Overexpression or mutation of α-synuclein (α-Syn), a protein associated with presynaptic vesicles, causes familial forms of Parkinson’s disease in humans and is also associated with sporadic forms of the disease. We used in vivo microdialysis, tissue content analysis, behavioral assessment, and whole-cell patch clamp recordings from striatal medium-sized spiny neurons (MSSNs) in slices to examine dopamine transmission and dopaminergic modulation of corticostriatal synaptic function in mice overexpressing human wild-type α-Syn under the Thy1 promoter (α-Syn mice). Tonic striatal extracellular dopamine and 3-methoxytyramine levels were elevated in α-Syn mice at 6 months of age, prior to any reduction in total striatal tissue content, and were accompanied by an increase in open-field activity. Dopamine clearance and amphetamine-induced dopamine efflux were unchanged. The frequency of MSSN spontaneous excitatory postsynaptic currents (sEPSCs) was lower in α-Syn mice. Amphetamine reduced sEPSC frequency in wild types (WTs) but produced no effect in α-Syn mice. Furthermore, whereas quinpirole reduced and sulpiride increased sEPSC frequency in WT mice, they produced the opposite effects in α-Syn mice. These observations indicate that overexpression of α-Syn alters dopamine efflux and D2 receptor modulation of corticostriatal glutamate release at a young age. At 14 months of age, the α-Syn mice presented with significantly lower striatal tissue dopamine and tyrosine hydroxylase content relative to WT littermates, accompanied by an L-DOPA-reversible sensory motor deficit. Together, these data further validate this transgenic mouse line as a slowly progressing model of Parkinson’s disease and provide evidence for early dopamine synaptic dysfunction prior to loss of striatal dopamine.

Key Points SYK is a suitable molecular target for nanotechnology-enabled therapy against ALL. Nanoscale liposomal formulation of SYK inhibitor C61 displayed a promising preclinical profile as an antileukemic drug candidate.

The decision to perform, or not perform, actions known to lead to a rewarding outcome is strongly influenced by the current incentive value of the reward. Incentive value is largely determined by the affective experience derived during previous consumption of the reward-the process of incentive learning. We trained rats on a two-lever, seeking-taking chain paradigm for sucrose reward, in which responding on the initial seeking lever of the chain was demonstrably controlled by the incentive value of the reward. We found that infusion of the -opioid Interestingly, none of these drugs affected the ability of the rats to encode a decrease in incentive value resulting from experiencing the sucrose in a novel reduced-hunger state. However, the agonist, DAMGO ([d-Ala2, NMe-Phe4, Gly5-ol]-enkephalin), appeared to attenuate this negative incentive learning. These data suggest that upshifts and downshifts in endogenous opioid transmission in the BLA mediate the encoding of positive and negative shifts in incentive value, respectively, through actions at -opioid receptors, and provide insight into a mechanism through which opiates may elicit inappropriate desire resulting in their continued intake in the face of diminishing affective experience.

Considerable evidence suggests that in instrumental conditioning rats learn the relationship between actions and their consequences, or outcomes. Such goal-directed actions are sensitive to changes in outcome value. The present study assessed the role of the endogenous opioid system in goal-directed reward learning. In two experiments, rats were trained to lever press for food pellets either under vehicle or naloxone-induced opioid receptor blockade. Specific satiety procedures were used for outcome devaluation, and the effect of this devaluation on instrumental responding was then tested in extinction. In Experiment 1 outcome devaluation resulted in a reduction in lever pressing in rats that were trained after vehicle injections, indicating that actions in these rats were goal-directed. In contrast, actions in rats trained under naloxone were insensitive to outcome devaluation when tested off drug, suggesting that lever pressing had become habitual in these rats. Interestingly, in Experiment 2 naloxone-induced habitual behavior was shown to be specific to the context in which the training occurred under naloxone; rats showed normal sensitivity to outcome devaluation when tested in an alternate vehicle-trained context. Additionally, in Experiment 2 we found that the acute administration of naloxone on test had no effect in itself, indicating that opioid receptor-related processes contribute to the acquisition of goal-directed actions and not to their general performance. These data suggest that an intact endogenous opioid system is necessary for normal goal-directed learning and more importantly, reveal that a compromised endogenous opioid system during learning enhances the habitual control of actions.