Nicole H Mutschler1, Jack Bergman. 1. Harvard Medical School-McLean Hospital, Alcohol and Drug Abuse Research Center, 115 Mill Street, Belmont, MA 02478-9106, USA.
Abstract
RATIONALE: Dopamine D1 receptor partial agonists have been proposed as candidate medications for the treatment of cocaine dependence. However, there currently is scant information regarding how chronic exposure to D1 agonists may modify behavioral effects of cocaine and, especially, whether tolerance develops to their effects on cocaine self-administration. OBJECTIVE: The present studies were conducted to evaluate the effects of chronic treatment with the D1 receptor partial agonist SKF 77434 on IV cocaine self-administration in rhesus monkeys. METHODS: A protocol was developed to rapidly evaluate the effects of chronic drug exposure on extinction behavior, threshold dose of self-administered cocaine, and the dose-effect function for cocaine self-administration behavior. Monkeys performed in daily sessions of IV cocaine self-administration under a fixed-ratio schedule of reinforcement and food presentation under either a fixed-ratio or fixed-interval schedule of reinforcement. When both types of performance were stable, chronic exposure to SKF 77434 followed with month-long regimens of IV treatment with each of two or three dosages. RESULTS: The effects of SKF 77434 were dose-related. Exposure to 1.0 mg/kg per day of SKF 77434 yielded a moderate and persistent rightward shift in the descending portion of the dose-effect function for cocaine self-administration but did not alter the threshold dose and did not disrupt either extinction behavior or food-maintained performance. An increase in dosage to 3.2-5.6 mg/kg per day displaced the dose-effect function for cocaine self-administration downward from its prechronic position, altered threshold dose values, and disrupted food-maintained performance. CONCLUSIONS: Chronic treatment with D1 receptor partial agonists produced dose-dependent effects on cocaine self-administration that may be relevant to their further evaluation as candidate medications for the treatment of cocaine dependence.
RATIONALE: Dopamine D1 receptor partial agonists have been proposed as candidate medications for the treatment of cocaine dependence. However, there currently is scant information regarding how chronic exposure to D1 agonists may modify behavioral effects of cocaine and, especially, whether tolerance develops to their effects on cocaine self-administration. OBJECTIVE: The present studies were conducted to evaluate the effects of chronic treatment with the D1 receptor partial agonist SKF 77434 on IV cocaine self-administration in rhesus monkeys. METHODS: A protocol was developed to rapidly evaluate the effects of chronic drug exposure on extinction behavior, threshold dose of self-administered cocaine, and the dose-effect function for cocaine self-administration behavior. Monkeys performed in daily sessions of IV cocaine self-administration under a fixed-ratio schedule of reinforcement and food presentation under either a fixed-ratio or fixed-interval schedule of reinforcement. When both types of performance were stable, chronic exposure to SKF 77434 followed with month-long regimens of IV treatment with each of two or three dosages. RESULTS: The effects of SKF 77434 were dose-related. Exposure to 1.0 mg/kg per day of SKF 77434 yielded a moderate and persistent rightward shift in the descending portion of the dose-effect function for cocaine self-administration but did not alter the threshold dose and did not disrupt either extinction behavior or food-maintained performance. An increase in dosage to 3.2-5.6 mg/kg per day displaced the dose-effect function for cocaine self-administration downward from its prechronic position, altered threshold dose values, and disrupted food-maintained performance. CONCLUSIONS: Chronic treatment with D1 receptor partial agonists produced dose-dependent effects on cocaine self-administration that may be relevant to their further evaluation as candidate medications for the treatment of cocaine dependence.
Authors: Anupam Karki; Reecan Juarez; Hari K Namballa; Ian Alberts; Wayne W Harding Journal: Bioorg Med Chem Lett Date: 2020-02-20 Impact factor: 2.823
Authors: Diana Martinez; Mark Slifstein; Rajesh Narendran; Richard W Foltin; Allegra Broft; Dah-Ren Hwang; Audrey Perez; Anissa Abi-Dargham; Marian W Fischman; Herbert D Kleber; Marc Laruelle Journal: Neuropsychopharmacology Date: 2009-01-28 Impact factor: 7.853