BRIEF REPORT Dopamine Partial Agonist Reverses Amphetamine Withdrawal in Rats Cristina Orsini, Ph.D., George F. Koob, Ph.D. and Luigi Pulvirenti, M.D. Decreased motivation to work for a natural reward is a sign reversed the decrease in responding for the sweet solution. of amphetamine withdrawal and is thought to be associated These results suggest that dopamine partial agonists, with hypofunction of the mesolimbic dopamine system. possibly due to their agonistic-like actions under these During withdrawal from repeated amphetamine conditions, are a potential therapeutic approach for the administration, rats showed reduced responding for a sweet acute withdrawal stage of the amphetamine addition cycle. solution in a progressive ratio schedule. Repeated systemic [Neuropsychopharmacology 25:789–792, 2001] treatment with terguride (0.2 and 0.4 mg/kg, i.p.) twice © 2001 American College of Neuropsychopharmacology. daily during the first four days of amphetamine withdrawal Published by Elsevier Science Inc. KEY WORDS: Dopamine; Partial agonist; Amphetamine; limited efficacy has been reported in both preclinical Withdrawal; Terguride; Dependence models and clinical trials with dopamine agonists and antagonists (for review see Withers et al. 1995; Mello Psychostimulant withdrawal in humans is associated and Negus 1996). with fatigue, depression of mood, anhedonia, and psy- Partial dopamine agonists bind to the dopamine re- chomotor retardation and is a critical component of the ceptor with high affinity but low intrinsic activity dependence cycle, but no pharmacotherapeutic treat- (Hoyer and Boddeke 1993), and have been hypothe- ments are currently available for psychostimulant with- sized to act as functional antagonists in conditions of drawal. In rats, psychomotor retardation and decreased high dopaminergic tone and as functional agonists in motivation to work for a natural reward are signs of conditions of DA depletion (Clark et al. 1991; Svensson amphetamine withdrawal (Pulvirenti and Koob 1993; et al. 1991; Pulvirenti and Koob 1994). Within the con- Barr and Phillips 1999). Although dopamine (DA) me- text of drug dependence, the DA D2 receptor partial ag- solimbic neurotransmission appears to be critically in- onists terguride and SDZ 208-911 showed activity as volved in psychostimulant dependence (Wise and functional antagonists in rats trained to self-administer Bozarth 1987; Wise 1996; Koob and Le Moal 1997), only cocaine and amphetamine under different schedules (Pulvirenti and Koob 1994; Pulvirenti et al. 1998; Izzo et al. 2001). However, DA partial agonists might restore From the Department of Neuropharmacology The Scripps the relative functional hypoactivity of the dopamine Research Institute (CO, GFK, LP) and Claude Bernard Neuroscience system during psychostimulant withdrawal (Pulvirenti Institute (LP), La Jolla, CA. and Koob 1994). Address correspondence to: Luigi Pulvirenti, M.D., Department of Neuropharmacology CVN-7, The Scripps Research Institute, The aim of the present study was to investigate the 10550 North Torrey Pines Rd., La Jolla, CA 92037. effects of terguride using a model of amphetamine Received August 26, 2000; revised April 6, 2001; accepted April withdrawal (Barr and Phillips 1999) from sustained, 17, 2001. Online publication: 4/19/01 at www.acnp.org/citations/Npp high doses of amphetamine shown to produce a de- 041901108. crease in operant responding for a sweet solution. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 5 © 2001 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 SSDI S0893-133X(01)00270-6 790 C. Orsini et al. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 5 METHODS RESULTS This study was performed in accordance with the Na- Figure 1 shows the effects of treatment with terguride tional Institutes of Health Guide for the Care and Use of on PR responding for a sweet solution. Overall ANOVA Laboratory Animals. Male Wistar rats (Charles River) revealed that there was a significant difference between were housed on a reversed light/dark cycle (lights on treatment groups: treatment with terguride prevented 10 PM to 10 AM). Testing was performed between 2 PM the reduction of BP (expressed as total reinforcement and 4 PM. Following an initial 48-h exposure to a sweet earned) in rats treated with amphetamine [F(2,162) ϭ solution [3% sucrose (Fisher Scientific) and 0.125% sac- 3.296, p Ͻ .05] and post-hoc analysis revealed that sta- charin (Sigma Chemical Co), all rats were water- tistical significance was reached for the dose of tergu- deprived for 20 h daily before being placed in standard ride 0.4 mg/kg (p Ͻ .05 vs. saline, Tukey’s test). In addi- operant chambers (Coulburn Instruments) (Roberts et tion, comparison at the various levels revealed a al. 2000). Subjects were placed on a progressive-ratio significant reduction of BP (expressed as total reinforce- (PR) schedule for the sweet solution (0.1 ml per rein- ment earned) in rats treated with amphetamine and sa- forcer) for 2 h daily [following initial training on a line [F(4,48) ϭ 3.98, p Ͻ .01] and statistical significance fixed-ratio (Barr and Phillips 1999)] and the response was reached during the first two days of withdrawal (p Ͻ requirement increased according to the following pro- .01, Tukey’s test). gression: 1, 3, 6, 10, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118, ANOVA revealed no significant reduction of break- 145, 175, 205, 235, 265, etc. ing point in rats treated with amphetamine and tergu- The breaking point (BP) was defined as the last ra- ride at the doses of 0.2 mg/kg [F(4,36) ϭ 1.74, NS] and tio attained prior to a 1-h period during which a ratio 0.4 mg/kg [F(4,36) ϭ 2.59, NS]. Finally, Tukey’s test re- was not completed. When stable responding was vealed a significant difference between terguride at the achieved (Ϯ 10% of reinforcements within three con- secutive days and BP Ͼ 16) the rats were injected in- traperitoneally (i.p.) three times per day (9 AM, 5 PM, and 12 AM), starting with a dose of 1 mg/kg of amphetamine and increasing by 1 mg/kg per injec- tion for 10 injections (Barr and Phillips 1999). After the last injection of amphetamine the rats were treated i.p. twice daily (9:30 AM and 9:30 PM) for four days with either saline (n ϭ 13) or terguride at the dose of 0.2 (n ϭ 10) or 0.4 mg/kg (n ϭ 10). PR re- sponding was monitored for the first four days of withdrawal (Pulvirenti and Koob 1993; Barr and Phil- lips 1999). A separate group of rats was trained as described and exposed to three days of saline administration ac- cording to the same amphetamine schedule described above. These rats then were treated with an effective dose of terguride (0.2 mg/kg; n ϭ 7) and PR responding was monitored as in the above experiment. Doses and schedules of terguride administration were chosen ac- cording to previous studies (Pulvirenti and Koob 1993; Pulvirenti et al. 1998). Terguride (Research Biochemicals International) was dissolved in distilled water and 1N HCl, and pH ad- justed to 5.5 with 1M NAOH. d-amphetamine sulfate Figure 1. Effect of repeated treatment with terguride (0.2 and (Sigma) was dissolved in saline and all drugs were in- 0.4 mg/kg, i.p. twice daily for four days) on responding for ϩ jected in a volume of 1.0 ml/kg. Data analyses were a sweet solution (3% sucrose 0.125% saccharin) under a progressive-ratio schedule of reinforcement. Values repre- performed using analysis of variance (ANOVA) as de- sent means Ϯ SEM of breaking points and cumulative total scribed by Pulvirenti and Koob (1993). First an overall responses (right) (saline, n ϭ 13; terguride 0.2 mg/kg, n ϭ analysis was performed to directly explore differences 10; terguride 0.4 mg/kg, n ϭ 10). * p Ͻ .01 Tukey’s test vs. between treatment groups. This was followed by com- baseline following significant ANOVA. Tukey’s test also parison at the various levels to explore at what time revealed a significant difference between terguride at the point (day) statistical significance was reached. Post- dose of 0.4 mg/kg and saline at Days 2, 3, and 4 (p Ͻ .05) but hoc Tukey’s test was used where appropriate. not at Day 1 (not indicated). NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 5 DA Partial Agonist and Amphetamine Withdrawal 791 Table 1. Effects of Repeated Treatment with Terguride on fects of lisuride on psychomotor retardation were evi- Progressive-Ratio Responding for a Sweet Solution in Rats dent since the first day of treatment. The reason for Not Previously Exposed to Amphetamine these differences is not presently clear, although it is possible that since terguride is a partial agonist its stim- Day ulatory effects on dopamine function may require re- Baseline 1234peated treatment to develop. Terguride 7.4 7.6 7.4 7.0 7.4 Although psychomotor retardation is also a compo- (0.2 mg/kg) Ϯ 0.35 Ϯ 0.81 Ϯ 0.72 Ϯ 0.79 Ϯ 0.65 nent of amphetamine withdrawal (Paulson et al. 1991; Pulvirenti and Koob 1993), it is unlikely that motor im- Ϯ ϭ Values represent means SEM of breaking points (n 7). pairment is solely responsible for the effects reported here and previously (Barr and Phillips 1999). Indeed rats have been shown to maintain high rates of operant dose of 0.4 mg/kg and saline at Days 2, 3, and 4 (p Ͻ responding for intracranial self-stimulation during psy- .05) but not at Day 1. chostimulant withdrawal (Markou and Koob 1992). Ad- Table 1 shows that terguride did not significantly ditionally, the pattern of sucrose consumption reported modify the total reinforcement earned on PR respond- by Barr and Phillips (1999) did not resemble the pattern ing for a sweet solution in animals not previously ex- of consummatory behavior observed after administra- posed to amphetamine [F(4,24)Ͻ1, NS].