Restructuring of basal ganglia circuitry and associated behaviors triggered by low striatal D2 receptor expression: implications for substance use disorders

Abstract

Dopamine D2 receptors (D2Rs) consistently emerge as a critical substrate for the etiology of some major psychiatric disorders. Indeed, a central theory of substance use disorders (SUDs) postulates that a reduction in D2R levels in the striatum is a determining factor that confers vulnerability to abuse substances. A large number of clinical and preclinical studies strongly support this link between SUDs and D2Rs; however, identifying the mechanism by which low D2Rs facilitate SUDs has been hindered by the complexity of circuit connectivity, the heterogeneity of D2R expression and the multifaceted constellation of phenotypes observed in SUD patient. Animal models are well‐suited for understanding the mechanisms because they allow access to the circuitry and the genetic tools that enable a dissection of the D2R heterogeneity. This review discusses recent findings on the functional role of D2Rs and highlights the distinctive contributions of D2Rs expressed on specific neuronal subpopulations to the behavioral responses to stimulant drugs. A circuit‐wide restructuring of local and long‐range inhibitory connectivity within the basal ganglia is observed in response to manipulation of striatal D2R levels and is accompanied by multiple alterations in dopamine‐dependent behaviors. Collectively, these new findings provide compelling evidence for a critical role of striatal D2Rs in shaping basal ganglia connectivity; even among neurons that do not express D2Rs. These findings from animal models have deep clinical implications for SUD patients with low levels D2R availability where a similar restructuring of basal ganglia circuitry is expected to take place.

Drug addictions: new insight into causes, comorbidity and potential treatments

“…They go on to discuss some of the possible neural mechanisms involved and set the stage for exploring these in future work by generating CD-1 × C57BL/6J F1 hybrid transgenic Cre mice that will allow for genetic access to dopamine D1 and D2 receptors. The dopamine system represents a particularly interesting mechanism based on a compelling literature implicating D2 receptor abnormalities in substance-use disorders (SUDs) that is authoritatively reviewed in this issue by Dobbs et al (2016). More specifically, they relay correlative evidence, from human, non-human primate and rodent subjects, that low striatal D2 receptor availability is a risk factor for psychostimulant addiction, and discuss findings from rodents that begin to establish a causal link between reduced D2 receptor function, altered intra-striatal neuronal connectivity and attendant shifts in behavioral responses to psychostimulants, as well as other AUD-and SUD-relevant traits.The question about the role of striatum in addiction is also taken up by Gremel and Lovinger (2016).…”

Boosting of Thalamic D2 Dopaminergic Transmission: A Potential Strategy for Drug-Seeking Attenuation

“…Whereas both groups showed comparable levels of activity during the acquisition of locomotor sensitization, D2R-overexpressing mice exhibited a significant reduction in locomotion in response to a cocaine injection challenge performed a few days later. A role of D2R in the modulation of cocaine-seeking behavior has been previously described for the striatum ( Dobbs et al, 2017 ). In addition, attenuation of cocaine-seeking responses following lesion or pharmacological manipulation of PVT has also been reported in previous studies ( Young and Deutch, 1998 ; James et al, 2010 ; Browning et al, 2014 ; Matzeu et al, 2015 , 2016 ).…”

Striatal Local Circuitry: A New Framework for Lateral Inhibition

“…Recent work has shown the strength of local GABA transmission provided by iSPN axon collaterals can be modulated by dopamine via activation of D2 receptors (Dobbs et al, 2016a, 2016b; Lemos et al, 2016). Acute activation of D2 receptors in iSPNs suppresses the lateral inhibition onto dSPNs and chronic loss of the D2 receptors in these neurons causes an increase in the strength of the GABA-mediated tonic current on dMSMs, which reduces the in vivo firing of SPNs and impairs locomotion (Lemos et al, 2016).…”