Neuropsychopharmacology (2005), 1–9& 2005 Nature Publishing Group Olanzapine-Induced Suppression of CocaineSelf-Administration in Rhesus Monkeys Leonard L Howell*,1,2, Kristin M Wilcox1, Kimberly P Lindsey1 and Heather L Kimmel1 Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; 2Department of Psychiatry and Behavioral Sciences, The neuropharmacological profile of the atypical antipsychotic, olanzapine, is consistent with a potentially useful medication for cocaine abuse. The present study utilized an i.v. drug self-administration paradigm in nonhuman primates to obtain definitive evidence regarding the effectiveness of olanzapine to modulate the reinforcing effects of cocaine. The effects of olanzapine were compared directly to those of the neuroleptic, haloperidol. Rhesus monkeys (n ¼ 7) were trained to self-administer cocaine (0.03–0.3 mg/kg/injection) under a second-order, fixed-interval 600-s schedule with fixed ratio 20 components. Experimental sessions comprised five consecutive fixed intervals, each followed by a 1-min timeout. In drug-interaction experiments, a single dose of olanzapine (0.03–0.3 mg/kg) or haloperidol (0.01–0.03 mg/kg) was administered i.v. 15 min presession for at least three consecutive sessions. In drug-substitution experiments, different doses of olanzapine (0.01–0.1 mg/kg/injection) were substituted for cocaine until responding stabilized. Olanzapine caused dose- related decreases in cocaine self-administration at pretreatment doses that had no overt behavioral effects indicative of sedation. A dose of 0.1 mg/kg eliminated cocaine self-administration in all subjects. In contrast, doses of haloperidol that suppressed cocaine self- administration induced marked sedation and catalepsy. Olanzapine failed to maintain self-administration behavior above saline extinction levels over a range of unit doses. In vivo microdialysis experiments in a second group of awake rhesus monkeys (n ¼ 3) confirmed previous reports in rodents that olanzapine effectively increases extracellular dopamine in ventral striatum. The dose of olanzapine that markedly suppressed cocaine self-administration behavior increased dopamine to approximately 190% of control values. Lastly, pretreatment with fluoxetine had no systematic effect on olanzapine-induced increases in striatal dopamine. The results indicate that olanzapine can effectively suppress cocaine self-administration behavior in nonhuman primates at doses that enhance dopamine release but do not maintain drug self-administration.
Neuropsychopharmacology advance online publication, 27 July 2005; doi:10.1038/sj.npp.1300828 Keywords: olanzapine; cocaine; dopamine; drug self-administration; microdialysis; nonhuman primates like drugs for DAT correlate well with their potencies forsupporting self-administration behavior (Ritz et al, 1987; Cocaine abuse remains a significant health concern, yet no Bergman et al, 1989, Wilcox et al, 1999). In humans, a effective pharmacotherapy is currently in clinical use.
significant correlation has been observed between DAT Cocaine blocks the reuptake of monoamines including occupancy and the intensity of subjective effects produced dopamine, norepinephrine, and serotonin with approxi- by intravenous cocaine (Volkow et al, 1997). Conversely, mately equal potency (Heikkila and Manzino, 1984; Reith dopamine antagonists can attenuate specific behavioral et al, 1986; Kuhar et al, 1991). However, the acute effects of cocaine in a surmountable manner including its behavioral effects of cocaine in rodents and primates have reinforcing effects (De Wit and Wise, 1977; Woolverton, been linked most closely to increases in dopamine 1986; Hemby et al, 1996). Cocaine affects neurotransmission associated with dopamine transporter (DAT) inhibition in various brain dopamine systems leading to a variety of (Wise, 1984; Ritz et al, 1987; Kleven and Woolverton, 1993; behavioral effects, but the mesolimbic/mesocortical dopa- Howell and Wilcox, 2001). The affinities of several cocaine- mine system appears to be a critical mediator of thereinforcing effects of cocaine (Kuhar et al, 1991; Wise, *Correspondence: Dr LL Howell, Yerkes National Primate Research 1998). Collectively, the results obtained in behavioral Center, Emory University, 954 Gatewood Road NE, Atlanta, GA studies provide compelling evidence that dopamine plays 30329, USA, Tel: þ 1 404 727 7730, Fax: þ 1 404 727 1266, a major role in the neuropharmacology and addictive E-mail: [email protected] 12 January 2005; revised 9 May 2005; accepted 7 June 2005 Online publication: 20 June 2005 at Given the obvious importance of dopaminergic mechan- isms in the addictive properties of cocaine, the development Olanzapine and cocaine self-administration and use of compounds that target dopaminergic systems Animals’ and were approved by the Institutional Animal represents a reasonable approach for the pharmacological Care and Use Committee of Emory University.
treatment of cocaine abuse. The neuropharmacologicalprofile of the atypical antipsychotic, olanzapine, is con- sistent with a potentially useful medication. Olanzapine isan antagonist with high affinity for dopamine D Each subject was prepared with a chronic indwelling venous catheter under sterile surgical conditions using a technique 4-receptors (Moore et al, 1993; Bymaster et al, 1996, 1997), and it appears to have mesolimbic selectivity (Moore et al, described previously (Wilcox et al, 2002). Preoperative 1993) consistent with other atypical antipsychotics (Hand antibiotics (Rocephin, 25 mg/kg or Cefazolin, 25 mg/kg) et al, 1987). Interestingly, olanzapine induces significant were given on the day of surgery to help prevent infection. A elevations in extracellular dopamine in vivo in the silicone catheter (0.65 mm ID, 1.75 mm OD; Access Techno- prefrontal cortex, striatum, and nucleus accumbens of rats logies, Skokie, IL) was implanted under a combination of (Li et al, 1998; Zhang et al, 2000; Koch et al, 2004). In Telazol (4.0 mg/kg) and isoflurane anesthesia using aseptic behavioral studies, pretreatment with olanzapine produced techniques. The proximal end of the catheter terminated in dose-dependent decreases in cocaine self-administration the vena cava above the right atrium, and the distal end was in rats trained under a simple fixed-ratio schedule of routed under the skin and attached to a subcutaneous i.v. drug delivery (Meil and Schechter, 1997). Clozapine, vascular access port (Access Technologies, Skokie, IL) another atypical antipsychotic with a pharmacological located in the center of the lower back. After surgery, the subject was returned to its home cage and received Bymaster et al, 1996), significantly attenuated the subjective Banamine (1.0 mg/kg) every 6 h for 24 h postoperatively to effects of cocaine in human cocaine abusers (Farren et al, reduce pain and discomfort associated with surgery.
2000). Collectively, these studies suggest a potential thera- Catheters were flushed daily with 100 U/ml heparinized peutic role for olanzapine in the treatment of cocaine saline to maintain patency. In experiments involving in vivo abuse. Moreover, its antipsychotic actions could serve to microdialysis, guide cannulae were implanted bilaterally alleviate stimulant-induced psychotic-like symptoms that into the caudate nucleus under sterile conditions. The are not targeted by other medications currently under positioning of the guide cannulae allowed for targeting of the ventral striatum corresponding to the nucleus accum- The present study determined the effectiveness of bens. Preoperative antibiotics (Rocephin, 25 mg/kg) were olanzapine in suppressing cocaine self-administration given on the day of surgery to help prevent infection. The behavior maintained by a complex schedule of i.v. drug animals were sedated with Telazol (4.0 mg/kg) and main- delivery in rhesus monkeys. The effects of olanzapine were tained on isoflurane anesthesia during the surgery. The compared directly to those of the neuroleptic, haloperidol, subjects were positioned in a stereotaxic frame, and in order to access the potential contribution of motor side coordinates derived from MRI were used for accurate effects. In addition, olanzapine was substituted for cocaine probe placement. A trephine drill was used to make two in drug self-administration experiments in order to small burr holes directly above the ventral striatum, and the characterize its reinforcing properties in monkeys with a guide cannulae were inserted to the appropriate depth.
history of cocaine use. The drug-substitution procedure is a Teflon screws attached to the skull were used to anchor well-validated predictor of abuse liability in humans. Lastly, cranioplastic cement, and the guide cannulae were enclosed the neurochemical effects of olanzapine on extracellular within a small plastic chamber to prevent access by the dopamine in the ventral striatum of conscious monkeys monkeys. Stainless-steel stylets were placed in the guide were determined with in vivo microdialysis techniques.
cannulae when not in use. Monkeys were allowed to recover Given the recent clinical interest in potential interactions from surgery for 2 weeks before initiating microdialysis between selective serotonin reuptake inhibitors (SSRIs) and experiments. All animals received Banamine (1.0 mg/kg) atypical antipsychotics, the effects of coadministration of every 6 for 24 h postoperatively, or longer if they exhibited fluoxetine and olanzapine on extracellular dopamine also were determined. Olanzapine suppressed cocaine self-administration at a dose that enhanced dopamine release, but did not exhibit abuse liability or overt motor sideeffects. Moreover, pretreatment with fluoxetine had no Cocaine HCl (National Institute on Drug Abuse, Rockville, systematic effect on olanzapine-induced increases in extra- MD) and fluoxetine HCl (Eli Lilly and Company) were dissolved in 0.9% saline. Drug doses were determined assalts. Olanzapine (Eli Lilly and Company) was dissolved in0.01 N HCl and diluted with distilled water to appropriate Subjects. Six female and four male adult rhesus monkeys(Macaca mulatta) weighing 7.5–13.0 kg were used as During behavioral testing, each monkey was seated in a subjects. Each subject was housed individually and fed commercially available primate chair (Primate Products, Purina monkey chow, fruits, and vegetables. Water was Redwood City, CA, USA), and a response panel with one continuously available. Animal care procedures strictly lever was mounted on the front of chair. Located above the followed the NIH ‘Guide for the Care and Use of Laboratory lever in the center of the response panel were red and white Olanzapine and cocaine self-administrationLL Howell et al stimulus lights. Once the monkey was seated in the chair, a chamber. The chair limited movement of the animals Huber needle (Access Technologies, Skokie, IL) was and facilitated connections between the implanted probes inserted into the venous access port. The polyvinyl-chloride and appropriate perfusion equipment. A Lexan plate tubing attached to the Huber needle was connected to a positioned perpendicular to the medial plane of the body, motor-driven syringe (Coulbourn Instruments, Allentown, just above shoulder height, ensured that animals could not PA) located outside of the chamber containing the drug contact the probe area. A microinjection pump (CMA/102) solution. A volume of 2.0 ml/infusion was delivered over 7 s.
located outside the chamber continuously delivered artifi- Testing during daily 1-h sessions occurred in a ventilated, cial cerebrospinal fluid (Na2HPO4, 1.0 mM; NaCl, 150 mM; sound-attenuating chamber. IBM compatible computers KCl, 3 mM; CaCl, 1.3 mM; MgCl, 1.0 mM; and ascorbic acid, controlled experimental events and recorded data.
0.15 mM) via FEP Teflon tubing to the probe for perfusion Subjects responded for i.v. infusions of cocaine under a second-order schedule of reinforcement, as described During a 2-h equilibrium period, animals sat in the previously (Wilcox et al, 2002). The training dose of chamber, and repeated 10-min samples were obtained.
cocaine was 0.1 mg/kg/infusion. When the daily session Subsequently, a single dose of cocaine (0.5 mg/kg), olanza- began, the red light on the response panel was illuminated pine (0.1 mg/kg), fluoxetine (3.0 mg/kg) or a combination of and responding resulted in the delivery of a drug infusion olanzapine (0.1 mg/kg) and fluoxetine (3.0 mg/kg) was and brief 2-s illumination of the white light. Initially, the administered i.v. to determine drug-induced increases in fixed ratio (FR) was one (FR 1) and gradually increased to extracellular dopamine. In drug-combination studies, FR 20. Ultimately, a second-order schedule of reinforcement fluoxetine was administered first, and olanzapine was was in effect, with the first FR 20 completed after 10 min administered 30 min later. The order of drug testing was (fixed-interval, FI 10) resulting in a drug infusion. FR 20 randomized and counterbalanced across treatment condi- components completed within the 10-min FI resulted in tions, and at least 1 week separated repeated determina- illumination of the white light for 2 s. There was a 30-s tions. Samples were collected outside the test chamber at limited hold for completion of the first FR 20 after the FI 10 10-min intervals to ensure that the monkeys were not had elapsed, and a drug infusion was not delivered if the disturbed during the experiments. Probes were tested in limited hold expired. Drug infusions were signaled by a vitro to determine the suitability of probe efficiency and change in the lights from red to white for 15 s. Following performance before and after in vivo experiments. Micro- each drug infusion there was a 1-min timeout during which bore HPLC and electrochemical detection quantitated responding on the lever had no programmed consequences.
extracellular levels of dopamine according to well-estab- A total of five infusions could be delivered during a daily lished analytical procedures (Church et al, 1987; Skirboll session comprising five FI 10-min (FR 20:s) components.
et al, 1990; Parsons and Justice, 1993).
The training sequence remained in effect until responding for cocaine was stable (o20% variance in daily response rate over five consecutive days), after which saline wassubstituted for cocaine until responding decreased to below Response rates for individual subjects were analyzed as a 30% of responding for the training dose of cocaine. After function of dose for each drug. Average rates of cocaine- saline extinction, the maintenance dose (0.1 mg/kg/infu- maintained responding following pretreatment drugs were sion) of cocaine was reinstated and responding was allowed compared to rates of cocaine-maintained responding to stabilize. For pretreatment studies, a given dose of drug following saline pretreatments using one-way ANOVA. Post was administered i.v. 15 min presession on three consecu- hoc comparisons were made using Dunnet’s method.
tive days, typically Tuesday, Wednesday, and Thursday.
Changes in percent basal dopamine were calculated for Vehicle was administered on all days that subjects did not each drug treatment (increase in extracellular dopamine in receive a drug pretreatment, and these data contributed to the presence of drug/basal level of dopamine) *100%. Mean ongoing calculations of baseline stability. Pretreatment percent basal dopamine was analyzed as a function of drug doses were administered on two separate occasions in an and time, and data were derived from individual subjects.
ascending order. All doses of a particular drug were studiedin combination with 0.1 mg/kg/infusion cocaine first.
Subsequently, the maintenance dose of cocaine was changed to 0.3 mg/kg/infusion, and drug pretreatments were re- peated as described above. For drug-substitution studies,each subject was allowed to self-administer several doses of Dose–effect curves for cocaine self-administration generally olanzapine in a randomized order. Substitution for each were characterized as inverted U-shaped functions in drug dose continued for at least five consecutive sessions, or until responding stabilized (o20% variance in daily (0.03 mg/kg/infusion) maintained peak rates of responding in two subjects (RMm-4 and ROu-4) (Figure 1). The highestunit dose (1.0 mg/kg/infusion) maintained rates of respond- ing well below peak rates in all subjects. Maintenance dosesof cocaine (0.03–0.3 mg/kg/infusion) for drug pretreatment At the time of testing, each monkey was seated in a studies were selected to encompass doses that maintained commercially available primate chair (Primate Products, high, stable rates of responding above saline extinction Inc., Miami, FL). Daily sessions lasted for approximately 4 h levels. Pretreatment with olanzapine (0.03–0.3 mg/kg) and were conducted within a ventilated, sound-attenuating produced significant (po0.05) reductions in cocaine Olanzapine and cocaine self-administration Response rates (percent control) for three maintenance doses of cocaine (0.03, 0.10, and 0.30 mg/kg/infusion) after pretreatment witholanzapine as a function of olanzapine dose under a second-order scheduleof reinforcement in rhesus monkeys. Each panel represents an individualmonkey. Data points over VEH indicate response rates when a vehiclepretreatment was given prior to the cocaine self-administration session.
The effects of olanzapine were compared directly to those of the neuroleptic, haloperidol (Figure 3). Pretreatment witheither 0.01 mg/kg (RMk-4 and RKs-4) or 0.03 mg/kg (ROu-4) produced significant reductions in cocaine self-adminis-tration. In contrast to olanzapine pretreatments, the effectsof haloperidol were greater on the second and third days ofpretreatment compared to the first day of pretreatment.
Moreover, doses of haloperidol that suppressed cocaineself-administration caused marked sedation and catalepsy.
Gross observations in the animal home room after testsessions indicated pronounced effects on motor behavior.
Note that lower doses of haloperidol were ineffective in Mean (7SD) rates of responding (responses/s) maintained by reducing cocaine self-administration and did not induce cocaine self-administration in individual subjects. Data were derived from observable effects on motor behavior (data not shown).
the last 5 days of each condition that met stability criterion of o20%variation. Dashed lines indicate the upper limit for responding during saline Drug doses shown in Figure 3 represent the lowest doses that suppressed cocaine self-administration in individualsubjects.
Olanzapine (0.01–0.1 mg/kg/infusion) also was substi- self-administration in all subjects (Figure 2). There was no tuted for cocaine in drug self-administration studies in change in effectiveness over consecutive 3-day pretreat- order to characterize its reinforcing effects (Figure 4). When ments, so data were pooled across all pretreatment sessions.
different unit doses of olanzapine were substituted for Responding was completely eliminated in three of four cocaine for a minimum of 5 consecutive sessions, response subjects (RVt-3, RSo-4, and ROu-4) and markedly sup- rates were similar to or less than those maintained under pressed in the fourth subject (RMm-4). Olanzapine was saline substitution (extinction) conditions. The latter results more effective in suppressing cocaine self-administration at clearly indicated that olanzapine lacked reinforcing effects.
the higher maintenance dose of cocaine in three of foursubjects (RMm-4, RVt-3, and RSo-4) as shown by the leftward position of the olanzapine dose–effect curves.
Doses of olanzapine that produced significant reductions Drug-induced changes in extracellular dopamine in ventral in cocaine self-administration had no overt behavioral striatum were characterized in awake subjects sitting quietly effects indicative of sedation. Gross observations in the in a primate chair. Cocaine (0.5 mg/kg) produced marked animal home room after test sessions indicated normal elevations in extracellular dopamine to approximately 270% of baseline values in a group of three subjects (Figure 5).
Olanzapine and cocaine self-administrationLL Howell et al Response rates (percent control) for two maintenance doses of cocaine (0.10 and 0.30 mg/kg/infusion) after pretreatment with haloperidol (0.01 mg/kg, RMk-3 and RKs-4; 0.03 mg/kg, ROu-4) as a function of pretreatment day under a second-order schedule of reinforcement in rhesus monkeys.
Each panel represents an individual monkey. Data points over VEH indicate response rates when a vehicle pretreatment was given prior to the cocaine self-administration session.
Response rates (responses/s) for olanzapine as a function of dose under a second-order schedule of reinforcement in rhesus monkeys. Each panel represents an individual monkey. Data points over COC indicate response rates for the baseline cocaine dose (0.10 mg/kg/infusion). Dashed linesindicate the upper limit of responding during saline extinction. Each data point is the mean of the last five sessions in a condition.
Peak effects were observed 10–30 min postinjection and behavior maintained by a complex, second-order schedule returned to baseline within 60–70 min. Compared to of i.v. drug delivery in nonhuman primates. Pretreatment cocaine, the effects of olanzapine were less pronounced.
with olanzapine completely eliminated cocaine self-admin- Olanzapine (0.1 mg/kg) increased extracellular dopamine to istration in three of four subjects, and markedly suppressed approximately 190% of baseline in the same group of three responding to less than 10% of control rates in the fourth subjects (Figure 5). Moreover, it had a slow onset of action subject. Effective doses of olanzapine were within the compared to cocaine. Peak effects were observed 60–70 min therapeutic dose range for treatment of psychosis in postinjection and returned to baseline within 110–120 min.
humans (Brown et al, 1999; Albers et al, 2005). In separate Olanzapine (0.1 mg/kg) was administered in combination experiments, substitution of olanzapine for cocaine failed to with fluoxetine (3.0 mg/kg) to characterize their interaction maintain self-administration behavior above saline extinc- on neurochemistry in vivo in two subjects (Figure 6). The tion levels in any subject. Hence, there was no indication in dose of fluoxetine selected was based on published studies nonhuman primates with a history of cocaine use that reporting interactions with cocaine on behavior in nonhu- olanzapine has abuse liability. A dose of olanzapine that man primates (Howell and Byrd, 1995). Administration of significantly suppressed cocaine self-administration also fluoxetine alone had no effect on extracellular dopamine.
induced moderate increases in extracellular dopamine in Moreover, pretreatment with fluoxetine had no systematic the ventral striatum of conscious subjects. Lastly, the effect on olanzapine-induced increases in extracellular olanzapine-induced increases in dopamine were not influ- dopamine. There was an attenuation of olanzapine-induced enced systematically by the SSRI, fluoxetine.
increases in extracellular dopamine in one subject (RBp-3) Doses of olanzapine that suppressed cocaine self-admin- and an enhancement in the other subject (RJj-7).
istration had no overt behavioral effects indicative ofsedation as evidenced by gross observations in the animalhome room after test sessions. In contrast, reductions incocaine self-administration induced by the neuroleptic, haloperidol, were accompanied by profound sedation and This is the first study to characterize the effects of catalepsy. Moreover, the effects of haloperidol were olanzapine on cocaine self-administration behavior and in enhanced over multiple pretreatment days, indicating an vivo neurochemistry in nonhuman primates. Olanzapine accumulation of drug effects on behavior with repeated was effective in suppressing cocaine self-administration dosing. It is unclear whether a more sensitive baseline of Olanzapine and cocaine self-administration Effects of cocaine (0.5 mg/kg) or olanzapine (0.1 mg/kg) on extracellular dopamine levels in ventral striatum of awake rhesus monkeys (n ¼ 3).
The 10-min sampling intervals indicated began 90 min after probe insertion. Data points over BL1-3 indicate three 10-min samples prior to druginjection.
Olanzapine and cocaine self-administrationLL Howell et al zapine for cocaine in self-administration experimentsmaintained rates of responding that were actually lowerthan saline extinction conditions in two of three subjects. Inthe only other study to report the effects of an atypicalantipsychotic on cocaine self-administration in nonhumanprimates, clozapine was marginally effective in blocking thereinforcing effects of cocaine under a fixed-ratio schedule,and a high dose of clozapine decreased cocaine self-administration in an apparently nonspecific manner (Van-over et al, 1993). Hence, olanzapine may have producednonspecific disruptions in operant behavior in the presentstudy that were not evident in gross observations of home-cage behavior.
The dose of olanzapine that significantly suppressed cocaine self-administration behavior induced a moderateincrease in extracellular dopamine measured in the ventralstriatum of conscious subjects. In the primate, the patternof limbic input to striatum includes areas of the ventralcaudate and medial ventral putamen outside that which hastraditionally been defined as the nucleus accumbens(Selemon and Goldman-Rakic, 1985; Lynd-Balta and Haber,1994; Haber and McFarland, 1999). Hence, the region ofinterest targeted in the present study may be broadlydefined as mesolimbic striatum (Bradberry et al, 2000).
Compared to a behaviorally relevant dose of cocaine, whichcorresponded to the total dose administered during dailytest sessions, olanzapine-induced increases in dopaminewere less pronounced. Olanzapine also had a slower onsetand longer duration of action. The results obtained areconsistent with those reported previously in rodentsshowing olanzapine-induced increases in extracellulardopamine in nucleus accumbens (Li et al, 1998). However,it is important to note that olanzapine increases bothdopamine and norepinephrine in nucleus accumbens,striatum, and prefrontal cortex (Li et al, 1998). Moreover,olanzapine and other atypical antipsychotics induce greaterincreases in dopamine and norepinephhrine in the pre-frontal cortex compared to subcortical areas in rodents (Liet al, 1998; Westerink et al, 1998; Kuroki et al, 1999) andnonhuman primates (Youngren et al, 1999). This prefer-ential augmentation of dopamine release in prefrontalcortex may be an important aspect of their antipsychoticeffects (Li et al, 1998; Youngren et al, 1999). Accordingly,the contribution of olanzapine-induced increases in dopa- Effects of olanzapine alone (0.10 mg/kg), fluoxetine alone mine in ventral striatum to its effects on cocaine self- (3.0 mg/kg), or the combination on extracellular dopamine levels in ventral administration remains to be defined.
striatum of awake rhesus monkeys (n ¼ 2). The 10-min sampling intervals Pretreatment with the SSRI, fluoxetine, had no systematic indicated began 90 min after probe insertion. Data points over BL1-3 effect on olanzapine-induced increases in striatal dopamine indicate three 10-min baseline samples prior to drug injection.
at a dose of fluoxetine that was approximately one log unithigher than the effective therapeutic dose in the treatmentof depression in humans (Wernicke et al, 1989). Similarly, operant behavior may have detected nonspecific motor fluoxetine failed to modulate olanzapine-induced increases effects induced by olanzapine. Meil and Schechter (1997) in dopamine in the striatum or nucleus accumbens of rats reported olanzapine-induced decreases in cocaine self- (Koch et al, 2004). It should be noted that combined administration in rodents, but similar decreases in food- administration of fluoxetine and olanzapine in rats maintained behavior were observed, suggesting a nonspe- produced sustained increases in dopamine in prefrontal cific disruption of operant behavior. In the present study, cortex that were significantly greater than either drug alone olanzapine was more effective at the higher maintenance (Zhang et al, 2000). Hence, interactions between fluoxetine dose of cocaine in three of four subjects as shown by and olanzapine on dopaminergic function may be regionally the leftward position of the olanzapine dose–effect curves.
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