Synaptic mechanisms underlying reward seeking and compulsive drug use

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Evidence for a key role of D2 auto-receptors rather than striatal postsynaptic D2 receptors in the susceptibility for cocaine abuse This study tested the hypothesis that low levels of D2 receptors in both striatum and midbrain neurons might synergize to give rise to a vulnerable phenotype with enhanced reinforcing properties for cocaine and impair loss of control over consumption. We developed this hypothesis based on collection of our published work that showed that D2 auto-receptors in dopamine neurons play different and sometimes complementary roles in the circuitry in comparison to D2Rs in striatal neurons. Thus, we reasoned that lowering levels of both D2 receptors in the same animals would generate a vulnerable circuitry and lead to increased reinforcing properties of cocaine, increased perseverance in cocaine seeking and intake that is insensitive to adverse outcomes. Previously we had shown that D2 auto-receptors act as negative regulators of dopamine synthesis and release and of dopamine neuron activity. Loss of D2 auto-receptors enhanced cocaine acute locomotor response and the acquisition of cocaine self-administration behavior. On the other hand, we also showed that D2 receptors in striatal neurons regulate the strength of the lateral inhibition between striatal neurons and when these receptors are expressed at low levels, the striatum is under potent inhibition. Loss of D2 auto-receptors from midbrain dopamine neurons or loss of D2 receptors on striatal neurons produce different alterations of synaptic physiology in the basal ganglia. We showed that each of the receptors contribute to selected changes in cocaine-driven behaviors. The goal of this project was to dissect out the contribution of the D2Rs in the striatum and the midbrain to the behavioral response to cocaine and the vulnerability to develop addictive behaviors. We generated transgenic mice with targeted single-allele deletion of Drd2 gene in either the medium spiny neurons (MSN) of the striatum (iMSN-D2HET), or the midbrain dopamine neurons (auto-D2HET), or both (double-D2HET). We argue that patients suffering from substance use disorders display a reduction rather than complete loss of D2 receptor availability and as such partial knockdown of D2 receptors is a more informative manipulation with improved face-validity for the clinical condition. We bred these mice such that mice of all three genotypes and wildtype were produced as littermates and tested a battery of striatal-controlled dopamine-mediated behaviors and the response to cocaine, including intravenous cocaine self-administration (IV-SA). These are the highlights of the findings: D2 auto-receptors contribute to D2/3 ligand binding in the striatum and are largely responsible for locomotor suppression produced by d2/3 agonists (via inhibition of DA release). D2 receptors in striatal neurons are responsible for mediating the acute effects of cocaine and its actions synergized with D1 receptors. Mice with low D2 receptors in striatal neurons show normal response to D2/3 agonists, display upregulation of striatal D1-like ligand binding and behavioral response, and show lower acute response but increased sensitized response to cocaine. Mice with low expression of D2 auto-receptors have reduced D2/3 binding in the striatum, have reduced D2/3 agonist responses, display downregulation of striatal D1-like ligand binding and its behavioral response, and show increased acute response to cocaine and desensitization over repeated exposure. Thus, our data shows that mice with low D2 auto-receptors and mice with low levels of striatal D2 receptors often display opposite phenotypes with regard to dopamine-related and cocaine-related behaviors. The study further shows that simultaneous reduction of both D2 auto-receptors and D2R in striatal neurons (double-D2HET mice) most often have the mildest phenotypes. Thus, contrary to our initial hypothesis that low D2Rs in both regions will synergize to produce the vulnerable phenotype, we found that balanced reduction of D2Rs led to behavioral phenotypes that most resemble the wild-type mice. We only found evidence of synergism in the acute response to cocaine. Double-D2HET resembles auto-D2HET alterations on some behaviors while they mimic the phenotype of striatum-D2HET on other behaviors. This study gives us a better understanding of the unique contributions of striatal and midbrain D2R to dopamine-dependent behaviors and the response to cocaine to better inform new treatments for substance use disorders.