Interactions of the basolateral amygdala with the dorsal hippocampus and dorsomedial prefrontal cortex regulate drug context‐induced reinstatement of cocaine‐seeking in rats

Abstract

The basolateral amygdala (BLA), dorsomedial prefrontal cortex (dmPFC) and dorsal hippocampus (DH) are critical elements of the neurocircuitry of drug context-induced reinstatement of cocaine-seeking; however, little is known about functional interactions between these brain regions. The present study tested the hypothesis that serial information processing by the BLA and dmPFC mediates drug context-induced cocaine-seeking, whereas the BLA and DH independently control this behaviour. Rats were trained to self-administer cocaine in a distinct environment (cocaine-paired context) followed by extinction training in a different environment (extinction context). On the test days, rats received unilateral microinfusions of baclofen + muscimol or of vehicle into the BLA and either the contralateral or ipsilateral dmPFC or DH. Cocaine-seeking behaviour (i.e. nonreinforced presses on the cocaine-associated lever) was then assessed in the cocaine-paired and extinction contexts. Following vehicle pretreatment, exposure to the cocaine-paired context reinstated extinguished cocaine-seeking behaviour. BLA-dmPFC asymmetrical inactivation attenuated cocaine-seeking behaviour relative to vehicle treatment; however, this impairment equaled that produced by ipsilateral BLA-dmPFC inactivation. Furthermore, unilateral inactivation of the BLA or dmPFC did not alter this behaviour. BLA-DH asymmetrical inactivation selectively attenuated cocaine-seeking behaviour relative to vehicle treatment whereas ipsilateral or unilateral inactivation of the BLA and DH did not alter this behaviour. These findings indicate that the BLA and DH exhibit sequential information processing within the relapse circuitry. In contrast, interactions between the BLA and dmPFC are more complex and include parallel loops of information processing and/or necessary interhemispheric input from the dmPFC to the BLA, probably in addition to direct intrahemispheric interactions.

Lateral Hypothalamus Is Required for Context-Induced Reinstatement of Extinguished Reward Seeking

“…used a renewal design (Bouton and Bolles, 1979) and reported that rats trained to self-administer a heroin-cocaine mixture in one context, context A, and then extinguished in a second, different context, context B, showed a pronounced reinstatement of extinguished drug seeking when tested in context A. This context-induced reinstatement or renewal of extinguished drug seeking has since been reported for a variety of drug rewards including cocaine Fuchs et al, 2007;Hamlin et al, 2008), heroin (Bossert et al, 2004), alcohol Zironi et al, 2006;Hamlin et al, 2007;Marinelli et al, 2007), and nicotine (Diergaarde et al, 2008), as well as the natural reward sucrose (Hamlin et al, 2006). Renewal is a signature phenomenon of extinction (Bouton, 2002).…”

“…It shows that extinction training does not erase the original learning that mediates drug seeking but instead imposes a mask on that learning to actively inhibit drug seeking in the extinction context. Studies using microinjections of dopamine and glutamate receptor antagonists, as well as reversible inactivation via baclofen/ muscimol or tetrodotoxin infusion, have implicated hippocampus, basolateral amygdala (BLA), nucleus accumbens shell (AcbSh), nucleus accumbens core (AcbC), ventral tegmental area (VTA), and dorsomedial prefrontal cortex (dmPFC) in contextinduced reinstatement of drug seeking (Bossert et al, 2004(Bossert et al, , 2006(Bossert et al, , 2007Fuchs et al, 2005Fuchs et al, , 2007Fuchs et al, , 2008. Recently, we have used c-Fos expression to identify the neural correlates of context-induced reinstatement.…”

Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

“…During extinction training, lever responses were recorded but had no scheduled consequences. Before the fourth extinction-training session, rats were adapted to the intracranial microinfusion procedure, as described previously (Fuchs et al, 2007). As active lever responses during cocaine self-administration training averaged between 50 and 75/session (see Supplementary Table S1), extinction training continued until a criterion of p25 active lever responses/session on at least two consecutive days was reached.…”

“…Active lever presses resulted in cocaine reinforcement (cocaine hydrochloride; 0.15 mg/0.05 ml per infusion, i.v. ; NIDA, Research Triangle Park, NC) under a FR-1/20 s-time-out schedule (Fuchs et al, 2007). Responses on the other (inactive) lever were recorded but had no scheduled consequences.…”

“…Forty-eight hours later, they were surgically implanted with intravenous jugular catheters and 26-Ga stainless steel guide cannulae (Plastics One), aimed bilaterally at the DH (angled laterally by 151; AP À 3.4 mm, ML þ / À 3.1 mm, DV À 2.15 mm). The food training, surgery, and post-operative care procedures have been described previously (Fuchs et al, 2007;Fuchs et al, 2008b;Xie et al, 2010).…”