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

Abstract

Using a reinstatement procedure, it has been shown that intermittent footshock stress reliably reinstates extinguished drug-taking behaviour in rats. Here we studied the role of noradrenaline (NE), one of the main brain neurotransmitters involved in responses to stress, in reinstatement of heroin seeking. We first determined the effect of clonidine, an alpha-2 adrenergic receptor agonist that decreases NE cell firing and release, on stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin (0.1 mg/kg per infusion, IV, three 3-h sessions per day) for 9-10 days. Extinction sessions were given for up to 11 days during which saline was substituted for the drug. Tests for reinstatement were then conducted after exposure to intermittent footshock (5, 15 and 30 min, 0.5 mA). During testing, clonidine was injected systemically (10-40 microgram/kg, i.p.) or directly into the lateral or fourth ventricles (1-3 microram). Clonidine (1-2 microgram per site) or its charged analogue, 2-[2, 6-diethylphenylamino]-2-imidazole (ST-91, 0.5-1 microgram per site), was also injected bilaterally into the locus coeruleus (LC), the main noradrenergic cell group in the brain. Clonidine blocked stress-induced reinstatement of drug seeking when injected systemically or into the cerebral ventricles. In contrast, neither clonidine nor ST-91 consistently altered stress-induced reinstatement when injected into the locus coeruleus. We therefore studied the effect of lesions of the lateral tegmental NE neurons on stress-induced reinstatement. 6-Hydroxydopamine (6-OHDA) lesions performed after training for heroin self-administration had no effect on extinction of heroin-taking behaviour, but significantly attenuated reinstatement 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 reinstatement of heroin seeking.

The Anxiogenic Drug Yohimbine Reinstates Palatable Food Seeking in a Rat Relapse Model: a Role of CRF1 Receptors

“…Yohimbine increases central release of noradrenaline, which previous studies have shown to play a critical role in footshock stress-induced reinstatement of drug seeking (Erb et al, 2000;Shaham et al, 2000b;Leri et al, 2002). Thus, we interpret the present data to indicate that brain noradrenaline is involved in yohimbine-induced reinstatement of palatable food seeking.…”

“…In this brain area, antagonism of either CRF receptors or b adrenoceptors attenuates footshock-stressinduced reinstatement of cocaine seeking (Erb and Stewart, 1999;Erb et al, 2001;Leri et al, 2002). In addition, 6-OHDA lesions of the main input to the BNST, the ventral noradrenergic bundle originating from the lateral tegmental noradrenergic nuclei (Aston-Jones et al, 1999), attenuate footshock-stress-induced reinstatement of heroin seeking (Shaham et al, 2000b); see also Wang et al (2001) for a similar finding using a morphine conditioned place preference model. Another potential brain site is the ventral tegmental area (VTA).…”

Involvement of Arginine Vasopressin and V1b Receptor in Heroin Withdrawal and Heroin Seeking Precipitated by Stress and by Heroin

“…Exposure to foot shock, for example, increases NA release in these regions (Quirarte et al, 1998;Hatfield et al, 1999;Erb et al, 2000). Also, partial 6-hydroxydopamine lesions of the ventral NA bundle projecting to the amygdala attenuate foot shock-induced reinstatement of heroin seeking (Shaham et al, 2000b), and blockade of beta-NA receptors within the central amygdala block the stress-induced reinstatement (Leri et al, 2002). In the present studies, we found that the AVP mRNA levels were enhanced by foot shock in the amygdala of rats withdrawn from heroin self-administration but not in the amygdala of the heroin naïve rats.…”

Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats

“…Vehicle (0.5 μl/side) or SB-277011A (1.5 μg/0.5 μl per side) was manually injected over a 1-min period into the brain 2 mm below the guide cannula tip via an internal injection needle. After drug administration, rats were returned to the testing chambers immediately and, after a delay of 60 or 30 min (depending on whether SB-277011A was given systemically or intracranially, see above), were exposed to 10 min of intermittent footshock stress (0.5 mA; 0.5 s on; mean off period of 40 s) (Shaham et al 2000b), delivered by a computer-controlled system. Following termination of footshock, reinstatement testing began with onset of the house light and introduction of the active and inactive levers.…”