The Signaling and Pharmacology of the Dopamine D1 Receptor

The dopamine D1 receptor (D1R) is a Gαs/olf-coupled GPCR that is expressed in the midbrain and forebrain, regulating motor behavior, reward, motivational states, and cognitive processes. Although the D1R was initially identified as a promising drug target almost 40 years ago, the development of clinically useful ligands has until recently been hampered by a lack of suitable candidate molecules. The emergence of new non-catechol D1R agonists, biased agonists, and allosteric modulators has renewed clinical interest in drugs targeting this receptor, specifically for the treatment of motor impairment in Parkinson's Disease, and cognitive impairment in neuropsychiatric disorders. To develop better therapeutics, advances in ligand chemistry must be matched by an expanded understanding of D1R signaling across cell populations in the brain, and in disease states. Depending on the brain region, the D1R couples primarily to either Gαs or Gαolf through which it activates a cAMP/PKA-dependent signaling cascade that can regulate neuronal excitability, stimulate gene expression, and facilitate synaptic plasticity. However, like many GPCRs, the D1R can signal through multiple downstream pathways, and specific signaling signatures may differ between cell types or be altered in disease. To guide development of improved D1R ligands, it is important to understand how signaling unfolds in specific target cells, and how this signaling affects circuit function and behavior. In this review, we provide a summary of D1R-directed signaling in various neuronal populations and describe how specific pathways have been linked to physiological and behavioral outcomes. In addition, we address the current state of D1R drug development, including the pharmacology of newly developed non-catecholamine ligands, and discuss the potential utility of D1R-agonists in Parkinson's Disease and cognitive impairment.

Effects of methamphetamine-induced neurotoxicity on striatal long-term potentiation

Rationale Methamphetamine (METH) exposure is associated with damage to central monoamine systems, particularly dopamine signaling. Rodent models of such damage have revealed a decrease in the amplitude of phasic dopamine signals and significant striatal dysfunction, including changes in the molecular, system, and behavioral functions of the striatum. Dopamine signaling through D1 receptors promotes corticostriatal long-term potentiation (LTP), a critical substrate of these striatal functions. Objectives Therefore, the purpose of this study was to determine if METH-induced dopamine neurotoxicity would impair D1 receptor-dependent striatal LTP in mice. Methods Mice were treated with a METH binge regimen (4 × 10 mg/kg d,l-methamphetamine, s.c.) that recapitulates all of the known METH-induced neurotoxic effects observed in humans, including dopamine toxicity. Three weeks later, acute brain slices containing either the dorsomedial striatum (DMS) or dorsolateral striatum (DLS) were prepared, and plasticity was assessed using white matter, high-frequency stimulation (HFS), and striatal extracellular electrophysiology. Results Under these conditions, LTP was induced in brain slices containing the DMS from saline-pretreated mice, but not mice with METH-induced neurotoxicity. Furthermore, the LTP observed in DMS slices from saline-pretreated mice was blocked by the dopamine D1 receptor antagonist SCH23390, indicating that this LTP is dopamine D1 receptor-dependent. Finally, acute in vivo treatment of METH-pretreated mice with bupropion (50 mg/kg, i.p.) promoted LTP in DMS slices. Conclusions Together, these studies demonstrate that METH-induced neurotoxicity impairs dopamine D1 receptor-dependent LTP within the DMS and that the FDA-approved drug bupropion restores induction of striatal LTP in mice with METH-induced dopamine neurotoxicity.

The Role of the Dopamine D1 Receptor in Cognition

<p>The dopamine D1 receptor (DD1R) has been linked to cognitive functioning in various human and animal studies using diverse methods from pharmacological manipulations to brain imaging. Moreover, suboptimal or supraoptimal functioning of the DD1R has been linked to cognitive dysfunction. However, the previous research on this topic has mainly relied on correlational evidence, or the use of drugs that are not selective to the DD1R. Therefore, the current study investigated whether cognitive dysfunction is due to suboptimal functioning of the DD1R. The DD1R mutant rat (Smits et al., 2006) provides an opportunity to examine the role of the DD1R in cognitive functioning. The performance of the DD1R mutant rats was compared to that of littermate control rats (wildtypes). Across five experiments we found tentative evidence to suggest that the DD1R is necessary for normal cognitive ability. First, the DD1R mutant rats were unable to improve their performance when an egocentric strategy was required in the starmaze, using both positive and negative reinforcement. Second, compared to wildtype rats, the DD1R mutants were impaired in learning an allocentric strategy in the starmaze with positive reinforcement when they had been previously trained in an egocentric task. Third, the mutants were unable to improve when an egocentric strategy was required in the Y-maze. Finally, the DD1R mutant rats took longer than the wildtypes to reverse their learning when a baited arm was switched after two weeks of training with a different arm as the baited arm in the T-maze. Despite some of the limitations of the experiments, these initial findings suggest an impairment in cognition. Ideas for future research and applications are discussed.</p>

The Role of the Dopamine D1 Receptor in Cognition

<p>The dopamine D1 receptor (DD1R) has been linked to cognitive functioning in various human and animal studies using diverse methods from pharmacological manipulations to brain imaging. Moreover, suboptimal or supraoptimal functioning of the DD1R has been linked to cognitive dysfunction. However, the previous research on this topic has mainly relied on correlational evidence, or the use of drugs that are not selective to the DD1R. Therefore, the current study investigated whether cognitive dysfunction is due to suboptimal functioning of the DD1R. The DD1R mutant rat (Smits et al., 2006) provides an opportunity to examine the role of the DD1R in cognitive functioning. The performance of the DD1R mutant rats was compared to that of littermate control rats (wildtypes). Across five experiments we found tentative evidence to suggest that the DD1R is necessary for normal cognitive ability. First, the DD1R mutant rats were unable to improve their performance when an egocentric strategy was required in the starmaze, using both positive and negative reinforcement. Second, compared to wildtype rats, the DD1R mutants were impaired in learning an allocentric strategy in the starmaze with positive reinforcement when they had been previously trained in an egocentric task. Third, the mutants were unable to improve when an egocentric strategy was required in the Y-maze. Finally, the DD1R mutant rats took longer than the wildtypes to reverse their learning when a baited arm was switched after two weeks of training with a different arm as the baited arm in the T-maze. Despite some of the limitations of the experiments, these initial findings suggest an impairment in cognition. Ideas for future research and applications are discussed.</p>