The neurobiology of opiate reinforcement.
ABSTRACT 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.
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ABSTRACT: Novel stimuli paired with exposure to addictive drugs can elicit approach through Pavlovian learning. While such approach behavior, or sign tracking, has been documented for cocaine and alcohol, it has not been shown to occur with opiate drugs like heroin. Most Pavlovian conditioned approach paradigms use an operandum as the sign, so that sign tracking can be easily automated. We were interested in assessing whether approach behavior occurs to an audiovisual cue paired with an intravenous heroin infusion. If so, would this behavior exhibit characteristics of other Pavlovian conditioned behaviors, such as extinction and spontaneous recovery? Rats were repeatedly exposed to an audiovisual cue, similar to that used in standard self-administration models, along with an intravenous heroin infusion. Sign tracking was measured in an automated fashion by analyzing motion pixels within the cue zone during each cue presentation. We were able to observe significant sign tracking after only five pairings of the conditioned stimulus (CS) with the unconditioned stimulus (US). This behavior rapidly extinguished over 2 days, but exhibited pronounced spontaneous recovery 3 weeks later. We conclude that sign tracking measured by these methods exhibits all the characteristics of a classically conditioned behavior. This model can be used to examine the Pavlovian component of drug memories, alone, or in combination with self-administration methods.Psychopharmacology 09/2013; 231(2). DOI:10.1007/s00213-013-3258-7 · 3.99 Impact Factor
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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 · 7.83 Impact Factor
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ABSTRACT: Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8-[(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione] were found previously to either decrease or increase self-administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 [2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose-response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results show that selectively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of THC.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2014; 34(19):6480-4. DOI:10.1523/JNEUROSCI.5073-13.2014 · 6.75 Impact Factor