Alterations in the dopaminergic receptor system after chronic administration of cocaine

Alburges, Mario E.; Narang, Neelam; Wamsley, James K.

doi:10.1002/syn.890140409

Cited by 75 publications

(38 citation statements)

References 43 publications

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“…Similarly, the 6-h access rats that exhibited neither a sensitized locomotor response nor an elevated c-Fos reactivity to cocaine, also exhibited no change in DAT density. These results are also consistent with the data of Alburges et al, (1993;using [3H]BTCP) and of Claye et al, (1995;using [3H] GBR-12935) who showed increased levels of DAT in the nucleus accumbens or striatum of rats receiving a cocaine treatment regimen previously shown to resulting behavioral sensitization. Finally, the current results are consistent with the data of Letchworth et al, (2001;[3H]WIN35,428) showing increased DAT density in the N.Acc of rhesus monkeys self-administering cocaine in a pattern resembling recreational drug use in humans.…”

Section: Discussionsupporting

confidence: 91%

One hour, but not six hours, of daily access to self-administered cocaine results in elevated levels of the dopamine transporter

2006

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We have previously shown that brief (1 h) and extended (6 h) daily access to IV cocaine selfadministration produce different behavioral and neural consequences following 2 weeks of drug withdrawal. Brief daily access produced stable consumption of the drug and, after withdrawal, a sensitized locomotor response and an enhanced c-Fos labeling to a single cocaine challenge. In contrast, extended daily cocaine self-administration produced escalation of drug consumption over trials but no enhanced behavioral or neurochemical response after withdrawal. Cocaine affects dopaminergic (DA) function by binding to the presynaptic transporter and thereby preventing reuptake of the neurotransmitter-an action thought to be responsible for the drug's reinforcing properties. In an extension of our previous work, the current study, using receptor autoradiography, compared binding (by [3H]WIN35428) of the dopamine transporter (DAT) in animals having experienced either brief or extended daily access to cocaine over 8 days, followed by 14 days of withdrawal. DAT densities were found to increase in the nucleus accumbens core (N.Acc Core) and the dorsal striatum (but not in the N.Acc shell, medial prefrontal cortex (mPFC), or ventral tegmental area (VTA)) of the 1-h, but not 6-h, subjects. In other words, elevations in DAT density were not associated with the 6-h access group, the group that models patterns of drug-use in human addicts, and therefore are likely to be independent of the neuroadaptations that occur in the "addictive" process. Such conclusions are also consistent with brain-imaging studies of human cocaine addicts. Additional research will be needed to identify the specific neural changes relevant to addiction.

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Section: Discussionsupporting

confidence: 91%

One hour, but not six hours, of daily access to self-administered cocaine results in elevated levels of the dopamine transporter

2006

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“…Whether this decreased D 2 receptor expression represents a vulnerability factor or a consequence of long-term cocaine exposure cannot be determined from these studies. Rodent studies investigating the long-term effects of cocaine exposure on D 2 receptor density have yielded inconsistent findings: studies have reported unchanged (Dwoskin et al, 1988;Alburges et al, 1993;Neisewander et al, 1994;Claye et al, 1995), increased (Taylor et al, 1979;Trulson and Ulissey, 1987;Zeigler et al, 1991) and decreased (Goeders and Kuhar, 1987;Kleven et al, 1990) D 2 receptor densities in the striatum. Studies in nonhuman primates are less numerous, but more consistent.…”

Section: Receptor Availability and Cocaine Dependencementioning

confidence: 99%

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

Martínez

Broft

Foltin

et al. 2004

Neuropsychopharmacol

268

164

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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.

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“…Studies have variously reported receptor downregulation (Maggos et al, 1998;Zeigler et al, 1991), upregulation (Alburges et al, 1992(Alburges et al, , 1993Macedo et al, 2004), and no alterations (Mayfield et al, 1992;Sousa et al, 1999) in D 1 densities between days 1 and 30 of withdrawal. Similar inconsistencies are reported with respect to D 2 receptors (upregulation (Macedo et al, 2004;Sousa et al, 1999;Zeigler et al, 1991); downregulation (Maggos et al, 1998;Volkow et al, 1993); no change (Alburges et al, 1992(Alburges et al, , 1993Maggos et al, 1998)). Given the complex interplay between mesostriatal ACh and DA described earlier, it is perhaps not surprising that the extant literature is inconsistent with respect to the direction of striatal cholinergic change resulting from, or effecting, cocaine administration.…”

Section: Neuroadaptation Ach Receptor Alterations Following Cocainementioning

confidence: 99%

The Role of Acetylcholine in Cocaine Addiction

Williams

Adinoff²

2007

Neuropsychopharmacol

160

138

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Central nervous system cholinergic neurons arise from several discrete sources, project to multiple brain regions, and exert specific effects on reward, learning, and memory. These processes are critical for the development and persistence of addictive disorders. Although other neurotransmitters, including dopamine, glutamate, and serotonin, have been the primary focus of drug research to date, a growing preclinical literature reveals a critical role of acetylcholine (ACh) in the experience and progression of drug use. This review will present and integrate the findings regarding the role of ACh in drug dependence, with a primary focus on cocaine and the muscarinic ACh system. Mesostriatal ACh appears to mediate reinforcement through its effect on reward, satiation, and aversion, and chronic cocaine administration produces neuroadaptive changes in the striatum. ACh is further involved in the acquisition of conditional associations that underlie cocaine self-administration and context-dependent sensitization, the acquisition of associations in conditioned learning, and drug procurement through its effects on arousal and attention. Long-term cocaine use may induce neuronal alterations in the brain that affect the ACh system and impair executive function, possibly contributing to the disruptions in decision making that characterize this population. These primarily preclinical studies suggest that ACh exerts a myriad of effects on the addictive process and that persistent changes to the ACh system following chronic drug use may exacerbate the risk of relapse during recovery. Ultimately, ACh modulation may be a potential target for pharmacological treatment interventions in cocaine-addicted subjects. However, the complicated neurocircuitry of the cholinergic system, the multiple ACh receptor subtypes, the confluence of excitatory and inhibitory ACh inputs, and the unique properties of the striatal cholinergic interneurons suggest that a precise target of cholinergic manipulation will be required to impact substance use in the clinical population.

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Alterations in the dopaminergic receptor system after chronic administration of cocaine

Cited by 75 publications

References 43 publications

One hour, but not six hours, of daily access to self-administered cocaine results in elevated levels of the dopamine transporter

One hour, but not six hours, of daily access to self-administered cocaine results in elevated levels of the dopamine transporter

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

The Role of Acetylcholine in Cocaine Addiction

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