Characterization of dopamine D1 and D2 receptor function in socially housed cynomolgus monkeys self-administering cocaine

Czoty, Paul W.; Morgan, Drake; Shannon, Erin; Gage, H. Donald; Nader, Michael A.

doi:10.1007/s00213-003-1752-z

Cited by 75 publications

(59 citation statements)

References 48 publications

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“…A correlation between increased vulnerability to cocaine reinforcement and lower D2 availability was also reported by Morgan et al (2002) who showed that social housing resulted in increased D2 receptor availability in dominant monkeys which was associated with significantly lower levels of cocaine self-administration. Interestingly, the same group of researchers (Czoty et al, 2004) reported that long term cocaine selfadministration equalized D2 levels in these monkeys across social ranks. Such data are consistent with the hypothesis that the decrease in D2 receptor availability found in human cocaine addicts is not the result of excessive cocaine consumption, but rather a pre-existing condition leading to a higher vulnerability to addiction.…”

Section: Discussionmentioning

confidence: 91%

Changes in levels of D1, D2, or NMDA receptors during withdrawal from brief or extended daily access to IV cocaine

et al. 2007

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We previously reported that brief (1 hr), but not extended (6 hrs), daily access to cocaine results in a sensitized locomotor response to cocaine and in elevated c-Fos immunoreactivity and DAT binding in the nucleus accumbens (N.Acc) core. In order to better our understanding of the neural adaptations mediating the transition from controlled drug-use to addiction, the current experiments were set to further explore the neural adaptations resulting from these two access conditions. Rats received either brief daily access to saline or cocaine, or brief daily access followed by extended daily access, to cocaine. Subjects were then sacrificed either 20 minutes, or 14 or 60 days, after the last selfadministration session. Samples of the ventral tegmental area (VTA), N.Acc core and shell, dorsal striatum, and medial prefrontal cortex (mPFC) were taken for analysis of D1 ([3H]SCH-23390), D2 ([3H]Spiperone), and NMDA ([3H]MK-801) receptor binding (using the method of receptor autoradiography). At 20 minutes into withdrawal D2 receptors were elevated and NMDA receptors were reduced in the mPFC of the brief access animals while D1 receptors were elevated in the N.Acc shell of the extended access animals, compared to saline controls. D2 receptors were reduced in the N.Acc shell of the brief access animals compared to saline controls after 14 days, and compared to extended access animals after 60 days of withdrawal. In summary, extended access to cocaine resulted in only transient changes in D1 receptors binding. These results suggest that the development of compulsive drug use is largely unrelated to changes in total binding of D2 or NMDA receptors.

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Section: Discussionmentioning

confidence: 91%

Changes in levels of D1, D2, or NMDA receptors during withdrawal from brief or extended daily access to IV cocaine

et al. 2007

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“…These findings suggested that with prolonged cocaine exposure, the impact of environmental variables (in this case dominance status) on certain measures of reinforcing effects was attenuated. Parallel changes in DA receptor function were observed (Czoty et al, 2004). One goal of the present study was to further evaluate the reinforcing effects of cocaine in socially housed monkeys with extensive experience self-administering cocaine.…”

mentioning

confidence: 75%

“…Whereas monkeys' social rank significantly influenced cocaine reinforcement during initial exposure, long-term cocaine self-administration under an FR 50 schedule resulted in progressive increases in cocaine-maintained responding by dominant monkeys to the point that, after several years, no significant differences between dominant and subordinate monkeys were observed (Czoty et al, 2004). These findings suggested that with prolonged cocaine exposure, the impact of environmental variables (in this case dominance status) on certain measures of reinforcing effects was attenuated.…”

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confidence: 93%

Assessment of the Relative Reinforcing Strength of Cocaine in Socially Housed Monkeys Using a Choice Procedure

Czoty

McCabe²,

Nader³

2004

J Pharmacol Exp Ther

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Position in the social hierarchy can influence brain dopamine function and cocaine reinforcement in nonhuman primates during early cocaine exposure. With prolonged exposure, however, initial differences in rates of cocaine self-administration between dominant and subordinate monkeys dissipate. The present studies used a choice procedure to assess the relative reinforcing strength of cocaine in group-housed male cynomolgus monkeys with extensive cocaine self-administration histories. Responding was maintained under a concurrent fixed-ratio 50 schedule of food and cocaine (0.003-0.1 mg/kg per injection) presentation. Responding on the cocaine-associated lever increased as a function of cocaine dose in all monkeys. Although response distribution was similar across social rank when saline or relatively low or high cocaine doses were the alternative to food, planned t tests indicated that cocaine choice was significantly greater in subordinate monkeys when choice was between an intermediate dose (0.01 mg/kg) and food. When a between-session progressive-ratio procedure was used to increase response requirements for the preferred reinforcer (either cocaine or food), choice of that reinforcer decreased in all monkeys. The average response requirement that produced a shift in response allocation from the cocaineassociated lever to the food-associated lever was higher in subordinates across cocaine doses, an effect that trended toward significance (p ϭ 0.053). These data indicate that despite an extensive history of cocaine self-administration, most subordinate monkeys were more sensitive to the relative reinforcing strength of cocaine than dominant monkeys.

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“…These experiments primarily focus on changing environmental conditions. For example, we found that the protective effect associated with being the dominant monkey can be attenuated by continual exposure to cocaine (Czoty et al 2004). That is, while there were differences in rates of self-administration when initially exposed to the FR 50 schedule (Morgan et al 2002), repeated exposure to cocaine over a 1-year period resulted in cocaine becoming a reinforcer in dominant monkeys (see e.g.…”

Section: Introductionmentioning

confidence: 91%

“…figure 2a). After several months to years of cocaine self-administration, neither response rates nor D 2 receptor availability were different in dominant compared with subordinate monkeys (Czoty et al 2004). As mentioned above, simple schedules do not provide information related to reinforcing strength.…”

Section: Introductionmentioning

confidence: 97%

Positron emission tomography imaging studies of dopamine receptors in primate models of addiction

Nader

Czoty

Gould

et al. 2008

Phil. Trans. R. Soc. B

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Animal models have provided valuable information related to trait and state variables associated with vulnerability to drug addiction. Our brain imaging studies in monkeys have implicated D 2 receptors in cocaine addiction. For example, an inverse relationship between D 2 receptor availability and rates of cocaine self-administration has been documented. Moreover, environmental variables, such as those associated with formation of the social hierarchy, can impact receptor availability and sensitivity to the abuse-related effects of cocaine. Similarly, both D 2 receptor availability and cocaine selfadministration can be altered by chronic drug administration and fluctuations in hormone levels. In addition, cocaine self-administration can be altered in an orderly fashion by presentation of an acute stressor, such as acting as an intruder into an unfamiliar social group, which can shift the cocaine dose-response curve to the left in subordinate monkeys and to the right in dominant animals, suggesting an interaction between social variables and acute stressors. Conversely, irrespective of social rank, acute environmental enrichment, such as increasing the size of the living space, shifts the cocaine dose-response curve to the right. These findings highlight a pervasive influence of the environment in modifying the reinforcing effects of cocaine and strongly implicate brain D 2 receptors.

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Characterization of dopamine D1 and D2 receptor function in socially housed cynomolgus monkeys self-administering cocaine

Cited by 75 publications

References 48 publications

Changes in levels of D1, D2, or NMDA receptors during withdrawal from brief or extended daily access to IV cocaine

Changes in levels of D1, D2, or NMDA receptors during withdrawal from brief or extended daily access to IV cocaine

Assessment of the Relative Reinforcing Strength of Cocaine in Socially Housed Monkeys Using a Choice Procedure

Positron emission tomography imaging studies of dopamine receptors in primate models of addiction

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