Psychopharmacology (2012) 220:771–785 subjective and motivational properties of cocaine. There- fore, we expected that α-flupenthixol would decrease both sucrose and cocaine seeking, but that its effects on cocaine seeking would be stronger. In addition, we expected that treatment with α-flupenthixol would affect cocaine taking, but not sucrose taking. To confirm whether the effects on seeking were a consequence of a decrease of the positive subjective properties and/or a suppression of the willing- ness to exert effort, we also performed an experiment in which we treated animals responding for sucrose or cocaine under an FR-1 schedule of reinforcement with α-flupenthixol. Here, we expected an increase in cocaine intake and no effect on sucrose intake after treatment with α-flupenthixol, indicating a role for dopamine in cocaine but not sucrose reward. Third, we measured responding after reward omission. Extinction of cocaine and sucrose taking, using ST chain schedules, has been shown to reduce seeking rates (Johnston et al. 2001; Olmstead et al. 2001). However, in these previous studies, extinction of the taking response was performed in the absence of the seeking lever. We here evaluated whether the absence of the primary reinforcer would also reduce seeking within the same sessions, which we expected to happen. In fact, the absence of a reduction of seeking rates when the primary reinforcer is not subsequently presented would indicate that responding had progressed from a goal-directed action–outcome, to a habitual stimulus– response associative structure (Dickinson 1985). Materials and methods Subjects Male Wistar rats (Charles River, Sulzfeld, Germany) weighing 250± 15 g at the time of arrival in our facility were used for all experiments. Animals were singly housed in Macrolon cages (40× 26 ×20 cm) in climate-controlled rooms (temperature 21±2°C, 60–65% relative humidity) under a reversed 12-h day/night cycle with lights on at 7 p.m. Animals were allowed to habituate to the housing conditions for at least 9 days before use. Prior to the start of the self-administration sessions, rats were subjected to scheduled feeding. To avoid association between the self- administration sessions and feeding, rats were fed with 20 g chow (SDS, England) at least 1 h after the sessions. This amount was sufficient to maintain body weight and growth. Throughout the experiment, water was available ad libitum, except during self-administration sessions. Self-administration sessions were carried out between 09:00 and 18:00, for 5 days a week. Experiments were approved by the Animal Ethics Committee of Utrecht University, The Netherlands and were conducted in 773 agreement with Dutch laws (Wet op de dierproeven, 1996) and European regulations (Guideline 86/609/EEC). Surgery Rats were anesthetized with ketamine hydrochloride (75 mg/kg, i.m.) and xylazine (10 mg/kg, i.m.) or medetomi- dine (0.4 mg/kg, s.c.), and a catheter was placed in the right jugular vein. Catheters consisted of a silastic tube connected to a guide cannula and a mesh on the base of the cannula (CamCaths, Cambridge, UK). The cannulas were secured by placing the mesh below the skin on the back of the animals. All objects and instruments used during surgery were thoroughly sterilized. Carprofen (5 mg/kg, s.c.) was adminis- tered before and two times after surgery for postsurgical pain relief. To prevent infection, rats were treated with gentamycine (5 mg/kg, s.c.) before surgery and for five consecutive days postsurgery. In two subjects, a defective catheter was replaced with a new catheter in the left jugular vein during the course of the experiment. Apparatus All subjects were trained and tested in operant conditioning chambers (29.5 cm L, 24 cm W 25 cm H; Med Associates, Georgia, VT, USA). The chambers were placed in light- and sound-attenuating cubicles equipped with a ventilation fan. Each chamber was equipped with two 4.8-cm-wide retractable levers, placed 11.7 cm apart and 6.0 cm from the grid floor. The assignment of the left and right lever as seeking and taking lever was counterbalanced across rats. A cue light was present above each lever (28 V, 100 mA) and a house light (28 V, 100 mA) was located on the opposite wall. Sucrose pellets (45 mg, formula F, Research Diets, New Brunswick, NJ, USA) could be delivered at the wall opposite to the levers via a dispenser. Cocaine infusions were controlled by a syringe pump placed on top of the cubicles. During the cocaine self-administration sessions, polyethylene tubing ran from the syringe placed in the syringe pump via a swivel to the cannula on the subjects’ back; in the operant chamber, tubing was shielded with a metal spring. Priming infusions of cocaine were never given. After each session, intravenous catheters were flushed with 0.15-ml heparinized saline. Experimental events and data recording were con- trolled by procedures written in MedState Notation using MED-PC for Windows (WMPC). Procedure ST(RI) schedule with cocaine reinforcement Rats were trained to lever press for cocaine under a heterogeneous ST chain schedule of reinforcement with an