Dissociation of Hedonic Reaction to Reward and Incentive Motivation in an Animal Model of the Negative Symptoms of Schizophrenia

Abstract

We previously showed that mice that selectively and reversibly overexpress striatal D2 receptors (D2R-OE) model the negative symptoms of schizophrenia. Specifically, D2R-OE mice display a deficit in incentive motivation. The present studies investigated the basis for this deficit. First, we assessed whether hedonic reaction to reward is intact in D2R-OE mice. We assessed licking behavior and videoscored positive hedonic facial reactions to increasing concentrations of sucrose in control and D2R-OE mice. We found no difference between D2R-OE mice and controls in hedonic reactions. To further understand the basis of the motivational deficit, mice were given a choice between pressing a lever for access to a preferred reward (evaporated milk) or consuming a freely available less preferred reward (home-cage chow). D2R-OE mice pressed less for the preferred milk and consumed more of the freely available less preferred chow, indicating that striatal overexpression of postsynaptic D2Rs can alter cost/benefit computations, leading to a motivational deficit. This motivational impairment was ameliorated when the transgene was turned off and D2R levels were normalized. Such a deficit may arise from impaired ability to represent the value of future rewards. To test this, we used operant concurrent schedules and found reduced sensitivity to the value of future outcomes in D2R-OE mice. These results demonstrate for the first time in a transgenic animal model of schizophrenia a dissociation between hedonic reaction to reward and incentive motivation, and show a striking parallel to the proposed neurobiological and psychological mechanisms of impaired incentive motivation in schizophrenia. Neuropsychopharmacology (2012Neuropsychopharmacology ( ) 37, 1699Neuropsychopharmacology ( -1707 doi:10.1038/npp.2012 published online 14 March 2012 Keywords: hedonia; incentive motivation; operant; D2 receptor overexpression; schizophrenia; mouse models INTRODUCTIONMotivational deficits in schizophrenia are of particular clinical significance, as they greatly impair the overall functioning and quality of life of patients and do not respond well to current medications. Reduced motivation could result from anhedonia, an inability to experience pleasure from events or stimuli that others find pleasurable, or avolition, a deficit in the initiation or maintenance of goal-directed behavior. Surprisingly, given the intuitive relation between hedonia and motivation, recent findings from several research groups indicate a dissociation between hedonic reaction to rewarding stimuli and motivated behavior in patients with schizophrenia (Cohen and Minor, 2010;Gard et al, 2007;Heerey and Gold, 2007). Although there are counterexamples , the majority of the current literature shows relatively intact subjective hedonic reaction to rewarding stimuli, but impaired incentive motivation.Although the molecular underpinnings of impaired incentive motivation in schizophrenia are not precisely known, animal research points to distinct neurobiological substrates u...

Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

“…In this task, mice must work increasingly harder to earn successive food rewards, and D2R-OE mice quit after earning fewer rewards than control littermates. In another assay, we found that D2R-OE mice also exert less effort and earn fewer rewards in a current choice paradigm in which the mice can press a lever to obtain a preferred reward (milk) or, instead, consume less preferred food (regular home cage chow) without any work requirement (17). Incentive motivation can be manipulated by modulating DA receptor activity in the NAc (30).…”

“…Cognitive phenotypes of D2R-OE mice include deficits in working memory tasks, behavioral flexibility, conditional associative learning, and timing (11)(12)(13)(14). D2R-OE mice also exhibit phenotypes similar to the negative symptoms of schizophrenia: a deficit in incentive motivation, without disruption of hedonic processes (13,(15)(16)(17). We previously reported that these behavioral deficits in striatal D2R-OE mice are accompanied by changes in cortical DA function (11,18).…”

Dopamine D2-Like Receptors and Behavioral Economics of Food Reinforcement

“…In comparison, striatal DA D 2 R overexpression has produced both increases (Trifilieff et al, 2013) and decreases in food-reinforced responding (Drew et al, 2007;Simpson et al, 2011;Ward et al, 2012), with outcomes possibly depending on age of induction, degree of overexpression, and selectivity of the overexpression for subregions of the striatum (Trifilieff et al, 2013). Finally, diet-induced obesity in rats was associated with reduced striatal DA D 2 R expression and striatal DA D 2 R reduction was associated with the development of consumption of high-fat, high-sugar foods that was resistant to suppression by electric-shockassociated stimuli (Johnson and Kenny, 2010).…”

Medial prefrontal lesions in mice impair sustained attention but spare maintenance of information in working memory

“…Animals were first trained to consume evaporated milk from the liquid dipper, which was centrally located between two retractable levers in standard testing chambers (ENV307W, MedAssociates). The mice were then trained to press the lever to obtain rewards on a continuous reinforcement (CRF) schedule as described previously (Ward et al 2012b). Each CRF session ended after 60 rewards or 60 min, whichever occurred first.…”