(±)VK4-40, a novel dopamine D3 receptor partial agonist, attenuates cocaine reward and relapse in rodents

Abstract

Background and purpose: Despite widespread abuse of cocaine, there are no approved treatments for cocaine use disorder. Chronic cocaine use is associated with up-regulated dopamine D₃ receptor expression in the brain. Therefore, most D₃ -based medication development has focused on D₃ antagonists. However, D₃ antagonists do not attenuate cocaine intake under "easy" self-administration conditions, when response requirements are low. We evaluated a novel, highly selective and metabolically stable D₃ partial agonist, (±)VK4-40, for its efficacy in reducing cocaine intake and relapse to drug seeking.

Experimental approach: The impact of (±)VK4-40 on cocaine intake and relapse was evaluated using intravenous self-administration procedures under a fixed-ratio 2 reinforcement schedule and cocaine-primed reinstatement conditions in rats. Optogenetic brain-stimulation reward procedures were used to evaluate the interaction of (±)VK4-40 and cocaine in the mesolimbic dopamine system in mice. Sucrose self-administration in rats and a conditioned place preference paradigm in mice were used to evaluate the abuse potential of (±)VK4-40 alone and other unwanted effects.

Key results: (±)VK4-40 dose-dependently reduced cocaine self-administration and cocaine-primed reinstatement of drug-seeking behaviour. (±)VK4-40 also inhibited cocaine-enhanced brain-stimulation reward caused by optogenetic stimulation of dopamine neurons in the ventral tegmental area. (±)VK4-40 alone decreased brain-stimulation reward but produced neither conditioned place preference nor place aversion. This new D₃ partial agonist also failed to alter oral sucrose self-administration.

Conclusion and implications: The novel D₃ partial agonist, (±)VK4-40 attenuates cocaine reward and relapse in rodents, without significant unwanted effects. These findings support further investigation of D₃ partial agonists as putative treatments for cocaine use disorder.

Keywords: addiction; brain-stimulation reward; cocaine; dopamine D3 receptor; optical intracranial self-stimulation; reinstatement; self-administration.

FIGURE 1

Impact of (±)VK4‐40 on cocaine self‐administration under the FR2 reinforcement schedule in rats. (a) General timeline of experimental procedures. (b) Cocaine self‐administration dose–response curves in the presence or absence of (±)VK4‐40 treatment, indicating that (±)VK4‐40 pretreatment dose‐dependently reduced the number of cocaine infusions earned. (c) Active lever responses for various doses of cocaine in the presence or absence of (±)VK4‐40 treatment. (d) Inactive lever responses during access to various doses of cocaine. ^* P < 0.05, compared to vehicle control group. Sample sizes for each treatment group were as follows: Vehicle, n = 10; (±)VK4‐40, 3 mg·kg⁻¹, n = 10; (±)VK4‐40, 10 mg·kg⁻¹, n = 8

FIGURE 2

Impact of (±)VK4‐40 on cocaine‐primed reinstatement of drug‐seeking behaviour in rats extinguished from previous cocaine self‐administration. (a) General experimental procedures. (b) Active lever responding during the last session (day) of cocaine self‐administration, the last session (day) of extinction, and the reinstatement test. (c) Inactive lever responding during the last session (day) of cocaine self‐administration, last session (day) of extinction, and reinstatement test. A priming dose of cocaine (10 mg·kg⁻¹, i.p.) significantly reinstated active lever responding compared to extinction levels, which was attenuated by pretreatment with 3 or 10 mg·kg⁻¹ (±)VK4‐40. ^* P < 0.05 compared to the vehicle treatment group. ^{^} P < 0.05 compared to the last session of extinction. Sample sizes for each treatment group were as follows: Vehicle, n = 6; (±)VK4‐40, 3 mg·kg⁻¹, n = 9; (±)VK4‐40, 10 mg·kg⁻¹, n = 10

FIGURE 3

Impact of (±)VK4‐40 and/or cocaine on optogenetic intracranial self‐stimulation (oICSS) of ventral tegmental area (VTA) dopamine neurons by DAT‐Cre mice. (a) Schematic of the experimental model, illustrating that AAV‐DIO‐ChR2‐eGFP was microinjected into the VTA and an optical fibre was implanted into the VTA in DAT‐Cre mice. Subsequent activation of VTA dopamine neurons via 473 nm laser should produce dopamine release to the nucleus accumbens (NAc). (b) Representative images, showing that AAV‐DIO‐ChR2‐eGFP is selectively expressed in VTA dopamine neurons in DAT‐Cre mice. (c) Schematic diagram showing the expression of channelrhodopsin‐2 (ChR2) in VTA dopamine neurons that can be activated by 473 nm laser activation. (d) General timeline of experimental procedures. (e) Systemic administration of cocaine dose‐dependently increased active lever responding for VTA dopamine neuron activation. (f) Pretreatment with (±)VK4‐40 attenuated cocaine‐induced increases in active lever responding for dopamine neuron stimulation. (g) Systemic administration of (±)VK4‐40 alone inhibited oICSS. ^* P < 0.05 compared to vehicle treatment group (for Figure 3f; *P < 0.05 cocaine treatment group vs. vehicle treatment group only). Sample sizes for each treatment group were as follows: Vehicle, n = 6; Cocaine, 2 mg·kg⁻¹, n = 6; Cocaine, 10 mg·kg⁻¹, n = 6; Vehicle + Cocaine, 10 mg·kg⁻¹, n = 6; (±)VK4‐40 (3 mg·kg⁻¹) + Cocaine (10 mg·kg⁻¹), n = 6; (±)VK4‐40 (10 mg·kg⁻¹) + Cocaine (10 mg·kg⁻¹), n = 6; (±)VK4‐40 (3 mg·kg⁻¹) alone, n = 6; (±)VK4‐40 (10 mg·kg⁻¹) alone, n = 6

FIGURE 4

Impact of (±)VK4‐40 on oral sucrose self‐administration and conditioned place preferences to (±)VK4‐40 or cocaine. (a) (±)VK4‐40 did not alter oral sucrose self‐administration and all animals reached the maximally allowed 100 sucrose deliveries. (b) (±)VK4‐40 also failed to alter the time spent to reach the maximal 100 sucrose deliveries. (c) General experimental timeline of conditioned place preference (CPP) procedure. (d) Cocaine produced significant CPP to the cocaine‐paired chamber. (e) (±)VK4‐40 produced neither CPP nor conditioned place aversion to the (±)VK4‐40‐paired side of the apparatus. Sample sizes for each treatment group in the sucrose experiment were as follows: Vehicle, n = 7; (±)VK4‐40, 1 mg·kg⁻¹, n = 7; (±)VK4‐40, 5 mg·kg⁻¹, n = 7. Sample sizes for each treatment group in the CPP experiments were as follows: Cocaine conditioning, n = 9; (±)VK4‐40 Conditioning, n = 9