Loss of Cocaine Locomotor Response in Pitx3-Deficient Mice Lacking a Nigrostriatal Pathway

Abstract

Both the dorsal and ventral striatum have been demonstrated to have a critical role in reinforcement learning and addiction. Dissecting the specific function of these striatal compartments and their associated nigrostriatal and mesoaccumbens dopamine pathways, however, has proved difficult. Previous studies using lesions to isolate the contribution of nigrostriatal and mesoaccumbens dopamine in mediating the locomotor and reinforcing effects of psychostimulant drugs have yielded inconsistent and inconclusive results. Using a naturally occurring mutant mouse line, aphakia, that lacks a nigrostriatal dopamine pathway but retains an intact mesoaccumbens pathway, we show that the locomotor activating effects of cocaine, including locomotor sensitization, are dependent on an intact nigrostriatal dopamine projection. In contrast, cocaine reinforcement, as measured by conditioned place preference and cocaine sensitization of sucrose preference, is intact in these mice. In light of the well-established role of the nucleus accumbens in mediating the effects of psychostimulants, these data suggest that the nigrostriatal pathway can act as a critical effector mechanism for the nucleus accumbens highlighting the importance of intrastriatal connectivity and providing insight into the functional architecture of the striatum.

Serotonin2C receptor stimulation inhibits cocaine-induced Fos expression and DARPP-32 phosphorylation in the rat striatum independently of dopamine outflow

“…Interestingly, control of striatal DA transmission, together with that of accumbal DA transmission (Cathala et al, 2014), could participate in the suppressant effect of 5-HT 2C R agonists on cocaine-induced hyperlocomotion (Filip et al, 2012;Devroye et al, 2013). Indeed, a recent study in mutant mice lacking nigrostriatal DA projections has shown that the nigrostriatal DA pathway is essential in mediating the locomotor activating effects of cocaine, thereby suggesting that it could function as an effector mechanism for the NAc (Beeler et al, 2009). The nigrostriatal DA pathway is also known to play a key role in the development of cocaine abuse and dependence (Wise, 2009;Koob and Volkow, 2010;Pierce and Vanderschuren, 2010).…”

IP3Receptor Sensitization duringIn VivoAmphetamine Experience Enhances NMDA Receptor Plasticity in Dopamine Neurons of the Ventral Tegmental Area

“…It is generally believed that the VTA→NAc pathway plays a predominant role in the initial learning of reward-related cues (Everitt and Robbins, 2005; Beeler et al, 2009). In the present study, we observed positive correlation between amphetamine CPP measured in behaving rats and mGluR-induced I K(Ca) facilitation in the VTA measured in brain slices prepared from those rats.…”

Preservation of function in Parkinson's disease: What's learning got to do with it?

“…First, we used the PITx3-deficient mouse line (aka, aphakia , Varnum and Stevens, 1968) that exhibits a 90% denervation of dorsal striatal dopamine (Beeler et al, 2009; Hwang et al, 2003; Nunes et al, 2003; Smits et al, 2005; van den Munckhof et al, 2003). These mice perform extremely poorly on the accelerating rotarod (Ardayfio et al, 2008; Beeler et al, 2010a), but their performance can be rescued with L-DOPA treatment (Beeler et al, 2010a).…”