Evidence suggests that the reinforcing effects of cocaine are related to its action as an indirect dopamine agonist ( Wise and Bozarth, 1987 Koob, 1992). We conclude that D 1 receptor knock-out mice do not reliably self-administer cocaine and that the D 1 receptor is critical for the reinforcing effects of cocaine and other dopamine agonists, but not food or opioids, in mice.Ĭocaine dependence is a serious public health problem for which there are no effective treatment medications ( Mendelson and Mello, 1996 National Institute on Drug Abuse, 2003). Finally, pretreatment with the D 1-like antagonist SCH 23390 produced surmountable antagonism of the reinforcing effects of cocaine in the commonly used strain C57BL/6J. The D 1-like agonist SKF 82958 (2,3,4,5,-tetrahydro-6-chloro-7,8-dihydroxy-1-phenyl-1 H-3-benzazepine hydrobromide) and the D 2-like agonist quinelorane both functioned as positive reinforcers in wild-type mice but not in D 1 receptor mutant mice, whereas food and intravenous injections of the opioid agonist remifentanil functioned as positive reinforcers in both genotypes. After extinction of responding with saline self-administration, dose–response studies showed that cocaine reliably and dose dependently maintained responding greater than saline in all wild-type mice but in none of the D 1 receptor knock-out mice. Two cohorts with varied breeding and experimental histories were tested, and, in both cohorts, there was a significant decrease in the number of D 1 receptor knock-out mice that met criteria for acquisition of cocaine self-administration (2 of 23) relative to wild-type mice (27 of 32). We studied the dopamine D 1 receptor and cocaine self-administration in mice using a combination of gene-targeted mutation and pharmacological tools. However, self-administration has been less often studied in the mouse species, and, to date, “knock-out” of individual dopamine-related genes in mice has not been reported to reduce the reinforcing effects of cocaine. Evidence suggests a critical role for dopamine in the reinforcing effects of cocaine in rats and primates.
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