Summary: ARCHIVAL REPORT
2 Adrenergic and Imidazoline Receptor Agonists
Prevent Cue-Induced Cocaine Seeking
Rachel J. Smith and Gary Aston-Jones
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 (I1) receptors, on relapse to cocaine seeking. To explore possible mechanisms of
clonidine's effects, we then tested more specific 2 or I1 agonists, postsynaptic adrenergic receptor ( 1 and ) antagonists, and corticotro-
pin-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 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 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 reinstate-
ment, as previously observed for stress-induced reinstatement, indicating possible overlap between stress and cue mechanisms.
Conclusions: These results indicate that 2 and I1 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 I1 agonist moxonidine seems to have substantial
potential for treating addictive disorders.