Cocaine Dependence and D2 Receptor Availability in the Functional Subdivisions of the Striatum: Relationship with Cocaine-Seeking Behavior

Abstract

Striatal dopamine D 2 receptors have been implicated in the neurobiology of cocaine addiction. Previous imaging studies showed reduced striatal D 2 receptor availability in chronic cocaine abusers, and animal studies suggested that low D 2 receptor availability promotes cocaine self-administration. Here, D 2 receptor availability was assessed with positron emission tomography (PET) and [ 11 C]raclopride in the limbic, associative, and sensori-motor subdivisions of the striatum in 17 recently detoxified chronic cocaine-dependent (CCD) subjects and 17 matched healthy control (HC) subjects. In addition, the relationship between regional D 2 receptor availability and behavioral measures obtained in cocaine self-administration sessions was investigated in CCD subjects. [11 C]Raclopride binding potential was significantly reduced by 15.2% in the limbic striatum, 15.0% in the associative striatum, and 17.1% in the sensori-motor striatum in CCD subjects compared to HC subjects. In CCD subjects, no relationship was detected between D 2 availability in striatal regions and either the positive effects of smoked cocaine or the choice of cocaine over an alternative reinforcer (money) following a priming dose of cocaine (a laboratory model of relapse). Thus, this study confirms previous reports of a modest decrease in D 2 receptor availability in CCD subjects, and establishes that this decrease is generalized throughout the striatum. However, this study failed to demonstrate a relationship between D 2 receptor availability and cocaine-induced cocaine-taking behavior. Additional research is warranted to unravel potential neurobiological traits that might confer vulnerability to relapse in detoxified CCD subjects.

The role of human drug self-administration procedures in the development of medications

“…Interestingly, the buprenorphine/naloxone combination was self-administered even at doses that produced no statistically significant increases in subjective responses. [Similar results (i.e., drug self-administration in the absence of changes in subjective responses) have been reported for morphine (Lamb et al, 1991) and for cocaine (Martinez et al, 2004).] When participants were asked why they self-administered buprenorphine/naloxone when they felt no measurable subjective effects, they reported that they slept better that night or that they had less muscle pain.…”

Cocaine self-administration produces a persistent increase in dopamine D2High receptors

“…It is clear, therefore, that to determine the nature of the relationship between the increase in D2 High receptors and any specific change in behavior or psychological process, including behavioral sensitization, will require examination of a greater range of cocaine doses, treatment regimens and conditions. Nevertheless, it is important to contrast the increase in striatal D2 High receptors produced by cocaine self-administration experience reported here with reports that there is a decrease in striatal D2 receptors in cocaine addicts (Volkow et al, 1990;Martinez et al, 2004) and in non-human primates allowed to self-administer cocaine (Volkow, et al, 1990, Volkow, et al, 1993, Martinez, et al, 2004, Nader and Czoty, 2005, Nader, et al, 2006. We did not find a decrease in the total number of D2 receptors, and therefore, there was presumably a decrease in the number of D2 receptors in the low-affinity state proportionate to the increase in D2 High receptors.…”

“…A consistent finding from imaging studies is that cocaine addicts show a small but very persistent decrease in dorsal striatal dopamine D2 receptors (Volkow, et al, 1990, Martinez, et al, 2004, Volkow, et al, 2004, and studies in non-human primates report similar decreases following cocaine self-administration, suggesting that this may be a consequence of cocaine use Czoty, 2005, Nader, et al, 2006). However, a long-standing puzzle in this area is that preclinical studies have consistently found that rats treated with amphetamine or cocaine, and then withdrawn, are hypersensitive to the psychomotor activating and incentive motivational effects of these "indirect agonists" (Robinson and Berridge, 1993), and even more importantly, to the psychomotor effects of direct-acting D2 agonists (Ujike, et al, 1990, De Vries, et al, 2002, Edwards, et al, 2007.…”

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

“…There are multiple lines of evidence that cocaine dependence is associated with a decrease in D 2 receptor binding [164-167], a pattern that seems to persist after disease remission [165]. Decreases in D 2 receptor binding have also been found in heroin addiction [168], alcohol dependence [169,170], methamphetamine abuse [171,172], prompting a number of researchers to posit that low D 2 receptor availability may serve as a biomarker for substance abuse, potentially reflecting an altered sensitivity to various rewards [173-175].…”