Clonidine blocks stress-induced reinstatement of heroin seeking in rats: an effect independent of locus coeruleus noradrenergic neurons

Using a reinstatement procedure, it has been shown that intermittent footsh ock stress reliably reinstates extinguished drug-taking behaviour in rats. Here we studied the role of noradrenaline (NE), one of the main brain neuro transmitters involved in responses to stress, in reinstatement of heroin se eking. We first determined the effect of clonidine, an alpha-2 adrenergic r eceptor agonist that decreases NE cell firing and release, on stress-induce d reinstatement of heroin seeking. Rats were trained to self-administer her oin (0.1 mg/kg per infusion, IV, three 3-h sessions per day) for 9-10 days. Extinction sessions were given for up to II days during which saline was s ubstituted for the drug. Tests for reinstatement were then conducted after exposure to intermittent footshock (5, 15 and 30 min, 0.5 mA). During testi ng, clonidine was injected systemically (10-40 mu g/kg, i.p.) or directly i nto the lateral or fourth ventricles (1-3 mu g) Clonidine (1-2 mu g per sit e) or its charged analogue, 2-[2,6-diethylphenylamino]-2-imidazole (ST-91, 0.5-1 mu g per site), was also injected bilaterally into the locus coeruleu s (LC), the main noradrenergic cell group in the brain. Clonidine blocked s tress-induced reinstatement of drug seeking when injected systemically or i nto the cerebral ventricles. In contrast, neither clonidine nor ST-91 consi stently altered stress-induced reinstatement when injected into the locus c oeruleus. We therefore studied the effect of lesions of the lateral tegment al NE neurons on stress-induced reinstatement. 6-Hydroxydopamine (6-OHDA) l esions performed after training for heroin self-administration had no effec t on extinction of heroin-taking behaviour, but significantly attenuated re instatement induced by intermittent footshock. These data suggest that: (i) clonidine prevents stress-induced relapse to heroin seeking by its action on neurons other than those of the locus coeruleus; and (ii) activation of the lateral tegmental NE neurons contributes to stress-induced reinstatemen t of heroin seeking.