Nucleus accumbens and effort-related functions: behavioral and neural markers of the interactions between adenosine A2A and dopamine D2 receptors

170

167

Many of the individual differences in cognition, motivation, and learningFand the disruption of these processes in neurological conditionsFare influenced by genetic factors. We provide an integrative synthesis across human and animal studies, focusing on a recent spate of evidence implicating a role for genes controlling dopaminergic function in frontostriatal circuitry, including COMT, DARPP-32, DAT1, DRD2, and DRD4. These genetic effects are interpreted within theoretical frameworks developed in the context of the broader cognitive and computational neuroscience literature, constrained by data from pharmacological, neuroimaging, electrophysiological, and patient studies. In this framework, genes modulate the efficacy of particular neural computations, and effects of genetic variation are revealed by assays designed to be maximally sensitive to these computations. We discuss the merits and caveats of this approach and outline a number of novel candidate genes of interest for future study.

Section: Introductionsupporting

confidence: 75%

Section: Dissociating Corticostriatal Genetic Components To Learningmentioning

confidence: 80%

Neurogenetics and Pharmacology of Learning, Motivation, and Cognition

Frank

Fossella

2010

170

167

“…This deficit is consistent with a large literature on the critical role of DAergic signaling in motivated behavior in a number of paradigms (see Salamone et al, 2007;Salamone et al, 2009, for reviews). In the effort-related choice paradigm, administration of DA antagonists (either systemically or targeted locally to the nucleus accumbens) decreases lever pressing and increases chow intake, as does depletion of accumbens DA (see, eg, Cousins and Salamone, 1994;Farrar et al, 2010;Salamone et al, 1991;Salamone et al, 1996;Salamone and Correa, 2002). The present results provide further evidence that normal striatal DA signaling is crucial to motivated behavior in this paradigm.…”

Section: D2r Overexpression Produces a Deficit In Willingness To Worksupporting

confidence: 60%

“…Next, we tested the D2R-OE mice in the effort-related choice paradigm, an operant paradigm that indexes incentive motivation and is dependent on normal D2R signaling (Farrar et al, 2010;Salamone et al, 2007). In this procedure, mice could earn evaporated milk by pressing a lever or could consume freely available home-cage chow that was placed in a dish on the floor of the test chamber.…”

Section: Striatal D2r Overexpression Produces Decreased Willingness Tmentioning

confidence: 99%

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

Ward

Simpson

Richards

et al. 2012

127

118

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...

“…Although further studies are needed to clarify the precise mechanisms through which CRF modulates VTA dopamine neuron activity, the fact remains that ICV or intra-VTA infusions of CRF alter effort-related decision-making in a manner similar to dopamine antagonism, either systemically or in the nucleus accumbens (Salamone et al, 1991Floresco et al, 2008;Nowend et al, 2001;Farrar et al, 2010). This resemblance would suggest that despite the complex actions of CRF in the VTA, the net effect of enhanced CRF transmission in these situations may be to reduce mesoaccumbens dopamine activity.…”

Section: Crf Actions In the Vta And Effort-related Decision-makingmentioning

confidence: 99%

Perturbations in Effort-Related Decision-Making Driven by Acute Stress and Corticotropin-Releasing Factor

Bryce

Floresco

2016

Acute stress activates numerous systems in a coordinated effort to promote homeostasis, and can exert differential effects on mnemonic and cognitive functions depending on a myriad of factors. Stress can alter different forms of cost/benefit decision-making, yet the mechanisms that drive these effects remain unclear. In the present study, we probed how corticotropin-releasing factor (CRF) may contribute to stress-induced alterations in cost/benefit decision-making, using an task where well-trained rats chose between a low effort/ low reward lever (LR; two pellets) and a high effort/high reward lever (HR; four pellets), with the effort requirement increasing over a session (2, 5, 10, and 20 presses). One-hour restraint stress markedly reduced preference for the HR option, but this effect was attenuated by infusions of the CRF antagonist, alpha-helical CRF. Conversely, central CRF infusion mimicked the effect of stress on decision-making, as well as increased decision latencies and reduced response vigor. CRF infusions did not alter preference for larger vs smaller rewards, but did reduce responding for food delivered on a progressive ratio, suggesting that these treatments may amplify perceived effort costs that may be required to obtain rewards. CRF infusions into the ventral tegmental area recapitulated the effect of central CRF treatment and restraint on choice behavior, suggesting that these effects may be mediated by perturbations in dopamine transmission. These findings highlight the involvement of CRF in regulating effort-related decisions and suggest that increased CRF activity may contribute to motivational impairments and abnormal decision-making associated with stress-related psychiatric disorders such as depression.