Brain circuitry and the reinstatement of cocaine-seeking behavior

Abstract

Rationale: Recent studies have attempted to identify the neuroanatomical substrates underlying primed reinstatement of drug-seeking behavior. Identification of neuronal substrates will provide a logical rationale for designing pharmacological interventions in treating drug relapse. Objective: The objective was to identify brain circuitry that is shared between cue-, drugand stress-primed reinstatement, as well as identifying aspects of brain circuitry that are distinct for each stimulus modality. The resulting circuit offers theoretical interpretations for consideration in future studies. Results: Aspects of the circuitry mediating reinstatement can be identified with reasonable confidence. The role of the basolateral amygdala in cue-primed reinstatement, the role of the ventral tegmental area in drug-primed reinstatement and the role of adrenergic innervation of the extended amygdala in stress-primed reinstatement are well characterized. Also, all three modes for priming reinstatement may converge on the anterior cingulate cortex and have a final common output through the core of the nucleus accumbens. Lacunae in our understanding of the circuit were identified, especially with regard to how stress priming is conveyed from the extended amygdala to the shared anterior cingulate accumbens core circuit. Conclusions: The proposed convergence of priming stimuli into the glutamatergic projection from anterior cingulate to the accumbens core combined with the changes in glutamate transmission and signaling that accompany repeated psychostimulant administration points to the potential value of pharmacological agents that manipulate glutamate release or postsynaptic glutamate receptor signaling and trafficking in treating primed relapse in addicts.

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

“…Human imaging studies have associated changes in the mPFC (Volkow et al, 2005;Childress et al, 1999) and NAc (Risinger et al, 2005) with cocaine craving. These reports are paralleled by rodent studies of relapse and reinstatement (for review, see Rebec and Sun, 2005;Kalivas and McFarland, 2003). At the molecular level, abstinence-induced or abstinence-persistent changes in mRNA and protein expression have been described in the mPFC and NAc after cocaine self-administration (Lu et al, 2003;Sutton et al, 2003).…”

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…Relevant to addiction, Homer transcripts or proteins are present in many of the structures within mesocorticolimbic circuits that exhibit pathology in addiction [cf. 2,4,23,53,[151][152][153][154][155][156]. CC-Homer and IEG Homer isoforms are found throughout the cerebral cortex [105,106].…”

“…Preclinical efforts to understand the cellular basis for drug addiction-related abnormalities in mesocorticolimbic glutamate function have employed a variety of experimental approaches to examine the psychobiological consequences of repeated, non-contingent drug administration [18][19][20][21][22] and many of these findings have been confirmed in various animal models of drugtaking or drug-seeking [c.f., [23][24][25][26][27]. The integrity of the corticoaccumbens glutamate pathway is required for expressing many drug-induced changes in behavior, including the sensitization To whom correspondence should be addressed: Karen K. Szumlinski, Ph.D., Department of Psychology, University of California Santa Barbara, Santa Barbara, CA, USA 93106-9660.of a drug's psychomotor-activating effects [e.g., 28-37], the development of tolerance to a drug's psychomotor-inhibiting effects [e.g., 38,39], drug-conditioned place-preference [e.g., 36,38,40-43], the maintenance of drug self-administration [e.g., [44][45][46] and the reinstatement of drug-seeking [47][48][49][50][51][52][53][54][55][56].…”

Estrogen Receptor β, but not α, Mediates Estrogen's Effect on Cocaine-Induced Reinstatement of Extinguished Cocaine-Seeking Behavior in Ovariectomized Female Rats

“…Although the pathways underlying relapse induced by these stimuli differ, there is some overlap in brain regions such as the prefrontal cortex and nucleus accumbens (Self and Nestler, 1998;Kalivas and McFarland, 2003;Kalivas and Volkow, 2005). Given the results of the present study, it is unlikely that the effects of estrogen on reinstatement are a result of ERb activation in the amygdala, as this region has been implicated in reinstatement of drug-seeking behavior induced by cocaine-associated cues, but not for reinstatement elicited by priming injections of cocaine (McFarland and Kalivas, 2001;Kalivas and McFarland, 2003;Bossert et al, 2005). This idea is supported by recent studies in rats indicating that gonadal hormones (eg, estrogen) influence reinstatement induced by cocaine (Kippin et al, 2005;, but not reinstatement elicited by exposure to cocaine-associated cues .…”