The alpha -2 adrenergic receptor agonists, clonidine, lofexidine and guanabenz, blocked stress-but not cocaineinduced reinstatement of cocaine seeking at doses that suppressed footshock-induced release of noradrenaline in prefrontal cortex and amygdala. Rats were trained to selfadminister cocaine (0.5 mg/kg/infusion, i.v; 10-12 days) and, after a drug-free period (7-13 days), were returned to the selfadministration chambers for daily extinction and reinstatement test sessions. Both intermittent footshock (15 min, 0.6 mA) and cocaine priming (20 mg/kg, i.p.) reinstated extinguished drug seeking. Pretreatment with eitherclonidine (20, or 40 g/kg, i.p.) or lofexidine (50, 100, 150, or 200 g/kg, i.p.) (e.g. Jaffe 1985) and reinstate drug-seeking in monkeys and rats with a history of drug self-administration (e.g., Stretch and Gerber 1973;de Wit and Stewart 1981). Another factor thought to be important to relapse in humans is stress (Kreek and Koob 1998). In a recent laboratory study, Sinha and colleagues (1999) found that induction of psychological stress provoked craving for drug in cocaine addicts. Using an animal model of stress-induced relapse, we and others have found in rats that exposure to brief intermittent footshock stress reliably reinstates heroin seeking (Shaham and Stewart 1995), cocaine seeking (Erb et al. 1996;Ahmed and Koob 1997;Mantsch and Goeders 1999), nicotine seeking (Buczek et al. 1999), and alcohol seeking (Lê et al. 1998).In a search for neurotransmitter systems involved in stress-induced relapse, and for pharmacological manipulations that might prevent it, we explored in the present set of experiments the role of the noradrenergic (NE) system, comprised of a dorsal stream of neurons originating in the locus-coeruleus and a ventral stream of neurons originating in the lateral tegmental nuclei (Aston-Jones et al. 1995;Moore and Bloom 1979). Although the stress-related functions of the ventral projections have been only partially characterized (Cole and Robbins 1987;Hansen et al. 1980), NE projections from the LC have been directly implicated in a number From the Center for Studies in Behavioral Neurobiology (SE, PKH, HR, DM, JS), Department of Psychology, Concordia University, Montreal, Quebec, Canada; Behavioral Neuroscience Department(YS), IRP/NIDA, Baltimore, MD.Address correspondence to: Dr. Jane Stewart, Center for Studies in Behavioral Neurobiology, Department of Psychology, 1455 de Maisonneuve Blvd. W., Montreal, Quebec, Canada H3G 1M8 Tel: 514-848-2193, Fax: 514-848-2817, E-mail: Stewart@CSBN.concordia.ca. Received September 20, 1999 revised December 21, 1999; accepted December 28, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 2 alpha -2 Agonists and Relapse to Cocaine Seeking 139 of stress-related responses. For example, electrical stimulation of the LC has been found to induce anxiety and to result in activation of the autonomic nervous system, whereas local injections of the alpha-2 adrenergic receptor agonist clonidine, which acts to inhibit NE cell fi...

Instrumental actions are a vital cognitive asset that endows an organism with sensitivity to the consequences of its behavior. Response-outcome feedback allows responding to be shaped in order to maximize beneficial, and minimize detrimental, outcomes. Lesions of the medial prefrontal cortex (mPFC) result in behavior that is insensitive to changes in outcome value in animals and compulsive behavior in several human psychopathologies. Such insensitivity to changes in outcome value is a defining characteristic of instrumental habits: responses that are controlled by antecedent stimuli rather than goal expectancy. Little is known regarding the neurochemical substrates mediating this sensitivity. The present experiments used sensitivity to posttraining outcome devaluation to index the action-habit status of instrumental responding. Infusions of dopamine into the ventral mPFC (vmPFC), but not dorsal mPFC, restored outcome sensitivity bidirectionally-decreasing responding following outcome devaluation and increasing responding when the outcome was not devalued. This bidirectionality makes the possibility that these infusions nonspecifically dysregulated vmPFC dopamine transmission unlikely. VmPFC dopamine promoted instrumental responding appropriate to outcome value. Reinforcer consumption data indicated that this was not a consequence of altered sensitivity to the reinforcer itself. We suggest that vmPFC dopamine reengages attentional processes underlying goal-directed behavior.

Sex differences in brain function and behavior are regularly attributed to gonadal hormones. Some brain sexual dimorphisms, however, are direct actions of sex chromosome genes that are not mediated by gonadal hormones. We used mice in which sex chromosome complement (XX versus XY) and gonadal sex (ovaries versus testes) were independent, and found that XX mice showed faster food-reinforced instrumental habit formation than XY mice, regardless of gonadal phenotype.

In the elevated plus-maze test of anxiety the scores of control animals remain stable over repeated tests. However, a single prior exposure to the plus-maze renders an animal insensitive to the anxiolytic effects of chlordiazepoxide. This phenomenon of "one-trial tolerance" persisted even when the two trials were separated by as much as 2 weeks. It has previously been shown that the drug state of the animal on trial 1 is not important to the development of the phenomenon, but one-trial tolerance did not develop if a very high dose (75 mg/kg) of chlordiazepoxide was given on trial 1; it is suggested that this is due to the amnesic effects of the drug. The learning on trial 1 was not specific to a particular plus-maze and tolerance could be observed even when the maze on trial 1 was made from different material. The crucial experience on trial 1 was experience of an open arm of the maze. Whereas tolerance could be obtained as a result of a previous plus-maze experience, there was no evidence of an anxiogenic withdrawal response when rats were tested the following day undrugged. The phenomenon of one-trial tolerance is explained within our recently proposed two-factor theory of benzodiazepine dependence; it is suggested that one-trial tolerance provides a method for studying the mechanism underlying the development of tolerance to anxiolytic effects, independently from the mechanism underlying the development of withdrawal responses.