For example, Gi/o signaling may do more than inhibit neuron firing, and each of these

G protein mediated pathways are complex and vary to some extent between cell types [6•]. Psychomotor sensitization is a progressive and persistent increase in the psychomotor activating effects (i.e., locomotion and stereotypy) induced by repeated, intermittent exposure to a drug [7]. Sensitization is a useful paradigm for studying addiction processes because it is an easily observable behavioral output of the neural circuitry thought to underlie the incentive-motivational aspects of drug-seeking that facilitate the transition to addiction 8, 9 and 10]. Using Gi/o-coupled DREADDs that selleck kinase inhibitor are expressed under cell-type specific promoters, we have examined the role of subtypes of medium spiny projection neurons (MSNs) in the dorsomedial striatum in the development of amphetamine-induced psychomotor sensitization. We found that increasing Gi/o signaling in indirect pathway MSNs (i.e., those that express the neuropeptide enkephalin and indirectly project to the substantia nigra (SN) via the globus pallidus external (GPe) and subthalamic nucleus this website (STN) [11]) enhances the development of locomotor sensitization to amphetamine whereas increasing Gi/o signaling in direct

pathway MSNs (i.e. those that express the neuropeptides dynorphin and substance P and directly project to the SN [11]) impairs the persistence of this behavior [12••]. Consistent with these findings, Farrell et al. [6•] found that increasing Gs signaling in all indirect pathway MSNs through generation of a transgenic

mouse with rM3Ds expression under control of the adenosine2A (adora2a) receptor promoter blocked the development of amphetamine-induced locomotor sensitization. Although MSNs regulate motor behaviors and increasing Gs signaling in all indirect pathway MSNs decreased novelty-induced locomotion [6•], the observed behavioral changes following amphetamine treatment are unlikely to be a result of merely changing motor second behaviors because these manipulations did not affect the acute locomotor responses to amphetamine. Further, increasing Gi/o signaling in a subset of indirect pathway neurons was sufficient to modulate amphetamine behaviors but had no effect on basal locomotor activity 6• and 12••]. Therefore, the preferential effects of DREADDs on the plasticity associated with this time and drug-dependent plasticity model suggest that DREADD activation has a more subtle impact than simply activating or silencing neurons, but rather acts to enhance or diminish the plasticity associated with repeated drug administration.