a1 Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA
a2 Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA
a3 Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
a4 Department of Psychology, St. Mary's College of Maryland, St. Mary's, MD, USA
a5 Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
a6 University of Lethbridge, Canadian Center for Behavioral Neuroscience, CCBN 4401 University Drive, Lethbridge, Canada
a7 Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug (APD) treatment. Most APDs are potent antagonists or partial agonists of dopamine (DA) D2 receptors; atypical APDs also have multiple serotonergic activities. DA and serotonin regulate many neurodevelopmental processes. Thus, early life APD treatment can, potentially, perturb these processes, causing long-term behavioural and neurobiological sequelae. We treated adolescent, male rats with olanzapine (Ola) on post-natal days 28–49, under dosing conditions that approximate those employed therapeutically in humans. As adults, they exhibited enhanced conditioned place preference for amphetamine, as compared to vehicle-treated rats. In the nucleus accumbens core, DA D1 receptor binding was reduced, D2 binding was increased and DA release evoked by electrical stimulation of the ventral tegmental area was reduced. Thus, adolescent Ola treatment enduringly alters a key behavioural response to rewarding stimuli and modifies DAergic neurotransmission in the nucleus accumbens. The persistence of these changes suggests that even limited periods of early life Ola treatment may induce enduring changes in other reward-related behaviours and in behavioural and neurobiological responses to therapeutic and illicit psychotropic drugs. These results underscore the importance of improved understanding of the enduring sequelae of paediatric APD treatment as a basis for weighing the benefits and risks of adolescent APD therapy, especially prophylactic treatment in high-risk, asymptomatic patients.
(Received September 13 2012)
(Reviewed November 05 2012)
(Revised December 07 2012)
(Accepted December 12 2012)
(Online publication January 25 2013)
c1 Address for correspondence: Professor D. O. Frost, Department of Pharmacology, University of Maryland School of Medicine, 655 West Baltimore St., Baltimore, MD 21201, USA. Tel.: 410 706 0413 Fax: 410 706 0032 Email: [email protected]
* These authors contributed equally to this work.