Elsevier

Biological Psychiatry

Volume 70, Issue 8, 15 October 2011, Pages 712-719
Biological Psychiatry

Archival Report
α2 Adrenergic and Imidazoline Receptor Agonists Prevent Cue-Induced Cocaine Seeking

https://doi.org/10.1016/j.biopsych.2011.06.010Get rights and content

Background

Drug-associated cues can elicit stress-like responses in addicted individuals, indicating that cue- and stress-induced drug relapse may share some neural mechanisms. It is unknown whether α2 adrenergic receptor agonists, which are known to attenuate stress-induced reinstatement of drug seeking in rats, also reduce cue-induced reinstatement.

Methods

Rats were tested for reinstatement of drug seeking following cocaine self-administration and extinction. We first evaluated the effects of clonidine, an agonist at α2 and imidazoline-1 (I1) receptors, on relapse to cocaine seeking. To explore possible mechanisms of clonidine's effects, we then tested more specific α2 or I1 agonists, postsynaptic adrenergic receptor1 and β) antagonists, and corticotropin-releasing factor receptor-1 antagonists.

Results

We found that clonidine, and the more selective α2 agonists UK-14,304 and guanfacine, decreased cue-induced reinstatement of cocaine seeking. The specific I1 receptor agonist moxonidine reduced cue-induced as well as cocaine-induced reinstatement. Clonidine or moxonidine effects on cue-induced reinstatement were reversed by the selective α2 receptor antagonist RS-79948, indicating a role for α2 receptors. Prazosin and propranolol, antagonists at the α1 and β receptor, respectively, reduced cue-induced reinstatement only when administered in combination. Finally, the corticotropin-releasing factor receptor-1 antagonist CP-154,526 reduced cue-induced reinstatement, as previously observed for stress-induced reinstatement, indicating possible overlap between stress and cue mechanisms.

Conclusions

These results indicate that α2 and I1 receptor agonists are novel therapeutic options for prevention of cue-induced cocaine relapse. Given that α2 receptor stimulation is associated with sedation in humans, the I1 agonist moxonidine seems to have substantial potential for treating addictive disorders.

Section snippets

Animals

Male Sprague Dawley rats (initial weight 250–300 g; Charles River, Raleigh, North Carolina) were single- or pair-housed in a temperature- and humidity-controlled animal facility at the Medical University of South Carolina accredited by the Association for Assessment and Accreditation of Laboratory Animal Care. Rats were housed under a reversed 12-hour light/dark cycle (lights off at 6:00 am), with ad libitum food and water (except for food self-administration study, described below). All

Results

For all rats undergoing cocaine self-administration (n = 189), the means (± SEM) for the last 2 days of self-administration were 38.5 (±.9) and 39.6 (±1.0) infusions (approximately 20 mg/kg per day) and 54.7 (±3.7) and 53.6 (±3.2) active lever presses. The mean (± SEM) active lever presses for days 1 and 7 of extinction were 84.3 (±3.2) and 18.2 (±.8), respectively, for animals that received no treatment on extinction days. Unless noted, there were no significant differences for responding on

Discussion

Our results indicate that the I1 receptor-preferring agonist moxonidine is a potential therapeutic option for maintaining cocaine abstinence. Moxonidine reduced cocaine seeking triggered by either drug-associated cues or cocaine prime without signs of sedation. These reinstatement findings highlight the potential functional importance of the relatively unknown imidazoline signaling system in drug addiction. In addition, the current studies revealed that α2 adrenergic receptor agonists and CRF

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