Psychopharmacology (2007) 191:759–765 DOI 10.1007/s00213-006-0520-2

ORIGINAL INVESTIGATION

Effects of aripiprazole on operant responding for a natural reward after psychostimulant withdrawal in rats Kerstin Schwabe & Michael Koch

Received: 4 May 2006 / Accepted: 16 July 2006 / Published online: 5 September 2006 # Springer-Verlag 2006

Abstract Rationale Withdrawal from repeated amphetamine administration has been shown to decrease the motivation to work for a natural reward in rats, a phenomenon thought to be associated with hypofunction of the mesolimbic dopamine system. Objectives We tested whether aripiprazole, a partial dopamine receptor agonist, can restore the animals_ responding for reward pellets after amphetamine withdrawal. Materials and methods Rats were trained to lever-press for food pellets under a progressive ratio-schedule of reinforcement. After reaching a stable breakpoint, i.e., the highest ratio completed, one group was injected ten times with increasing doses of amphetamine (1 to 10 mg/kg, three times a day for 4 days), while the other group received vehicle injections. The rats were again tested for their breakpoint 24 h after the last amphetamine injection under 0.0, 0.25, 0.75, and 2.5 mg/kg aripiprazole. Results Withdrawal from repeated amphetamine injection reduced the breakpoint while low doses of aripiprazole (0.25 and 0.75 mg/kg) prevented this effect. In addition, the rats needed a longer time for the first 20 pellets (fixed ratioschedule training before starting the progressive ratioschedule) after amphetamine withdrawal but not after subsequent injection with aripiprazole. It is notable that

M. Koch Brain Research Institute, Department of Neuropharmacology, University of Bremen, P.O. Box 33 04 40, 28 334 Bremen, Germany K. Schwabe (*) Department of Neurosurgery, Medical University, MHH, Carl-Neuberg-Str. 1, 30625 Hanover, Germany e-mail: [email protected]

the injection of 2.5 mg/kg aripiprazole reduced responding for reward pellets and prolonged the duration for the first 20 pellets irrespective of previous amphetamine or vehicle treatment. However, withdrawal from repeated administration of 0.25 and 2.5 mg/kg aripiprazole did not reduce responding for reward pellets. Conclusions These results suggest that aripiprazole may have potential use as a treatment for the motivational effects of the acute withdrawal stage of the psychostimulant addiction cycle. Keywords Amphetamine . Addiction . Breakpoint . Dopamine . Psychostimulant

Introduction Several neuropsychiatric disorders are related to abnormalities in a cortico–striato–pallido–thalamic circuitry with disturbed dopamine and serotonin action playing an important role (Swerdlow et al. 2001). Mesolimbic dopamine neurotransmission is critically involved in psychostimulant dependence with phases of high-dose intake of drugs (Fdrug binges_) together with increased dopamine levels, followed by periods of withdrawal with relative functional dopamine hypoactivity (Pulvirenti and Koob 2002). Psychostimulant withdrawal in humans is associated with fatigue, psychomotor retardation, and anhedonia, i.e., decreased pleasure from normally rewarding activities, all of which bear remarkable similarities to the symptoms of major depressive disorder (Pathiraja et al. 1995). The pharmacological treatment of this condition is of high importance. Some studies suggest a role of the dopamine D3 receptor in drug addiction. It has been shown that a D3 receptor partial agonist inhibits cocaine-seeking behavior

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that depends on the presentation of drug-associated cues (Pilla et al. 1999). In rats, amphetamine withdrawal causes psychomotor retardation and decreases motivation to work for a natural reward, akin to some aspects of the human depressive condition. In this context, withdrawal of repeated administration of amphetamine in rats has been shown to decrease operant responding for a sweet solution, as measured by a progressive ratio-schedule (Barr and Phillips 1999; Orsini et al. 2001). In this test, the ratio at which the subject ceases responding (Hodos 1961) or the highest ratio completed within a time constrained session (Abermann et al. 1998) has been regarded either as a measure of reinforcer efficacy (Hodos 1961; Cheeta et al. 1995) or as a measure of the organism_s motivation to obtain a reinforcer (Barr and Phillips 1999). Although this effect is typically observable for less than 1 week, it may be used to detect novel, rapidacting antidepressant compounds (Barr et al. 2002). The partial dopamine agonist aripiprazole is used as an antipsychotic compound for the treatment of schizophrenia (Taylor 2003). With regard to the dopamine system, aripiprazole is a potent, partial agonist at dopamine D2 receptors (Inoue et al. 1996; Lawler et al. 1999). In vivo, aripiprazole reduced apomorphine-induced stereotypy, thus behaving as a dopamine D2 receptor antagonist in rodent models of dopaminergic hyperactivity, but blocked the increase of dopamine synthesis in reserpine-treated rats, thus behaving as a dopamine D2 receptor agonist in a test of dopaminergic hypoactivity (Kikuchi et al. 1995). As aripiprazole behaves as a functional antagonist in conditions of high but as an agonist in conditions of low receptor occupancy by dopamine (McGawin and Goa 2002; Taylor 2003), it will also possibly restore the relative functional hypoactivity of the dopamine system during psychostimulant withdrawal. Thus, we addressed in this paper the question whether aripiprazole restores the animals_ responding for casein pellets after amphetamine withdrawal under a progressive ratio-schedule of reinforcement. As aripiprazole has partial agonistic activity at the dopamine receptor, we were also interested whether withdrawal after repeated administration of aripiprazole would decrease operant responding in this paradigm.

Materials and methods Animals Experiments were performed with male Wistar rats (n=95; Harlan and Winkelmann GmbH, Borchen, Germany) weighing 200–250 g. They were housed in groups of five to six animals in Type IV Macrolon cages under controlled environmental conditions (22-C, 12 h dark cycle, lights on

Psychopharmacology (2007) 191:759–765

at 07:00 A.M.). Rats were maintained on a body weight of approximately 85% of the free feeding weight by controlled feeding of 12 g rodent chow (Altromin 1324 standard diet; Lage, Germany) per rat per day. They had free access to tap water. A softly playing radio during the light cycle was used to provide a continuous background noise and to minimize the disturbing effects of sudden noise. The Principles of laboratory animal care were followed. All experiments were performed in strict adherence to the German law on the protection of animals as well as to the Guidelines for the care and use of mammals in neuroscience and behavioral research (National Research Council). Progressive ratio test The progressive ratio test was conducted in standard operant conditioning chambers (Coulborne). The rats were trained daily on a fixed ratio-schedule of responding with one pellet per lever-pressing (FR1) until they received 200 reward pellets (Caseinpellets; Bioserv, Frenchtown, NJ, USA) per 30 min for two consecutive days. After completing fixed ratio training, the rats were once daily placed on a progressive ratio-schedule of reinforcement. Each session was started with a FR1 schedule for 20 pellets, which was subsequently followed by the progressive ratio-schedule whereby successive reinforcement could be earned according to the following number of bar presses: from 1 to 10, one additional lever press per ratio (i.e., 1, 2, 3, ..., 10), from 10 to 20, two additional lever-presses per ratio (i.e., 10,12,14, ...,20), and so forth. The session ended when rats ceased lever pressing for 5 min with the final ratio achieved representing the Fbreakpoint_ value. The rats were trained in the progressive ratio-schedule once daily until their individual breakpoint was stable, i.e., the breakpoint did not differ by more than four ratios on three consecutive days. The measures taken were the breakpoint and additionally the time the rats needed to get the first 20 pellets in the FR1 schedule. Experiment I Upon reaching criterion, the subjects were randomly assigned to two different groups. One group was placed on an amphetamine (d-amphetamine sulfate; Sigma, Deisenhofen, Germany) drug administration schedule, the other group served as control [injection of vehicle (saline), 1 ml/kg]. The rats were injected subcutaneously three times per day (7 A.M., 2 P.M., and 9 P.M.), starting with a dose of 1 mg/kg of amphetamine (dose referring to the salt) and increasing by 1 mg/kg per injection for ten injections, i.e., last injection of 10 mg/kg on the fourth day at 7 A.M. The injection volume was 1 ml/kg for all doses. The subjects were not exposed to the test chambers at any time during administration of the drug.

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On the day after the last injection, the rats were assigned to four different groups. Each group was composed of rats previously treated with vehicle or amphetamine (n=8). For injection, we used a solution supplied by Bristol-Myers Squibb containing 7.5 mg aripiprazole in 1 ml vehicle, which was diluted to the required concentration with saline. The injection volume was 1 ml/kg for all doses. Twentyfour hours after the last amphetamine injection, the rats were injected intraperitoneally with doses of 0.0, 0.25, 0.75, and 2.5 mg/kg and tested in the progressive ratio-schedule 30 min after drug application. In a control experiment, we tested whether withdrawal after repeated amphetamine or acute injection of aripiprazole would affect the primary motivation to consume reward pellets. Twenty-four hours after repeated treatment with an escalating dose of amphetamine or vehicle (each group n=5) as well as 30 min after injection of 0.0, 0.25, or 2.5 mg/kg aripiprazole (each group n=7), the rats were placed in a standard Makrolon cage and the consumption of freely available reward pellets was measured for 10 min. Experiment II The rats were trained as described for Experiment I. Upon reaching the criterion, the subjects were randomly assigned to three different groups. Three groups (each n=7) were placed on an aripiprazole drug administration schedule (0.0, 0.25, and 2.5 mg/kg intraperitoneally b.i.d. at 7 A.M. and 7 P.M.). The rats were injected for 4 days (seven injections, last injection on the fourth day at 7 A.M.). Twenty-four hours after the last aripiprazole injection, the rats were tested in the progressive ratio test for 1 day. Statistical analysis Data analyses were performed using the statistical software Sigma Stat (Version 2.00 for Windows). First, analysis of variance (ANOVA) was carried out for each dose of aripiprazole using the data (breakpoint and FR1) before/after administration as within-subject factor and amphetamine/vehicle withdrawal as between-subjects factor. We then used the breakpoint values after amphetamine/vehicle withdrawal relative to the pre-injection data for comparison between different aripiprazole doses to control for slight shifts in baseline performance. The groups were compared by using a two-way ANOVA with amphetamine/vehicle withdrawal and dose of aripiprazole as between-subject factors. In addition, the amounts of freely available pellets consumed after amphetamine/ vehicle withdrawal were compared by using Student t test and the effects of acute injection of different doses of aripiprazole by one-way ANOVA. In case of significance, the ANOVA was followed by post hoc Tukey t test. All tests were performed two-sided and p<0.05 was considered significant.

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Results Experiment I The rats reached criterion of stable responding after 3–11 days (mean 5.4T0.25). After assigning the rats to their future treatment statistical analysis, two-way ANOVA revealed no difference between these groups with respect to amphetamine/vehicle administration or the aripiprazole dose used (all F-values <0.420; all p-values >0.74). The administration of an escalating dose of ten amphetamine injections over 4 days decreased the breakpoint of responding for reward pellets 24 h after withdrawal while vehicle administration over 4 days had no effect. The statistical analysis revealed a significant effect for the interaction between the factors before/after (i.e., the basal breakpoint value compared to the one after amphetamine or vehicle administration) and amphetamine/vehicle withdrawal (F1,14=12.562, p=0.03). In addition, ANOVA showed a significant effect for the factor before/after administration (F1,14=5.039, p=0.041) but no effect for the factor amphetamine/vehicle withdrawal (F1,14=2,288, p=0.153). Post hoc testing revealed that withdrawal after vehicle administration did not affect the breakpoint (p=0.374), while amphetamine withdrawal significantly reduced the breakpoint, both compared to pre-treatment value (p=0.001) and to vehicle-treated rats (p=0.013; Fig. 1).

Fig. 1 Effect of amphetamine withdrawal on responding for casein pellets under a progressive ratio-schedule of reinforcement. Values represent the breakpoint values (meanTSEM) for different groups (each group n=8) before (open bars) and after (closed bars) vehicle (no shading) or amphetamine administration (shading). Groups were treated with 0.0, 0.25, 0.75, and 2.5 mg/kg aripiprazole after withdrawal from repeated administration of vehicle or amphetamine. Significant differences within one dose of aripiprazole between groups before and after amphetamine or vehicle administration are indicated by asterisks and between groups with previous amphetamine or vehicle administration by a circle (two-way ANOVA, post hoc Tukey t test, p<0.05)

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The injection of the lower doses of aripiprazole (0.25 and 0.75 mg/kg) did not modify basal responding for reward pellets after vehicle administration but prevented the breakpoint-reducing effect of amphetamine withdrawal. The statistical analysis revealed no effect for amphetamine/vehicle withdrawal (0.25 mg/kg, F1,14=0.624, p=0.436; 0.75 mg/kg, F1,14=0.156, p=0.699). However, while 0.75 mg/kg aripiprazole reduced the effect of amphetamine withdrawal (F1,14=1.015, p=0.331), 0.25 mg/kg aripiprazole was only marginally effective (F1,14=4.384, p=0.055). For both doses of aripiprazole, no interaction between the factors before/after administration or amphetamine/vehicle withdrawal were found (0.25 mg/kg, F1,14=2.161, p=0.164; 0.75 mg/kg, F1,14=1.735, p=0.209; Fig. 1). The injection of the high dose of aripiprazole (2.5 mg/kg) reduced the breakpoint, both after vehicle and amphetamine withdrawal. The statistical analysis revealed a significant effect for the factor before/after amphetamine injection (F1,14=16.016, p=0.001) but no effect for amphetamine/ vehicle withdrawal (F1,14=0.391, p=0.542) and no interaction between these factors (F1,14=0.039, p=0.846). Post hoc testing revealed that 2.5 mg/kg aripiprazole reduced the breakpoint both after vehicle and amphetamine withdrawal compared to the pre-treatment data (vehicle, p=0.0181; amphetamine, p=0.01; Fig. 1). For comparison of the different doses of aripiprazole, we then used the breakpoint values after withdrawal relative to the data before amphetamine/vehicle administration. As the previous analysis showed a breakpoint-reducing effect for 2.5 mg/kg aripiprazole by itself, these data were excluded from this analysis. The ANOVA showed an effect of amphetamine/vehicle withdrawal (F1,14=9.296, p=0.004) but no effect of aripiprazole (F1,14=0.087, p=0.917) and no interaction between those treatments (F1,14=0.225, p=0.8). Post hoc testing revealed that, without aripiprazole, the breakpoint was reduced after amphetamine withdrawal compared to vehicle administration (p=0.044). The injection of 0.25 mg/kg aripiprazole abolished the breakpointreducing effect of repeated amphetamine withdrawal (p=0.231) while the dose of 0.75 mg/kg only marginally reduced the effect of amphetamine withdrawal (p=0.053; Table 1). An analysis of the time needed for getting the first 20 pellets in the FR1 schedule showed that withdrawal from repeated administration of amphetamine over 4 days increased the time needed to obtain these pellets, while repeated vehicle administration had no effect. The statistical analysis revealed a nearly significant effect for the factor before/after amphetamine injection (F1,14=3.936, p=0.067) and a significant interaction between this factor and the factor amphetamine/vehicle withdrawal (F1,14=10.127, p=0.007), while the factor amphetamine/vehicle withdrawal only was not significant (F1,14=0.206, p=0.657). Post hoc

Psychopharmacology (2007) 191:759–765 Table 1 Effect of amphetamine withdrawal on responding for casein pellets under a progressive ratio-schedule of reinforcement Aripiprazole (mg/kg)

Previous injection of vehicle

Previous injection of amphetamine

0.00 0.25 0.75

105T2.8 97.2T6.6 104.2T6.4

81.7T5.4 83.5T7.2 81.6T14

Data represent the breakpoint values after repeated vehicle or amphetamine administration relative to the pre-injection values (meanTSEM). The groups (each n=8) were treated with 0.0, 0.25, or 0.75 mg/kg aripiprazole. A significant difference between groups with previous amphetamine or vehicle administration is indicated by the italicized value (two-way ANOVA, post hoc Tukey t test, p<0.05).

testing revealed that vehicle treatment did not affect the time needed for the first 20 pellets (p=0.411), while after amphetamine withdrawal this time was significantly prolonged compared to the pre-treatment value (p=0.003). In addition, there was a trend for significance compared to rats previously treated with vehicle (p=0.064; Table 2). The injection of the lower doses of aripiprazole (0.25 and 0.75 mg/kg) did not affect the time needed to get the first 20 pellets after vehicle administration but prevented the increase in time needed by rats after amphetamine withdrawal. The statistical analysis revealed no effect for the factor amphetamine/vehicle withdrawal (0.25 mg/kg, F1,14=0.773, p=0.394; 0.75 mg/kg, F1,14=0.551, p=0.470), no effect for the factor before/after injection (0.25 mg/kg, F1,14=1.480, p=0.244; 0.75 mg/kg, F1,14=3.037, p=0.103), and no interaction between these factors for both doses of aripiprazole (0.25 mg/kg, F1,14=1.890, p=0.191; 0.75 mg/kg, F1,14=2.619, p=0.128; Table 2). The injection of the high dose of aripiprazole (2.5 mg/kg) prolonged the time needed to obtain the first 20 pellets both after vehicle and amphetamine injection. The statistical analysis revealed a trend of an effect for amphetamine/ vehicle withdrawal (F1,14=3.225, p=0.094) and a significant effect for the factor before/after amphetamine administration (F1,14=5.800, p=0.030) but no interaction between these factors (F1,14=0.400, p=0.537). Post hoc testing revealed that 2.5 mg/kg aripiprazole increased the time needed for the first 20 pellets after previous amphetamine administration compared to the pre-treatment value (p=0.050), while after vehicle administration this effect did not reach the level of significance (p=0.230; Table 2). Our control experiment for primary motivation to consume freely available palatable casein pellets showed that amphetamine withdrawal reduced the intake of freely available casein pellets (p<0.001, Student t test). In addition, a one-way ANOVA showed that 0.0, 0.25, and 2.5 mg/kg aripiprazole did not affect the intake of freely available reward pellets (F1,17=0.837, p=0.451; data not shown).

Psychopharmacology (2007) 191:759–765

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Table 2 Effect of amphetamine withdrawal on responding for casein pellets under a fixed ratio-schedule of reinforcement Aripiprazole (mg/kg)

0.00 0.25 0.75 2.50

Previous injection of vehicle

Previous injection of amphetamine

Before

After

Before

After

76.3T5.2 64.6T2.3 87.1T10 69.4T4.2

70.6T4.8 63.7T1.7 88.8T5.7 91.5T16.0

65.1T5.1 61.3T4.5 77.8T7.0 82.4T6.9

89.4T10.5a,b 77.6T11.2 122T26 120T16.1a

Data represent the time needed for the first 20 pellets (in seconds) in a fixed ratio-schedule before and after repeated vehicle or amphetamine administration (meanTSEM). The groups (each n=8) were treated with 0.0, 0.25, 0.75, or 2.5 mg/kg aripiprazole. a Significant differences before and after amphetamine or vehicle administration (two-way ANOVA, post hoc Tukey t test, p<0.05) b Significant differences between groups with previous amphetamine or vehicle administration (two-way ANOVA, post hoc Tukey t test, p<0.05)

Experiment II The rats reached criterion of stable responding after 3–10 days (mean 5.4T0.4). After assigning the rats to their future treatment, the statistical analysis revealed no difference between these groups with respect to amphetamine/vehicle administration or aripiprazole dose used (F2,20=0.107; p=0.899). The breakpoint of responding for reward 24 h after the last injection did not differ between groups that were injected with 0.0, 0.25, and 2.5 mg/kg aripiprazole seven times over 4 days. The statistical analysis revealed an effect for the factor before/after injection (F1,18=5.170, p=0.035), no effect for the factor aripiprazole withdrawal (F1,18=0.130, p=0.879), and no interaction between these factors (F1,14=0.242, p=0.787). Post hoc testing revealed that the breakpoint was increased in all groups after the 4 days of injection independent of the dose of aripiprazole used (Fig. 2).

40

*

30

breakpoint

Fig. 2 Effect of repeated aripiprazole injection on responding for casein pellets under a progressive ratio-schedule of reinforcement 24 h after the last injection. Values represent the breakpoint values (meanTSEM) for different groups (each group n=7) before (open bars) and after (closed bars) aripiprazole administration (0.0, 0.25, and 2.5 mg/kg). Significant differences before and after aripiprazole administration are indicated by asterisks (two-way ANOVA)

20

10

0

0.0

0.25

0.75

aripiprazole (mg/kg) before after

The time needed to obtain the first 20 pellets 24 h after the last injection did not differ between the groups that were injected with 0.0, 0.25, and 2.5 mg/kg aripiprazole seven times over 4 days. The statistical analysis revealed no effect for the factor before/after injection (F1,18=0.437, p=0.517), no effect for the factor aripiprazole treatment (F1,18=0.420, p=0.663), and no interaction between these factors (F1,14=0.415, p=0.666; data not shown).

Discussion We showed that amphetamine withdrawal is associated with decreased motivation to respond for rewarding food pellets as measured by a reduced breakpoint in a progressive ratioschedule, thus confirming previous results (Barr and Phillips 1999). Low doses of aripiprazole (0.25 and 0.75 mg/kg) did not modify basal responding for reward pellets but attenuated the reduction of breakpoint in rats previously treated with amphetamine. Low doses of aripiprazole likewise reduced the time needed to get the first 20 pellets (FR1 schedule), which was prolonged after amphetamine withdrawal. However, the injection of a high dose of aripiprazole (2.5 mg/kg) reduced responding for reward pellets both after amphetamine and vehicle injection. It was notable that even a high dose of aripiprazole did not reduce the primary motivation to consume reward pellets when freely available, suggesting that aripiprazole at lower doses did not affect the primary motivation to consume reward pellets but attenuated withdrawal effects on instrumental behavior. Aripiprazole is a partial agonist at dopamine D2 receptors and 5-HT1A receptors and acts as an antagonist at 5-HT2A receptors, thus representing the first member of a new generation of antipsychotic drugs (Grady et al. 2003). In schizophrenia, where positive symptoms are hypothesized to result from excess subcortical dopamine release while negative symptoms may result from hypofunction of cortical dopamine systems, the application of aripiprazole already proved to be successful in the pharmacological treatment of both classes of symptoms (Taylor 2003). Disturbed mesolimbic dopamine neurotransmission also appears to be critically involved in psychostimulant dependence. The course of the cocaine or amphetamine addiction cycle includes phases of intake of high doses of drugs (Fdrug binges_) with high dopamine levels, followed by periods of withdrawal with relative dopamine hypoactivity (Pulvirenti and Koob 2002). Partial dopamine receptor agonists like aripiprazole may therefore be valuable for the treatment of various phases of the psychostimulant addictive cycle. In this study, they might counteract the high dopamine levels found during the binging periods of the dependence cycle, but due to their

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intrinsic agonistic activity they also restore the relative functional dopamine hypoactivity during the withdrawal phase (Pulvirenti and Koob 2002). It is interesting that it has been shown that the D3 receptor partial agonist BP 897 inhibits cocaine-seeking behavior that depends on the presentation of drug-associated cues, without having any intrinsic, primary rewarding effects (Pilla et al. 1999). In rodents, amphetamine withdrawal causes decreased motivation to work for a natural reward, an effect thought to be associated with hypofunction of the mesolimbic dopamine system and is therefore used as a measure for withdrawal-induced psychomotor retardation and anhedonia, which are also regarded as symptoms of major depression (Pulvirenti and Koob 1993; Barr and Phillips 1999). The present study showed that, during amphetamine withdrawal, the administration of aripiprazole attenuated the decrease in responding for the palatable pellets while not affecting baseline responses. This finding suggests that aripiprazole, possibly due to its agonistic-like actions on dopamine receptors under these conditions, is a potential therapeutic approach for the acute withdrawal stage of the amphetamine and perhaps of cocaine addiction cycle. The results presented here are in line with the effect of systemic treatment with the partial dopamine agonist terguride, which has been shown to restore responding for rewarding pellets during withdrawal from repeated amphetamine administration (Orsini et al. 2001). Similar to aripiprazole, terguride itself did not modify basal responding for food pellets in rats not exposed to amphetamine, thus ruling out possible nonspecific effects of the partial agonist on operant behavior during the test. It is interesting to note that it has recently been shown that aripiprazole augments the effect of selective serotonin reuptake inhibitors for treatmentresistant major depressive disorder (Papakostas et al. 2005). There have been relatively few studies on the effects of neuroleptics on progressive ratio performance. The data available indicate that the breakpoint is reduced after acute injection of typical neuroleptics (i.e., those dopamine receptor antagonists with relatively high affinity for D2 dopamine receptors), including raclopride (Cheeta et al. 1995; Abermann et al. 1998), haloperidol (Abermann et al. 1998), and chlorpromazine (Ferguson and Paule 1996), while the atypical antipsychotic clozapine has been shown to increase the breakpoint (Mobini et al. 2000). The putative anhedonic effects of Ftypical_ neuroleptics are generally attributed to the blockade of central dopamine receptors (primarily D2 receptors; Wise and Rompre 1982) while Fatypical_ antipsychotic drugs, such as clozapine, have much lower affinity for these receptors. It is interesting to note that, after vehicle withdrawal (i.e., under baseline condition), the lower doses of aripiprazole had no

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effect on breakpoint in the present study, whereas after amphetamine withdrawal it restored instrumental responding. However, in agreement with its partial agonistic properties at higher doses, aripiprazole reduced instrumental responding both after vehicle and amphetamine withdrawal. The withdrawal of amphetamine also prolonged the time needed for the first 20 pellets, raising the possibility of a motor impairment. Psychomotor retardation or decreased levels of locomotor activity have previously been reported during amphetamine withdrawal (Paulson et al. 1991; Pulvirenti and Koob 1993; Schindler et al. 1994), whereas others have shown that rats maintain high rates of operant responding for intracranial self-stimulation during psychostimulant withdrawal (Markou and Koob 1992). In addition, although previous studies did not observe any effect of amphetamine withdrawal on free consumption of food pellets or sweet solution (Barr and Phillips 1999), this measure was reduced in the present study, indicating that the reduced responding for reward pellets during amphetamine withdrawal may be due to an anorectic effect (Caul et al. 1988). However, aripiprazole at low dose antagonized these effects, while in rats that had not been exposed to amphetamine it did not modify basal responding for reward pellets, thus ruling out possible nonspecific effects on the behavior used in this test. It is interesting to note that although aripiprazole at a high dose reduced the breakpoint and prolonged the time needed for the first 20 pellets independent of previous amphetamine administration, this effect is apparently due to reduced willingness to work for food reward, as it did not influence the consumption of the palatable reward pellets when it was freely available, i.e., it did not affect the primary motivation to consume casein pellets. It is of note that withdrawal after repeated treatment with aripiprazole did not decrease operant responding in a progressive ratio-schedule, even when the high dose was used for repeated treatment. Thus, although aripiprazole has partial agonistic activity at the dopamine receptor, withdrawal after repeated administration of aripiprazole did not affect motivation to work for a natural reward, indicating that aripiprazole itself does not alter measures of motivation. Aripiprazole is successfully used clinically for the treatment of positive and negative symptoms of schizophrenia with low risk of side effects such as extrapyramidal symptoms, sedation, or elevated prolactine levels (Kane et al. 2002). The results presented here altogether suggest that aripiprazole may also have potential use as a treatment for the motivational effects of acute and maybe protracted abstinence from psychostimulant drugs. Our findings also support the contention that psychostimulant withdrawal in rodents may be used to screen for novel, rapidly acting antidepressant treatments.

Psychopharmacology (2007) 191:759–765 Acknowledgments We thank Bristol-Myers Squibb for providing aripiprazole and Simone Sikora for technical assistance.

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