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Comparative Study
. 2013 May;39(3):692-702.
doi: 10.1093/schbul/sbs077. Epub 2012 Aug 27.

Prior haloperidol, but not olanzapine, exposure augments the pursuit of reward cues: implications for substance abuse in schizophrenia

Anne-Marie Bédard  1 , Jérôme Maheux, Daniel Lévesque, Anne-Noël Samaha
Affiliations
Comparative Study

Prior haloperidol, but not olanzapine, exposure augments the pursuit of reward cues: implications for substance abuse in schizophrenia

Anne-Marie Bédard et al. Schizophr Bull. 2013 May.

Abstract

Drug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain's dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous haloperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) challenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c-fos mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH challenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction.

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Figures

Fig. 1.
Fig. 1.
The sequence of experimental procedures for Experiment 1 (A), where operant responding for a conditioned reward was assessed following haloperidol/olanzapine treatment cessation, and Experiment 2 (B), where amphetamine (AMPH)-induced c-fos mRNA expression was measured. Loco, locomotion.
Fig. 2.
Fig. 2.
Continuous haloperidol (0.5mg/kg/day via minipump; CONT-HAL), but not continuous olanzapine (10mg/kg/day via minipump; CONT-OLZ) or intermittent olanzapine (1mg/kg/day via subcutaneous [SC] injection; INT-OLZ) treatment enhanced the ability of amphetamine (AMPH) to potentiate operant responding for a conditioned reward. n′s = 14/condition. *P < .05 compared with vehicle (VEH) and INT-OLZ. Data are means ± SEM. VEH, group injected daily with SC phosphate-buffered saline. SAL, saline.
Fig. 3.
Fig. 3.
Continuous haloperidol (0.5mg/kg/day via minipump; CONT-HAL), but not continuous olanzapine (10mg/kg/day via minipump; CONT-OLZ) or intermittent olanzapine (1mg/kg/day via subcutaneous [SC] injection; INT-OLZ) treatment enhanced amphetamine-induced locomotion. n′s = 14/condition. *P < .05 compared with vehicle (VEH). Data are means ± SEM. VEH, group injected daily with SC phosphate-buffered saline. AMPH, amphetamine.
Fig. 4.
Fig. 4.
Continuous haloperidol treatment (0.5mg/kg/day via minipump; CONT-HAL) enhanced the c-fos mRNA response to amphetamine in the quadrants of the caudate-putamen (A–D) but not in the nucleus accumbens shell (E) or core (F). n′s = 6–9/condition. *P < .05 compared with VEH. Data are means ± SEM. VEH, group injected daily with subcutaneous phosphate-buffered saline. CONT-OLZ, group treated with 10mg/kg/day olanzapine via osmotic minipump; CTRL, combined control group receiving saline; AMPH, amphetamine; AcbSh, nucleus accumbens shell; AcbC, nucleus accumbens core; DM, dorsomedial; DL, dorsolateral; VM, ventrolateral; VL, ventrolateral.
Fig. 5.
Fig. 5.
Continuous treatment with either haloperidol (0.5mg/kg/day via minipump; CONT-HAL) or olanzapine (10mg/kg/day via minipump; CONT-OLZ) enhanced amphetamine-induced c-fos mRNA expression in the ventrolateral (A: VLO) and lateral (B: LO) orbitofrontal cortices and in the infralimbic (C: IL) and anterior cingulate (D: Cg1 and Cg3) cortices when compared with the CTRL group. n′s = 6–9/condition. α: P < .05 compared with CTRL. Data are means ± SEM. VEH, group injected daily with subcutaneous phosphate-buffered saline; CTRL, combined control group receiving saline; AMPH, amphetamine.
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