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Reward-related behavior is complex and its dysfunction correlated with neuropsychiatric illness. Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been associated with different aspects of reward function, but it remains to be disentangled how distinct VTA DA neurons contribute to the full range of behaviors ascribed to the VTA. Here, a recently identified subtype of VTA neurons molecularly defined by NeuroD6 (NEX1M) was addressed. Among all VTA DA neurons, less than 15% were identified as positive for NeuroD6. In addition to dopaminergic markers, sparse NeuroD6 neurons expressed the vesicular glutamate transporter 2 (Vglut2) gene. To achieve manipulation of NeuroD6 VTA neurons, NeuroD6(NEX)-Cre-driven mouse genetics and optogenetics were implemented. First, expression of vesicular monoamine transporter 2 (VMAT2) was ablated to disrupt dopaminergic function in NeuroD6 VTA neurons. Comparing Vmat2lox/lox;NEX-Cre conditional knock-out (cKO) mice with littermate controls, it was evident that baseline locomotion, preference for sugar and ethanol, and place preference upon amphetamine-induced and cocaine-induced conditioning were similar between genotypes. However, locomotion upon repeated psychostimulant administration was significantly elevated above control levels in cKO mice. Second, optogenetic activation of NEX-Cre VTA neurons was shown to induce DA release and glutamatergic postsynaptic currents within the nucleus accumbens. Third, optogenetic stimulation of NEX-Cre VTA neurons in vivo induced significant place preference behavior, while stimulation of VTA neurons defined by Calretinin failed to cause a similar response. The results show that NeuroD6 VTA neurons exert distinct regulation over specific aspects of reward-related behavior, findings that contribute to the current understanding of VTA neurocircuitry.

Rationale: Repeated treatment with morphine has been shown to sensitize rats to its stimulant effects on motor activity and mesolimbic dopamine (DA) transmission. Objectives: The aim of this study is to investigate if morphine sensitization is associated to changes in the behavioral reactions to appetitive and aversive taste stimuli and in the response of in vivo DA transmission in the nucleus accumbens (NAc) shell and core and medial prefrontal cortex (PFCX) to the same stimuli. Methods: Rats were administered twice a day for three consecutive days with increasing doses of morphine [10, 20, and 40 mg/kg, subcutaneously (sc)] or with saline. After 15 days of withdrawal, rats were infused intraorally with either an appetitive (sweet chocolate, 1 ml) or an aversive solution (quinine HCl 5 × 10 M, 1 ml). The behavioral taste reactions were recorded during microdialysis of DA in the NAc shell and core and PFCX. Results: Opiate sensitization did not affect behavioral reactions to intraoral chocolate or quinine. In rats naive to the taste stimuli, morphine sensitization was associated to potentiation of stimulatory DA response to appetitive and aversive taste stimuli in the NAc core. Morphine sensitization reciprocally affected habituation of DA responsiveness after one trial exposure to appetitive and aversive taste stimuli (abolition it in the shell, induction in the PFCX). No habituation of DA responsiveness to taste was observed in the NAc core in controls as well as in morphine-sensitized rats. Conclusions: These results suggest that opiate sensitization is associated to differential adaptive changes of the responsiveness of DA transmission to taste stimuli in DA terminal areas. [ABSTRACT FROM AUTHOR]

In animal models of Parkinson's disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonist MTEP in the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA- and Ca(2+)-dependent signaling pathways that is critically modulated by striatal mGluR5.