Effects of Isradipine on Cocaine-Induced Subjective Mood

Abstract

We hypothesized that in humans, as in animals, isradipine, a dihydropyridine-class calcium channel antagonist, would antagonize cocaine's rewarding effects, based on preclinical evidence that isradipine inhibits cocaine-mediated increases in mesolimbic dopamine (DA), thereby reducing cocaine's abuse liability. Confirmation of our hypothesis would make isradipine a promising medication for treating cocaine dependence. Eighteen male and female volunteers (mean age, 32.6 years) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for cocaine dependence participated in a double-blind, placebo-controlled, crossover study. Subjects received placebo or sustained-release (SR) low-dose or high-dose isradipine (15 or 30 mg), plus placebo or low-dose or high-dose cocaine HCl (0.325 or 0.650 mg/kg), for 9 treatment sessions separated by a 2-day interval. Standardized assessments of abuse liability, including a choice procedure to determine preference for cocaine with and without isradipine over monetary incentives, were conducted at scheduled intervals. Cocaine administration produced dose-related prototypic increases in stimulant-related effects, including euphoria, and drug preference over monetary incentives. Isradipine lacked any stimulant or abuse liability effects or the propensity to elicit craving, and it did not antagonize any of cocaine's stimulant-related effects associated with its abuse liability. In conclusion, SR isradipine (up to 30 mg) does not antagonize cocaine's rewarding effects in cocaine-dependent individuals. While higher isradipine doses may have been more effective at antagonizing cocaine reward, we could not test such doses due to the risk of serious adverse events. Also, isradipine-mediated inhibition of mesolimbic DA release may be an ineffective treatment of cocaine dependence.

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

“…LCCBs also reduce the development of tolerance to morphine (Vaupel et al, 1993;Santillan et al, 1998). Interestingly, LCCBs modify vascular tone in alcohol withdrawal but not abstinence (Kähkönen (Muntaner et al, 1991;Johnson et al, 1999) and morphine (Vaupel et al, 1993, Santillan et al, 1998, while others have not (Hasegawa and Zacny 1997;Johnson et al, 2004b), and LCCBs have no effect on ethanol intoxication (Perez-Reyes et al, 1992). Some results have been considered particularly encouraging; for example, an LCCBmediated increased the ability to refuse further doses of methamphetamine (Johnson et al, 1999).…”

L‐type calcium channels and psychiatric disorders: A brief review

“…As summarized in Table III, conflicting results have been reported in preliminary clinical studies examining stimulants' abuse liability in humans [Muntaner et al, 1991;Rosse et al, 1994;Fabian and Silverstone, 1997;Johnson et al, 1999Johnson et al, , 2004Johnson et al, , 2005bMalcolm et al, 1999;Gottschalk and Kosten, 2002;Sofuoglu et al, 2003;Roache et al, 2005]. Roache et al [2005] suggested that isradipine could even increase subjective effects and reinforcement caused by cocaine use.…”

“…Isradipine attenuated blood pressure (BP) changes Sofuoglu et al [2003] SR-isradipine (15, 30 mg) No benefits on cocaine effects, abuse liability or craving Johnson et al [2004] Isradipine 30 mg 8 12 cocaine-dependent and 19 amphetamine-dependent subjects DB, Rz PC, CO; two 8-day study periods separated by at least 1 wk; EKG, heart rate (HR) and blood pressure (BP) Isradipine reduced stimulant-associated increases in BP but produced elevation of HR Johnson et al [2005a,b] SR-Isradipine 30 mg 10 12 cocaine-dependent subjects DB, PC, CO Isradipine enhanced rather than reduced subjective effects of cocaine Roache et al [2005] CBF, cerebral blood flow; CO, cross-over; DB, double-blind; OL, open-label; P, placebo; PC, placebo-controlled; Pts, patients; RCT, randomized controlled trial; Rz, randomized; mo, month; wk, week.…”

Effects of isradipine on cocaine-induced changes in cognitive performance in recently abstinent cocaine-dependent individuals

“…During the experiment, measures of cognitive performance were done 30 min prior to dosing and at 30, 60, and 120 min post-dosing. Behavioural measures of euphoria, craving, and drug reinforcement also were collected at scheduled intervals ; these findings have been described elsewhere (Johnson et al, 2004 ;Roache et al, In Press).…”