Olanzapine-Induced Suppression of Cocaine Self-Administration in Rhesus Monkeys

Abstract

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 doserelated 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 selfadministration 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.

Establishment of Multi-stage Intravenous Self-administration Paradigms in Mice

“…We assessed stable lever responding at 5 cocaine doses (0.1, 0.3, 0.5, 1.0, and 3.0 mg/kg/infusion) and 6 remifentanil doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg/infusion), permitting of the establishment of dose-effect curves. As demonstrated previously in rats and non-human primates (9,26,27), there was a clear drug dosedependency to self-administration responses. For both cocaine and remifentanil, there was a characteristic inverted U-shape relationship (25,28) between the earned reinforcements relative to the log drug dose (Fig 3A,I) and active lever responses relative to log drug dose (Fig 3B,J).…”

Human reward system activation is modulated by a single dose of olanzapine in healthy subjects in an event-related, double-blind, placebo-controlled fMRI study

“…Olanzapine reduced the incentive properties of cocaine and amphetamine in monkeys (Howell et al 2006) and rats (Mechanic et al 2002), respectively. It has been suggested as a valuable agent to treat addiction in schizophrenic patients because of its effects on the reward system (Potvin et al 2003).…”

“…Peak plasma levels at 6 h after intake occurred concurrently with peak occupancy rates (Tauscher et al 2002). Furthermore, it has been shown in monkeys that the acute administration of a single dose of olanzapine interferes with reward functions in the context of drug rewards (Howell et al 2006). Medication with olanzapine reduced the incentive properties of addictive drugs in rats as well (Mechanic et al 2002) and was suggested a valuable treatment of addiction in schizophrenic patients (Potvin et al 2003).…”

Functional connectivity in frontal-striatal brain networks and cocaine self-administration in female rhesus monkeys

“…Over a period of at least 6 years starting in early adulthood, all three subjects engaged in daily cocaine self-administration with no planned periods of extended abstinence. Drug histories were complex and varied across subjects as reported in published studies for RMv-3 (Kimmel et al 2008; Lindsey et al 2004; Murnane and Howell 2010; Wilcox et al 2002), RRg-4 (Howell et al 2001; Howell et al 2002; Kimmel et al 2008) and RBp-3 (Banks et al 2009; Howell et al 2006; Murnane and Howell 2010). Based on self-administration protocols used in these studies and the duration of study assignments, each subject consumed > 10 g of cocaine.…”