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Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated [...]

Decision-making depends on the ability to extract predictive information from the environment to guide future actions. Outcomespecific Pavlovian-instrumental transfer (PIT) provides an animal model of this process in which a stimulus predicting a particular outcome biases choice toward actions earning that outcome. Recent evidence suggests that cellular adaptations of opioid receptors (DORs) on cholinergic interneurons (CINs) in the nucleus accumbens shell (NAc-S) are necessary for PIT. Here we found that modulation of DORsinCINscriticallyinfluencesD1-receptor(D1R)-expressingprojectionneuronsintheNAc-StopromotePIT.First, we assessed PIT-induced changes in signaling processes in dopamineD1- andD2-receptor-expressing neurons using drd2-eGFP mice, and found that PIT-related signaling was restricted to non-D2R-eGFP-expressing neurons, suggesting major involvement of D1R-neurons. Next we confirmed the role of D1Rs pharmacologically: theD1Rantagonist SCH-23390, but not theD2Rantagonist raclopride, infused into theNAc-Sabolished PIT in rats, an effect that depended on DOR activity. Moreover, asymmetrical infusion of SCH-23390 and the DOR antagonist naltrindole into the NAc-S also abolishedPIT. DORagonistswerefoundto sensitizethefiringresponsesofCINsinbrainslicespreparedimmediatelyafterthePITtest. We confirmed the opioid-acetylcholinergic influence over D1R-neurons by selectively blocking muscarinic M4 receptors in the NAc-S, which tightly regulate the activity of D1Rs, a treatment that rescued the deficit in PIT induced by naltrindole. We describe a model of NAc-S function in which DORs modulate CINs to influence both D1R-neurons and stimulus-guided choice between goal-directed actions. [ABSTRACT FROM AUTHOR]

The ability of animals to extract predictive information from the environment to inform their future actions is a critical component of decision-making. This phenomenon is studied in the laboratory using the pavlovian-instrumental transfer protocol in which a stimulus predicting a specific pavlovian outcome biases choice toward those actions earning the predicted outcome. It is well established that this transfer effect is mediated by corticolimbic afferents on the nucleus accumbens shell (NAc-S), and recent evidence suggests that S-opioid receptors (DORs) play an essential role in this effect. In DOR-eGFP knock-in mice, we show a persistent, learning-related plasticity in the translocation of DORs to the somatic plasma membrane of cholinergic interneurons (CINs) in the NAc-S during the encoding of the specific stimulus- outcome associations essential for pavlovian-instrumental transfer. We found that increased membrane DOR expres-sion reflected both stimulus-based predictions of reward and the degree to which these stimuli biased choice during the pavlovian-instrumental transfer test. Furthermore, this plasticity altered the firing pattern of CINs increasing the variance of action potential activity, an effect that was exaggerated by DOR stimulation. The relationship between the induction of membrane DOR expression in CINs and both pavlovian conditioning and pavlovian-instrumental transfer provides ahighly specific function for DOR-related modulation in the NAc-S, and it is consistent with an emerging role for striatal CIN activity in the processing of predictive information. Therefore, our results reveal evidence of along-term, experience-dependent plasticity in opioid receptor expression on striatal modulatory interneurons critical for the cognitive control of action. [ABSTRACT FROM AUTHOR]

A single exposure to psychostimulants or morphine is sufficient to induce persistent locomotor sensitization, as well as neurochemical and electrophysiological changes in rodents. Although it provides a unique model to study the bases of long-term behavioral plasticity, sensitization mechanisms remain poorly understood. We investigated in the mouse, a species suited for transgenic studies, the mechanisms of locomotor sensitization showed by the increased response to a second injection of drug (two-injection protocol of sensitization, TIPS). The first cocaine injection induced a locomotor sensitization that was completely context-dependent, increased during the first week, and persisted 3 months later. The induction of sensitized responses to cocaine required dopamine D1 and glutamate NMDA receptors. A single injection of the selective dopamine transporter blocker GBR12783 was sufficient to activate extracellular signal-regulated kinase (ERK) in the striatum to the same level as cocaine and to induce sensitization to cocaine, but not to itself. The induction of sensitization was sensitive to protein synthesis inhibition by anisomycin after cocaine administration. Morphine induced a pronounced context-dependent sensitization that crossed with cocaine. Sensitization to morphine injection was prevented in knockin mutant mice bearing a Thr-34-Ala mutation of DARPP-32, which suppresses its ability to inhibit protein phosphatase-1 (PP1), but not mutation of Thr-75 or Ser-130. These results combined with previous ones show that TIPS in mouse is a context-dependent response, which involves an increase in extracellular dopamine, stimulation of D1 and NMDA receptors, regulation of the cAMP-dependent and ERK pathways, inhibition of PP1, and protein synthesis. It provides a simple and sensitive paradigm to study the mechanisms of long-term effects of drugs of abuse. [ABSTRACT FROM AUTHOR]

Psychostimulants and other drugs of abuse activate extracellular signal-regulated kinase (ERK) in the striatum, through combined stimulation of dopamine D1 receptors (D1Rs) and glutamate NMDA receptors. Antipsychotic drugs activate similar signaling proteins in the striatum by blocking dopamine D2 receptors (D2Rs). However, the neurons in which these pathways are activated by psychotropic drugs are not precisely identified. We used transgenic mice, in which enhanced green fluorescent protein (EGFP) expression was driven by D1R promoter (drd1a-EGFP) or D2R promoter (drd2-EGFP). We confirmed the expression of drd1a-EGFP in striatonigral and drd2- EGFP in striatopallidal neurons. Drd2-EGFP was also expressed in cholinergic interneurons, whereas no expression of either promoter was detected in GABAergic interneurons. Acute cocaine treatment increased phosphorylation of ERK and its direct or indirect nuclear targets, mitogen- and stress-activated kinase-1 (MSK1) and histone H3, exclusively in D1R-expressing output neurons in the dorsal striatum and nucleus accumbens. Cocaine-induced expression of c-Fos and Zif268 predominated in D1R-expressing neurons but was also observed in D2R-expressing neurons. One week after repeated cocaine administration, cocaine-induced signaling responses were decreased, with the exception of enhanced ERK phosphorylation in dorsal striatum. The responses remained confined to D1R neurons. In contrast, acute haloperidol injection activated phosphorylation of ERK, MSK1, and H3 only in D2R neurons and induced c-fos and zif268 predominantly in these neurons. Our results demonstrate that cocaine and haloperidol specifically activate signaling pathways in two completely segregated populations of striatal output neurons, providing direct evidence for the selective mechanisms by which these drugs exert their long-term effects. [ABSTRACT FROM AUTHOR]