactive lever pressing after 15 days of abstinence likely represents an alternative cocaine-seeking strategy in rats with heightened motivation to seek the drug when it is no longer available on the previously cocaine-paired lever. …”

“…On post-cocaine day 15, one third of the rats were returned to the alternate environment (ALT; n=5/group for Coc and Sal), one third to the self-administration chamber with no levers available (NL; n=5/group for Coc and Sal), and one third to the self-administration chamber with the levers available (LA; n=5/group for Coc and Sal) for 1 h. The number of lever presses for the latter group was recorded but had no scheduled consequences. We included the ALT environment group in order to distinguish the impact of recent contextual familiarity from remote familiarity (dishabituation) when rats were re-exposed to the selfadministration chamber without extinguishing the motivational effects of the cocaine-paired environment (Fuchs et al 2006). The similar transport procedures and temporal pattern used for the ALT environment and the self-administration environment also controlled for general handling and arousal.…”

“…Similarly, in animal studies, during chronic drug self-administration, the drug-paired environment acquires conditioned reinforcing properties that trigger drug-seeking behavior upon reexposure to the context following forced abstinence (Crombag and Shaham 2002;Fuchs et al 2005Fuchs et al , 2006. Thus, like other forms of learning, relapse to drug-seeking involves the formation and retrieval of instrumental memories (Hyman 2005).…”

“…Homologous brain regions in rats are implicated in drug seeking (Porrino and Lyons 2000); however, a growing body of evidence suggests that distinct and overlapping neural substrates are important following abstinence versus extinction training. Following chronic cocaine selfadministration and subsequent extinction of operant responding, inactivation of the anterior cingulate (specifically Cg1 using the Paxinos and Watson 1998 nomenclature), the prelimbic (PrL) or the OFC, but not the infralimbic (IL) cortex suppressed cue-induced ( However, inactiva-tion of the PrL/Cg1 cortex failed to alter cocaine seeking evoked by reexposure to the self-administration chamber following forced abstinence without extinction training (Fuchs et al 2006). Together, these reports suggest that the dorsomedial (dm) PFC is differentially involved in drug seeking depending on the environmental circumstances or model used.…”

“…The mean density and number of pixels per area were measured in the selected PFC areas (Fig. 2) 2003;Fuchs et al 2004Fuchs et al , 2005Fuchs et al , 2006Berglind et al 2007). The measurements were expressed as integrated density (no.…”