Comparison of interactions of D1-like agonists, SKF 81297, SKF 82958 and A-77636, with cocaine: locomotor activity and drug discrimination studies in rodents.

Abstract

RATIONALE:

Recent data suggest that dopamine (DA) D1-like receptor full agonists may be potential pharmacotherapeutic agents for treating cocaine abuse. The structurally novel isochroman D1-like agonist, A-77636, has not been well characterized and may prove to be useful as such an agent.

OBJECTIVES:

The interactions of cocaine and A-77636 were compared to those obtained with the better investigated benzazepine D1-like dopamine agonists, SKF 82958 and SKF 81297. The alterations in the locomotor stimulant and discriminative-stimulus effects of cocaine by the full D1-like dopamine receptor agonists were investigated across a full range of doses in order to characterize their interactions.

METHODS:

Drug-naive Swiss-Webster mice were pretreated with SKF 81297, SKF 82958 or A-77636 (1-10 mg/kg) and cocaine (5-56 mg/kg) prior to a 30-min period in which locomotor activity was assessed. Rats were trained on a fixed ratio 20 (FR20) schedule to discriminate IP saline from cocaine (10 mg/kg) injections. Cocaine alone (1-10 mg/kg) and with either A-77636 (0.56-1.7 mg/kg), SKF 82958 (0.01-0.1 mg/kg) or SKF 81297 (0.1-0.56) were injected IP 5 min prior to a 15-min test session.

RESULTS:

Cocaine maximally stimulated activity at 20-40 mg/kg with higher and lower doses stimulating activity less. Each D1-like agonist produced a dose-related decrease in cocaine-induced locomotor activity and lowered its maximal rate. Each of the D1-like agonists partially substituted for cocaine, with maximal substitution approximating 49, 35, and 24% for SKF 81297, SKF 82958, and A-77636, respectively. SKF 82958 significantly shifted the cocaine dose-effect curve approximately 3-fold to the left. With SKF 81297, there was a trend towards a leftward shift of cocaine dose effects, however the change was not statistically significant. In contrast to the other two D1-like agonists, A-77636 either did not affect the cocaine dose-effect curve or shifted it to the right.

CONCLUSIONS:

All three agonists produced similar effects on cocaine-induced locomotor activity, however the discriminative-stimulus effects of cocaine were affected differently by the D1 agonists. These results suggest fundamental differences in the actions of these D1 agonists. Because A-77636 consistently attenuated the present effects of cocaine, it may prove more useful than the others as a pharmacotherapy to treat cocaine abuse.

• Authors: Allison L Chausmer, Jonathan L Katz
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 159 Issue 2 Pg. 145-53 (Jan 2002) ISSN: 0033-3158 [Print] Germany
• PMID: 11862342 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Benzazepines
• Benzopyrans
• Dopamine Agonists
• Dopamine Uptake Inhibitors
• Receptors, Dopamine D1
• A 77636
• SK&F 81297
• SK&F 82958
• Cocaine
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Animals
• Benzazepines (pharmacology)
• Benzopyrans (pharmacology)
• Cocaine (pharmacology)
• Discrimination, Psychological (drug effects, physiology)
• Dopamine Agonists (pharmacology)
• Dopamine Uptake Inhibitors (pharmacology)
• Dose-Response Relationship, Drug
• Drug Interactions (physiology)
• Male
• Mice
• Motor Activity (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Dopamine D1 (agonists, physiology)