Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function

Abstract

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.

Fig. 1

Effects of adolescent olanzapine (Ola) treatment on body weight. (a) Body weight as a function of age during the treatment period [based on n=47 Ola-treated and 39 vehicle (Veh)-treated rats]. (b). Mature body weight of rats treated with Veh or Ola (based on n=22 Ola-treated and 21 Veh-treated rats). Error bars are S.E.M.

Fig. 2

Effects of adolescent olanzapine (Ola) treatment on conditioned place preference (CPP) for amphetamine (Amph) at maturity. (a) Time spent in the Amph-associated chamber expressed as a percentage of the total time spent in both chambers. At baseline, neither Ola-treated (n=22) nor vehicle (Veh)-treated (n=20) rats preferred one chamber to the other and the two groups did not differ significantly in their baseline preference for the Amph-paired chamber. Both Ola- and Veh-treated rats showed a significant post-conditioning increase in preference for the Amph-paired chamber (# indicates p<0.01). Post-conditioning, Ola-treated rats had a greater preference for the Amph-paired chamber than Veh-treated controls (* indicates p=0.022). (b) CPP, measured by the increase from baseline, was greater in Ola- than in Veh-treated rats ($ indicates p=0.014). Error bars are S.E.M.

Fig. 3

Effects of adolescent olanzapine (Ola) treatment on specific dopamine D₁ and D₂ receptor binding (D₁R and D₂R, respectively) in the nucleus accumbens core at maturity. D₁ binding is reduced by 20% and D₂ binding is increased by 30%. * Indicates p≤0.001. Error bars are S.E.M. [based on n=9 for Ola- and for vehicle (Veh)-treated rats ; statistics based on n=3 independent samples in each group; each sample consists of pooled tissue from three cases].

Fig. 4

Effects of adolescent olanzapine (Ola) treatment on dopamine (DA) release in the nucleus accumbens core (NAcC) at maturity [n=9 for Ola- and for vehicle (Veh)-treated rats]. Stimulation frequency is 60 Hz and error bars are S.E.M. (a) Changes in [DA]_MAX with depth along the electrode track in the NAcC (300 μA stimulation amplitude). To allow comparison of data across cases, for each rat, [DA]_MAX at each depth was normalized to the smallest value of [DA]_MAX at the depths shown (‘Depth normalized’). (b) ‘Surface plots’ showing the time-course of extracellular DA concentration ([DA]_EXT) along the entire electrode penetration are shown for typical Veh- and Ola-treated cases (stimulation amplitude is 300 μA). (c, d) Effects of increasing stimulus amplitude on [DA]_EXT in typical Veh- and Ola-treated cases respectively. Data illustrated in (c) and (d) are from the same rats as the data shown in (b). (e) Changes in [DA]_MAX with stimulation amplitude. We used a normalization procedure to analyse treatment effects across rats : At DV 6.4 mm, [DA]_MAX, the maximum value of [DA]_EXT at each stimulation amplitude was divided by [DA]_MAX at the lowest stimulation amplitude (100 μA), to obtain ‘normalized [DA]_MAX’. Insert : Average concentration vs. time plots of [DA]_EXT as a function of time following ventral tegmental area (VTA) stimulation at 500 μA, 60 Hz. Arrow marks the time of VTA stimulation ; shading indicates S.E. Similar effects are obtained at other stimulation amplitudes. ( f ) Decay of [DA]_EXT (normalized to [DA]_MAX) following VTA stimulation at 500 μA, 60 Hz. Insert : Distribution of decay constant values calculated from single exponential curve fits of the data from individual rats.