New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders

Abstract

The abuse of illicit psychostimulants such as cocaine and methamphetamine continues to pose significant health and societal challenges. Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions about what mechanism(s) of action should be targeted for developing pharmacotherapies. As both cocaine and methamphetamine rapidly increase dopamine (DA) levels in mesolimbic brain regions, leading to euphoria that in some can lead to addiction, targets in which this increased dopaminergic tone may be mitigated have been explored. Further, understanding and targeting mechanisms underlying relapse are fundamental to the success of discovering medications that reduce the reinforcing effects of the drug of abuse, decrease the negative reinforcement or withdrawal/negative affect that occurs during abstinence, or both. Atypical inhibitors of the DA transporter and partial agonists/antagonists at DA D₃ receptors are described as two promising targets for future drug development.

Keywords: JJC8-091; VK4-40; cocaine; dopamine D3 receptor; dopamine transporter; methamphetamine; modafinil.

Fig. 1.

Chemical structures of cocaine, benztropine, JHW007, rimcazole, GBR12909, modafinil, JJC8-016, 8-088, 8-089, 8-091, RDS3-094 with binding data from the Newman lab; ^adata from reference (78).

Fig. 2.

Effects of the novel atypical DAT inhibitor JJC8-091 and the novel D₃R partial agonist (±)-VK4-40 on cocaine self-administration (0.5 mg/kg, FR2) (A, B) and cocaine-primed reinstatement of drug-seeking behavior (C, D) in rats extinguished from previous cocaine self-administration. *p<0.05 compared to the vehicle control group.

Fig. 3.

Chemical structures of D₃R antagonists and partial agonists studied as potential medications for PUD, including highly selective bitopic D₃R antagonists and partial agonists (CJB090, PG01037, VK4-116 and VK4-40) developed in the Newman lab (–140). Binding data from Newman lab; ^adata from reference (141).

Fig. 4.

Effects of the racemic (±)-VK4-40 (a D₃R partial agonist) and its enantiomers R-VK4-40 (a D₃R antagonist) and S-VK4-40 (a D₃R partial agonist) on lever responding for brain-stimulation reward maintained by optogenetic stimulation of VTA DA neurons in DAT-Cre mice. A: Schematic of the experimental model, illustrating AAV-ChR2-EGFP was microinjected into the VTA and an optical fiber was implanted into the VTA to stimulate DA neurons in DAT-Cre mice; B: Representative images, showing that AAV-ChR2-EGFP is selectively expressed in VTA tyrosine hydroxylase (TH)-positive DA neurons. C, D, E: Systemic administration of (±)-VK4-40 (C), R-VK4-40 (D), or S-VK4-40 (E) alone inhibits optical brain-stimulation reward and dose-dependently shifts the stimulation frequency-active lever responding curve downward. F, G, H: Pretreatment with (±)-VK4-40 (F), R-VK4-40 (G), or S-VK4-40 (H) dose-dependently attenuated cocaine-enhanced brain-stimulation reward as assessed by the upward or leftward shift of the stimulation-response curve after cocaine administration. * p < 0.05, ** p < 0.01, *** p < 0.001, compared to vehicle control group.