This article provides a basic introduction into two commonly used behavioral paradigms used for the assessment of the reinforcing and rewarding effects of drugs in experimental animals. Behavioral as well as neurochemical data regarding the neural basis of opiate reward are then critically reviewed in order to evaluate the neuroanatomical and neurochemical substrates mediating the primary and conditioned reinforcing effects of opiates as well as current hypotheses of drug-induced reward and aversion.
"Extensive evidence indicates that KOR agonists produce aversion and negative effect in rodents (Mucha and Herz, 1985; Carlezon Jr, et al, 2006; Land et al, 2009), and psychotomimetic and anxiogenic effects in humans (Pfeiffer et al, 1986). There is also compelling evidence that DA neurotransmission is regulated by KORs and that the aversive effects of KOR agonists are mediated via the suppression of DA in the NAc (Bals-Kubik et al, 1993b; Shippenberg et al, 1992; Spanagel et al, 1994; Shippenberg and Elmer, 1998). Thus, the KOR system exerts a tonic control on DA release and uptake in the NAc (Heijna et al, 1990; Spanagel et al, 1992; Thompson et al, 2000; Chefer et al, 2005), and this is consistent with the high expression of KORs observed in the region, including on DA axon terminals (Svingos et al, 2001). "
[Show abstract][Hide abstract] ABSTRACT: Kappa-opioid receptor (KOR) agonists have dysphoric properties in humans and are aversive in rodents. This has been attributed to the activation of KORs within the mesolimbic dopamine (DA) system. However, the role of DA in KOR-mediated aversion and stress remains divisive as recent studies have suggested that activation of KORs on serotonergic neurons may be sufficient to mediate aversive behaviors. To address this question, we used conditional knock-out (KO) mice with KORs deleted on DA neurons (DAT(Cre/wt)/KOR(loxp/loxp), or DATCre-KOR KO). In agreement with previous findings, control mice (DAT(Cre/wt)/KOR(wt/wt) or WT) showed conditioned place aversion (CPA) to the systemically administered KOR agonist U69,593. In contrast, DATCre-KOR KO mice did not exhibit CPA with this same agonist. In addition, in vivo microdialysis showed that systemic U69,593 decreased overflow of DA in the nucleus accumbens (NAc) in WT mice, but had no effect in DATCre-KOR KO mice. Intra- ventral tegmental area (VTA) delivery of KORs using an adeno-associated viral gene construct, resulted in phenotypic rescue of the KOR-mediated NAc DA response and aversive behavior in DATCre-KOR KO animals. These results provide evidence that KORs on VTA DA neurons are necessary to mediate KOR-mediated aversive behavior. Therefore, our data, along with recent findings, suggest that the neuronal mechanisms of KOR-mediated aversive behavior may include both dopaminergic and serotonergic components.Neuropsychopharmacology advance online publication, 7 August 2013; doi:10.1038/npp.2013.171.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2013; 38(13). DOI:10.1038/npp.2013.171 · 7.05 Impact Factor
"The CB 1 antagonist/inverse agonist rimonabant can block the development of morphine-induced conditioned place preference in rodents (Navarro et al., 2001; Singh et al., 2004). Although rimonabant does not block heroin-induced increases in extracellular dopamine levels in the nucleus accumbens shell (Tanda et al., 1997; Caillé and Parsons, 2003), it decreases heroin self-administration in rats, with more robust effects under progressive-ratio schedules than fixed-ratio 1 or fixed-ratio 5 schedules (Caillé and Parsons, 2003; De Vries et al., 2003; Solinas et al., 2003); these findings are consistent with findings that heroin self-administration is not dependent on accumbens dopamine (Shippenberg & Elmer, 1998). The reinforcing effects of heroin were enhanced by CB 1 agonists (THC, WIN 55,212-2) under a progressive-ratio schedule, but THC only altered heroin self-administration under a fixed-ratio one schedule when a three-fold higher dose of THC was given, which might have produced depressant effects when combined with heroin (Solinas et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: Enhancing the effects of endogenously-released cannabinoid ligands in the brain might provide therapeutic effects more safely and effectively than administering drugs that act directly at the cannabinoid receptor. Inhibitors of fatty acid amide hydrolase (FAAH) prevent the breakdown of endogenous ligands for cannabinoid receptors and peroxisome proliferator-activated receptors (PPAR), prolonging and enhancing the effects of these ligands when they are naturally released. This review considers recent research on the effects of FAAH inhibitors and PPAR activators in animal models of addiction and cognition (specifically learning and memory). These studies show that FAAH inhibitors can produce potentially therapeutic effects, some through cannabinoid receptors and some through PPAR. These effects include enhancing certain forms of learning, counteracting the rewarding effects of nicotine and alcohol, relieving symptoms of withdrawal from cannabis and other drugs, and protecting against relapse-like reinstatement of drug self-administration. Since FAAH inhibition might have a wide range of therapeutic actions but might also share some of the adverse effects of cannabis, it is noteworthy that at least one FAAH-inhibiting drug (URB597) has been found to have potentially beneficial effects but no indication of liability for abuse or dependence. Although these areas of research are new, the preliminary evidence indicates that they might lead to improved therapeutic interventions and a better understanding of the brain mechanisms underlying addiction and memory.
"In this context, it is generally accepted that systemic and local region-specific administration of MOPr, and to a lesser extent DOPr, agonists stimulate positive reinforcement , whereas KOPr agonists inhibits positive reinforcement and induces aversion and dysphoria. While there is compelling evidence that the aversive effects of KOPr are mediated via the suppression of DA release in the NAc (Shippenberg and Elmer, 1998; Van Ree et al., 2000), the role of DA in mediating the reinforcing effects of MOPr agonists is less clear. While MOPr and DOPr stimulation induce DA release in the striatum (Di-Chiara and Imperato, 1988; Fusa et al., 2005), at least in animal models, evidence (Robinson and Berridge, 1993; Daglish et al., 2008) suggests that DA may not be critical in mediating the 'high' from opioids in opioiddependent subjects but the 'drug wanting' instead (Daglish et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Cocaine addiction has become a major concern in the UK as Britain tops the European 'league table' for cocaine abuse. Despite its devastating health and socio-economic consequences, no effective pharmacotherapy for treating cocaine addiction is available. Identifying neurochemical changes induced by repeated drug exposure is critical not only for understanding the transition from recreational drug use towards compulsive drug abuse but also for the development of novel targets for the treatment of the disease and especially for relapse prevention. This article focuses on the effects of chronic cocaine exposure and withdrawal on each of the endogenous opioid peptides and receptors in rodent models. In addition, we review the studies that utilized opioid peptide or receptor knockout mice in order to identify and/or clarify the role of different components of the opioid system in cocaine-addictive behaviours and in cocaine-induced alterations of brain neurochemistry. The review of these studies indicates a region-specific activation of the µ-opioid receptor system following chronic cocaine exposure, which may contribute towards the rewarding effect of the drug and possibly towards cocaine craving during withdrawal followed by relapse. Cocaine also causes a region-specific activation of the κ-opioid receptor/dynorphin system, which may antagonize the rewarding effect of the drug, and at the same time, contribute to the stress-inducing properties of the drug and the triggering of relapse. These conclusions have important implications for the development of effective pharmacotherapy for the treatment of cocaine addiction and the prevention of relapse.
British Journal of Pharmacology 03/2012; 166(7):1993-2014. DOI:10.1111/j.1476-5381.2012.01952.x · 4.84 Impact Factor
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