(2) Adrenergic and imidazoline receptor agonists prevent cue-induced cocaine seeking.
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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 (2) 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 (2) and imidazoline-1 (I(1)) receptors, on relapse to cocaine seeking. To explore possible mechanisms of clonidine's effects, we then tested more specific (2) or I(1) agonists, postsynaptic adrenergic receptor ((1) and ) antagonists, and corticotropin-releasing factor receptor-1 antagonists. RESULTS: We found that clonidine, and the more selective (2) agonists UK-14,304 and guanfacine, decreased cue-induced reinstatement of cocaine seeking. The specific I(1) 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 (2) receptor antagonist RS-79948, indicating a role for (2) receptors. Prazosin and propranolol, antagonists at the (1) and 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 (2) and I(1) receptor agonists are novel therapeutic options for prevention of cue-induced cocaine relapse. Given that (2) receptor stimulation is associated with sedation in humans, the I(1) agonist moxonidine seems to have substantial potential for treating addictive disorders.
author list (cited authors)
Smith, R. J., & Aston-Jones, G.
complete list of authors
Smith, Rachel J||Aston-Jones, Gary