Emotional learning is necessary for individuals to survive and prosper. Once acquired, however, emotional associations are not always expressed. Indeed, the regulation of emotional expression under varying environmental conditions is essential for mental health. The simplest form of emotional regulation is extinction, in which conditioned responding to a stimulus decreases when the reinforcer is omitted. Two decades of research on the neural mechanisms of fear conditioning have laid the groundwork for understanding extinction. In this review, we summarize recent work on the neural mechanisms of extinction learning. Like other forms of learning, extinction occurs in three phases: acquisition, consolidation, and retrieval, each of which depends on specific structures (amygdala, prefrontal cortex, hippocampus) and molecular mechanisms (receptors and signaling pathways). Pharmacological methods to facilitate consolidation and retrieval of extinction, for both aversive and appetitive conditioning, are setting the stage for novel treatments for anxiety disorders and addictions.

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Emotional arousal strengthens memory. This is most apparent in aversive conditioning, in which the stress-related neurotransmitter norepinephrine (NE) enhances associations between sensory stimuli and fear-inducing events. In contrast to conditioning, extinction decreases fear responses, and is thought to form a new memory. It is not known, however, whether NE is necessary for extinction learning. Previous work has shown that the infralimbic prefrontal cortex (IL) is a site of extinction consolidation. Here, we show that blocking noradrenergic ␤-receptors in IL before extinction training impaired retrieval of extinction the following day, consistent with a weakened extinction memory. We further found that the sequelae of ␤-receptor activation, including protein kinase A (PKA), gene transcription and translation in IL, are necessary for extinction. To determine whether activation of this cascade modulates IL excitability, we measured the response of IL pyramidal neurons to injected current. NE increased the excitability of IL neurons in a ␤-receptor-and PKA-dependent manner. We suggest that NE released in IL during fear extinction activates a PKA-mediated molecular cascade that strengthens extinction memory. Thus, emotional arousal evoked by conditioned fear paradoxically promotes the subsequent extinction of that fear, thereby ensuring behavioral flexibility.

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...

Background Fear extinction is dependent on plasticity in the infralimbic prefrontal cortex (IL), an area heavily innervated by midbrain dopaminergic inputs. Dopamine D2 receptors are concentrated in infralimbic output neurons that are involved in the suppression of conditioned fear after extinction. Here we examined the specific role of the D2 receptor in mediating associative learning underlying fear extinction, using the selective D2 antagonist raclopride. Methods Raclopride was administered systemically or infused into IL prior to fear extinction, and extinction retention was tested the following day. Rats were also prepared for single unit recording in IL to assess the effect of raclopride on firing properties. Results We found that systemic injection of raclopride given prior to extinction impaired retrieval of extinction when tested drug free the next day, but also induced catalepsy during extinction training. To determine whether impaired extinction was due to impaired motor function or disruption of extinction consolidation, we infused raclopride directly into IL. Raclopride infused immediately before extinction training did not produce motor deficits, but impaired recall of extinction when tested drug free. Furthermore, in animals that underwent extinction training, systemic raclopride reduced the tone responsiveness of IL neurons in layers 5/6, with no changes in average firing rate. Conclusion We suggest that D2 receptors facilitate extinction by increasing the signal-to-noise of IL neurons that consolidate extinction.