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) D 1 -like receptor full agonists may be potential pharmacotherapeutic agents for treating cocaine abuse. The structurally novel isochroman D 1 -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 D 1 -like dopamine agonists, SKF 82958 and SKF 81297. The alterations in the locomotor stimulant and discriminativestimulus effects of cocaine by the full D 1 -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 D 1 -like agonist produced a dose-related decrease in cocaine-induced locomotor activity and lowered its maximal rate. Each of the D 1 -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 D 1 -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 D 1 agonists. These results suggest fundamental differences in the actions of these D 1 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.

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

“…As dopamine released from the substantia nigra is critical for motor behaviors and striatally driven behaviors (Andersson et al, 2006), it may be difficult to completely dissociate motoric components of dopamine neurotransmission and D1/5 receptor activation from expression of the motor behaviors associated with aversive and reward learning (Chausmer and Katz, 2002;Diaz Heijtz and Castellanos, 2006). It is possible that even a subtle effect of D1/5 activation on locomotion could influence the effects on behavior.…”

Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal

“…All doses of drugs are expressed as milligram of free base per kilogram of body weight. Doses and time of injections were selected based on previous studies (19,20,28,(41)(42)(43)(44).…”

Behavioral responses during the initial exposures to a low dose of cocaine in late preweanling and adult rats

“…Considering the trends in human drug use patterns, it is important to use preclinical models to understand how drugs affect children in this target age group relative to older adolescents and adults. Furthermore, late childhood is when the use of psychoactive drugs, which can exert long-term consequences on the developing organism [4,15,61], frequently begins.…”

“…We examined the responsiveness to a relatively modest dose (10 mg/kg) because this dose is sufficient to stimulate locomotor activity in both preweanlings and adults [15,41,43,74] but avoids stereotypy and physiological pathologies [70,74]. This dose is reported to be the lowest effective dose with hedonic properties in both adult and postnatal day 35 (p35) adolescent rats [12].…”