Dopamine D3 Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

Abstract

The chronic and relapsing nature of addiction presents unique challenges for ensuring the safety of a potential medication. A patient may use cocaine, for example, while taking the medication or take more medication than prescribed. Thus, a potential medication must be safe and not exacerbate the effects of cocaine. Multiple published studies support antagonism of brain dopamine D3 receptor function as a potential mechanism of action for an anti-addiction medication. Dopamine D3 receptors are widely distributed outside the central nervous system, however; for example, dopamine D3 receptors in the kidneys are implicated in regulating blood pressure. The selective dopamine D3 receptor antagonist GSK598809 [1-(2-fluoro-4-trifluoromethyl-phenyl)-3-{3-[4-methyl-5-(4-methyl-oxazol-5-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-propyl}-3-aza-bicyclo[3.1.0]hexane] has been proposed as a medication to treat cocaine and other substance use disorders. The US Food and Drug Administration has established guidelines recommending safety studies to investigate potential undesirable pharmacodynamic effects of a substance in relation to exposure in the therapeutic range and above. Hence, we assessed the interaction between this selective dopamine D3 receptor antagonist and cocaine on hemodynamics and cardiac function in freely-moving, telemetered dogs before conducting a clinical trial. GSK598809 increased the hemodynamic effect of cocaine in this model. Thus, the increase in blood pressure after intravenous cocaine was greater in animals that had been pretreated with GSK598809 compared with vehicle. This finding suggests that GSK598809 in particular, and perhaps dopamine D3 receptor antagonists as a class, may produce unacceptable cardiovascular risks as medications to treat cocaine use disorder.

Fig. 1.

Study design. Male beagle dogs were dosed with combinations of oral GSK598809 or its vehicle (first arrow) and then with intravenous doses of cocaine or its vehicle (second arrow) 45 minutes later (the T_max of oral GSK598809) over a period of 9 weeks. The interval between successive study dates was at least 6 days to ensure completeness of drug washout.

Fig. 2.

Time courses of mean arterial blood pressure in unrestrained dogs treated with combinations of oral GSK598809 and intravenous cocaine. Data were collected in 30-second bins via telemetry. Two sequential 30-second bins were averaged to produce 1-minute values that were defined as the beginning of the first 30-second bin. Male beagle dogs were dosed with either vehicle or GSK598809 by oral gavage (time -47 minutes), and then the technicians left the room. Forty-five minutes later, infusion pumps automatically dosed the animals with either intravenous vehicle or cocaine. Pumps started at time point -2 minutes and shut off at time point 0 on the graph. Results are depicted at 1-minute intervals for the 30-minute period beginning after the infusion pumps shut off (0 on abscissa) and at 5-minute intervals otherwise. One person entered the room at times 60 and 120 minutes to conduct postdose observations. (A) Mean arterial blood pressure time courses after GSK598809 vehicle and cocaine (n = 6 in all treatment groups except the 0.56 mg/kg cocaine treatment group, where n = 5 as the result of a telemetry malfunction). (B) Mean arterial blood pressure time courses after 3 mg/kg GSK598809 and cocaine (n = 6 in all treatment groups). (C) Mean arterial blood pressure time courses after 9 mg/kg GSK598809 and cocaine (n = 6 in all treatment groups).

Fig. 3.

Effects of oral GSK598809 and intravenous cocaine on peak mean arterial blood pressure in dogs. Six male beagle dogs were dosed with GSK598809 vehicle (white bars), 3 mg/kg GSK598809 (gray bars) or 9 mg/kg GSK598809 (black bars), followed by saline, 0.56 mg/kg cocaine, or 1.7 mg/kg cocaine 45 minutes later. Data represent averaged peak mean arterial blood pressures (± S.E.M.) during the 5-minute interval immediately after the end of the cocaine infusion. Dosing sessions were separated by at least 6 days. *P < 0.05 compared with cocaine alone.

Fig. 4.

Time courses of heart rate in unrestrained dogs treated with combinations of oral GSK598809 and intravenous cocaine. Data were collected in 30-second bins via telemetry. Two sequential 30-second bins were averaged to produce 1-minute values that were defined as the beginning of the first 30-second bin. Male beagle dogs were dosed with either vehicle or GSK598809 by oral gavage (time -47 minutes), and then the technicians left the room. Forty-five minutes later, infusion pumps automatically dosed the animals with either intravenous vehicle or cocaine. Pumps started at time point -2 minutes and shutoff at time point 0 on the graph. Results are depicted at 1-minute intervals for the 30-minute period beginning after the infusion pumps shut off (0 on abscissa) and at 5-minute intervals otherwise. One person entered the room at times 60 and 120 minutes to conduct postdose observations. (A) Heart rate time courses after GSK598809 vehicle and cocaine (n = 6 in all treatment groups except the 0.56 mg/kg cocaine treatment group, where n = 5 as the result of a telemetry malfunction). (B) Heart rate time courses after 3 mg/kg GSK598809 and cocaine (n = 6 in all treatment groups). (C) Heart rate time courses after 9 mg/kg GSK598809 and cocaine (n = 6 in all treatment groups).