Hypocretin-1 and -2 (Hcrt-1 and Hcrt-2), also referred to as orexin-A and -B, are neuropeptides synthesized by a few thousand neurons in the lateral hypothalamus. Hypocretin-containing neurons project throughout the brain, with a prominent input to basal forebrain structures involved in motivation, reward, and stress. However, the role of hypocretins in addiction-related behaviors remains largely unexplored. Here we show that intracerebroventricular infusions of Hcrt-1 lead to a dose-related reinstatement of cocaine seeking without altering cocaine intake in rats. Hcrt-1 also dramatically elevates intracranial self-stimulation thresholds, indicating that, unlike treatments with reinforcing properties such as cocaine, Hcrt-1 negatively regulates the activity of brain reward circuitries. Hypocretin-induced reinstatement of cocaine seeking was prevented by blockade of noradrenergic and corticotropinreleasing factor systems, suggesting that Hcrt-1 reinstated drug seeking through induction of a stress-like state. Consistent with this interpretation, the selective Hcrt-1 receptor antagonist SB-334867 blocked footshock-induced reinstatement of previously extinguished cocaine-seeking behavior. These findings reveal a previously unidentified role for hypocretins in driving drug seeking through activation of stress pathways in the brain.D rug addiction is characterized by relapse to drug-taking behavior during periods of abstinence. Identification of brain mechanisms responsible for vulnerability to relapse is crucial for the development of effective treatments for drug addiction (1). Hypocretin-1 and -2 (Hcrt-1 and Hcrt-2), recently discovered lateral hypothalamic (LH) neuropeptides (2, 3), regulate a wide variety of physiological processes such as feeding, energy metabolism (4), and the maintenance of arousal (5, 6). Compelling evidence also indicates that Hcrt neurons in the LH receive inputs from diverse sensory and limbic systems and drive hyperarousal through modulation of stress responses (7,8) and adaptive behavior associated with energy metabolism (9). Mutant mice deficient in Hcrt fail to respond to fasting with increased activity and wakefulness (10) and display diminished signs of precipitated opiate withdrawal (11). Further, leptin, which hyperpolarizes Hcrt neurons in mice (10), attenuates fasting-induced heroin-seeking behavior in rats (12). These observations suggest a role for LH Hcrt neurons in reward seeking (13)(14)(15). Consistent with this hypothesis, c-Fos activation of LH Hcrt neurons was recently correlated with preference, in rats, for an environment repeatedly paired with food and drug rewards (16). Importantly, however, the mechanisms by which Hcrt systems may reinstate drug-seeking behaviors remain largely unexplored. Here, we show that the Hcrt-1 peptide reinstates previously extinguished cocaine-seeking behavior and induces a long-lasting brain reward deficit. Further, we demonstrate that antagonism of Hcrt-1 receptors prevents footshockinduced reinstatement of cocaine-seeking behavior in ra...

Metabotropic glutamate receptors (mGluRs) have been implicated in regulating anxiety, stress responses, and the neurobehavioral effects of psychostimulants. The present study sought to determine whether group II mGluR activation by the potent mGlu2/3 receptor agonist, (Ϫ)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), antagonizes reinstatement of cocaine-seeking induced by cocaine-related stimuli and whether this effect extends to behavior induced by stimuli conditioned to a potent conventional reinforcer, sweetened condensed milk (SCM). Also, we tested whether the suppressant effects of LY379268 on conditioned reinstatement extend to the primary reinforcing effects of cocaine or SCM. Rats were trained to associate discriminative stimuli (S D ) with the availability of cocaine or SCM versus non-reward and then subjected to repeated extinction sessions during which the respective reinforcers and S D were withheld. Subsequent reexposure to the cocaine or SCM S D , but not the non-reward S D , produced recovery of responding at the previously active lever. LY379268 (0.3-3.0 mg/kg, s.c.) dose-dependently attenuated recovery of cocaine seeking but reduced conditioned reinstatement by the SCM S D only at the highest dose. LY379268 did not alter responding reinforced directly by SCM, and only the highest LY379268 dose reduced cocaine self-administration. The results suggest that the effects of LY379268 are selective for behavior maintained by cocaine as opposed to palatable conventional reinforcers. More importantly, the results show that LY379268 suppresses behavior motivated by stimuli conditioned to cocaine or SCM more effectively than consummatory behavior maintained by the unconditioned effects of these substances. As such, the results identify group II mGluRs as a pharmacotherapeutic target for craving and relapse prevention associated with cocaine cue exposure.

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Major precipitating factors for relapse to drug use are stress and exposure to drug-related environmental stimuli. Group II (mGlu 2/3 ) metabotropic glutamate receptors (mGluRs) are densely expressed within circuitries mediating the motivating effects of stress and drug cues and, therefore, may participate in regulating drug-seeking linked to both of these risk factors. Thus, we tested the hypothesis that pharmacological activation of group II mGluRs modifies both stress-and cue-induced ethanol-seeking, using reinstatement models of relapse. In parallel, brain c-fos expression was examined to identify neural substrates for the behavioral effects of group II mGluR activation. The selective mGlu 2/3 agonist LY379268 (1R,4R,5S,6R-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate) (0.3, 1.0, and 3.0 mg/kg, s.c.) dose dependently blocked the recovery of extinguished ethanol-seeking induced by either footshock stress or ethanolassociated discriminative stimuli. These effects were accompanied by modulation of c-fos expression in the hippocampus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and medial parvocellular paraventricular nucleus of the hypothalamus. The results implicate group II mGluRs as a shared neuropharmacological substrate for ethanol-seeking elicited by both drug cues and stress and identify group II mGluRs as promising treatment targets for relapse prevention.

This study examined whether nociceptin/orphanin FQ (NC), the endogenous ligand of the opioid receptor-like1 (ORL1) receptor, can block drug-seeking behavior induced by foot-shock stress. Male Wistar rats were trained to operantly self-administer ethanol or cocaine, and then subjected to daily extinction training until responding ceased. Subsequent exposure to 15 min of intermittent footshock elicited robust reinstatement of responding at the previously drug-paired lever. NC (0.1-2.0 microg; i.c.v.) significantly inhibited the effects of footshock stress on ethanol- but not cocaine-seeking behavior. The results support the hypothesis that the NC system participates in the regulation of behavioral responses to stress, and that drugs interacting with NC receptors may have therapeutic potential for the treatment of stress-induced alcohol-seeking behavior and relapse.

The involvement of the sigma 1 receptor on the rewarding effects of cocaine was examined using the conditioned place preference (CPP) procedure in C57BL/6 mice. Acquisition or expression of cocaine (20 mg/kg i.p.)-induced CPP was significantly decreased by pre-treatment with the selective sigma 1 receptor antagonists N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) or N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047), 1-10 mg/kg, i.p. The sigma 1 receptor agonists igmesine or 2-(4-morpholinoethyl-1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084) failed to induce CPP when injected alone. Moreover, the CPP induced by N-[1-(2-benzo(b)Cocaine is a highly addictive substance that is abused by humans worldwide (Warner 1993;Higgins 1997). Cocaine also acts as a potent reinforcer in laboratory animals (Pickens and Thompson 1968;Koob 1992;Stolerman 1992;Woolverton and Johnson 1992). While cocaine inhibits the transport of serotonin (5-HT), norepinephrine and dopamine (DA), it is widely accepted that the ad- NO . 4 Sigma 1 Receptor and Cocaine 445 dictive and reinforcing actions of cocaine are dependent on the drug's ability to block the dopamine transporter (DAT), thereby increasing dopamine (DA) neurotransmission (Kuhar 1992;Ritz et al. 1987;Parsons et al. 1998;Woolverton 1992). Because of the link between cocaine's addictive liability and the DA reward/reinforcement circuitry of the forebrain (Koob 1992), treatment strategies against cocaine abuse have logically targeted the DA system. However, it has been described that cocaine also interacts with the sigma 1 receptor at a similar dose range as observed for the DAT and that the sigma 1 receptor is implicated in some of cocaine's effects such as locomotor activation, sensitization, convulsion and lethality (Koe 1976;Reith et al. 1986;Menkel et al. 1991;Ujike et al. 1992;Ritz and George 1993). Therefore, the diverse pharmacological profile of cocaine may contribute to, or modulate, its behavioral effects through a complex mechanism of action affecting the different monoaminergic transporters as well as other targets. Consistent with this hypothesis is the study by Sora et al. (2000) demonstrating that it is possible to establish cocaineinduced place preference in DA or 5-HT transporter knockout mice, leading to the hypothesis that other targets might be involved in producing the rewarding effects of cocaine. An alternative therapeutic approach to treating cocaine addiction, therefore, would be to target the sigma 1 receptor, which has recently been demonstrated to be involved in cocaine's rewarding effects measured using a conditioned place preference (CPP) paradigm in mice (Romieu et al. 2000). The sigma 1 receptor, localized intracellularly within the neurons, is a 223 amino acid protein, cloned in several animal species and humans (Hanner et al. 1996;Kekuda et al. 1996;Seth et al. 1997Seth et al. , 1998Pan et al. 1998). The receptor appeared devoid of analogy with any other known mammalian protein and its ...

Background-Growing evidence supports a role of metabotropic glutamate receptors (mGluRs) in ethanol reinforcement, ethanol-seeking, and ethanol withdrawal. To extend the understanding of the role of mGluRs in the addiction-relevant effects of ethanol as well as of the treatment target potential of these receptors for alcohol abuse, the effects of a selective mGlu2/3 agonist (LY379268) and a selective mGlu5 antagonist (MTEP) were tested on two processes central to alcohol addiction: ethanol reinforcement and stress-induced reinstatement of ethanol-seeking in rats with a history of ethanol dependence.