Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function.
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.
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
Monika
M
Vinish
Ahmed
A
Elnabawi
Jean A
JA
Milstein
Jesse S
JS
Burke
Jonathan K
JK
Kallevang
Kevin C
KC
Turek
Carien S
CS
Lansink
Istvan
I
Merchenthaler
Aileen M
AM
Bailey
Bryan
B
Kolb
Joseph F
JF
Cheer
Douglas O
DO
Frost
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000493:pharmacokinetics; D001552:Benzazepines / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D005500:Follow-Up Studies; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology*; D000077152:Olanzapine; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D012201:Reward; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014316:Tritium / Q000493:pharmacokinetics
D001549:Benzamides; D001552:Benzazepines; D001569:Benzodiazepines; D004298:Dopamine; D018492:Dopamine Antagonists; D000077152:Olanzapine; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium; C534628:SCH 23390; C030265:nemonapride