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Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from theOFCof marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behaviorinadiscriminationlearningparadigm.OFCdopaminedepletioncausedanincreaseintonicdopaminelevelsinthecaudatenucleusand a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but notOFCD2/D3 receptor binding. These results demonstrate thatOFCdopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia. [ABSTRACT FROM AUTHOR]

The involvement of mesoaccumbens dopamine in adaptive learning and behaviour is unclear. For example, dopamine may act as a teaching signal to enable learning, or more generally modulate the behavioural expression, or selection, of an already-learned response. The present study investigated the involvement of the mesoaccumbens dopamine system in a fundamental form of learning: Pavlovian conditioning. In this case, the temporal association of a previously neutral visual stimulus and a biologically significant unconditioned stimulus (US), subsequently led to the production of the conditioned response (CR) of discriminated approach behaviour directed toward the conditioned stimulus (CS+), relative to a control (CS-) stimulus. 6-hydroxydopamine lesions of the nucleus accumbens (NAcc), leading to approximately 80% reductions in tissue dopamine, were made at varying time points in four experimental groups of rats, either before or subsequent to the acquisition of the CR. NAcc dopamine depletion produced long-term neuroadaptations in dopamine function 2 months after surgery, and profoundly impaired discriminated Pavlovian approach regardless of when the lesion was made. Thus, NAcc dopamine not only plays a role in conditioned behavioural activation, but also in making the appropriate discriminated response i.e. the direction of response. Further, acquisition lesions produced a far greater impact on discriminated approach than performance lesions. This difference in lesion-induced impairment implies that mesoaccumbens dopamine may play differential roles in the learning and performance of preparatory Pavlovian conditioning.

Stimuli paired with primary rewards can acquire emotional valence and the ability to elicit automatic, Pavlovian approach responses that have been shown to be mediated by the nucleus accumbens. The present experiment investigated the effects of infusions of glutamatergic or dopaminergic receptor antagonists into the core of the nucleus accumbens on the acquisition and performance of Pavlovian discriminated approach to an appetitive conditioned stimulus. Rats were trained on an autoshaping task in which a conditioned stimulus (CS+; a lever) was inserted into the operant chamber for 10 sec, after which a food pellet was delivered. Presentation of another lever (CS-) was never followed by food. Subjects developed a conditioned response of approaching and contacting the CS+ selectively, although food delivery was not in any way contingent on the animals' response. A triple dissociation in the effects of AP-5, LY293558 [(3SR, 4aRS, 6RS, 8aRS)-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroiso-quinoline-3-carboxylic acid], and alpha-flupenthixol infused into the nucleus accumbens core on the acquisition and performance of this conditioned response was observed. The AMPA/kainate receptor antagonist LY293558 disrupted discriminated approach performance but not acquisition, as evidenced by increased approaches to the CS-. In contrast, the NMDA receptor antagonist AP-5 impaired only the acquisition, but not performance, of autoshaping whereas the dopamine D1/D2 receptor antagonist alpha-flupenthixol decreased approaches to the CS+ during both acquisition and performance. The data are discussed with reference to dissociable interactions of these receptor types with limbic cortical and dopaminergic afferents to the nucleus accumbens core during the acquisition and expression of Pavlovian conditioned approach.

Optimization of cognitive processing may depend on specific and distinct functions of the cortical cholinergic and noradrenergic systems. This investigation dissociates functions of cortical acetylcholine (ACh) and noradrenaline (NA) in arousal and visual attention by simultaneously measuring ACh and NA efflux in the rat prefrontal cortex during sustained attentional performance. The five-choice serial reaction time task was used to provide a continuous assessment of visuospatial attention. Previous studies using this task have established a critical role for the cortical cholinergic system in the detection of visual targets. However, selective lesions of the locus coeruleus noradrenergic system impair performance only when additional attentional demands are placed on the subject by distractors or temporally unpredictable targets. To test the hypothesis that the cortical noradrenergic system is particularly sensitive to novel task contingencies, we also assessed NA and ACh efflux in rats that been trained previously on the task but for whom the instrumental contingency coupling responding with stimulus detection and reward was abolished. Cortical ACh efflux showed a robust and task-related increase during established contingent performance. This response was significantly attenuated in noncontingent subjects, although it still exceeded pretask values. In contrast, NA efflux only increased transiently in contingent subjects after task onset but showed sustained elevations in noncontingent subjects on the first day when contingencies were changed. These data also implicate cortical ACh in aspects of attentional functioning but highlight a specific involvement of the cortical noradrenergic system in detecting shifts in the predictive relationship between instrumental action and reinforcement.

Impulsive choice is exemplified by choosing a small or poor reward that is available immediately, in preference to a larger but delayed reward. Impulsive choice contributes to drug addiction, attention-deficit/hyperactivity disorder, mania, and personality disorders, but its neuroanatomical basis is unclear. Here, we show that selective lesions of the nucleus accumbens core induce persistent impulsive choice in rats. In contrast, damage to two of its afferents, the anterior cingulate cortex and medial prefrontal cortex, had no effect on this capacity. Thus, dysfunction of the nucleus accumbens core may be a key element in the neuropathology of impulsivity.

Rationale: Inability to tolerate delays to reward is an important component of impulsive behaviour, and has been suggested to reflect dysfunction of dopamine systems., Objectives: The present experiments examined the effects of signalling a delayed, large reward on rats' ability to choose it over a small, immediate reward, and on the response to amphetamine, a dopamine receptor antagonist, and a benzodiazepine., Methods: Three groups of Lister hooded rats were tested on a two-lever discrete-trial delayed reinforcement task in which they chose one pellet delivered immediately or four pellets delivered after a delay. This delay increased from 0 to 60 s during each session. Trials began with illumination of a houselight: in the Houselight group, this remained on during the delay and feeding period. In the No Cue group, the houselight was extinguished at the moment of choice. In the Cue group, a stimulus light was illuminated during the delay. Once trained, the rats were challenged with d-amphetamine (0.3, 1.0, 1.6 mg/kg), chlordiazepoxide (1.0, 3.2, 5.6, 10 mg/kg), alpha-flupenthixol (0.125, 0.25, 0.5 mg/kg), and various behavioural manipulations., Results: Subjects' choice became and remained sensitive to the delay; the cue speeded learning. Amphetamine decreased choice of the large reinforcer in the No Cue group and increased it in the Cue group. alpha-Flupenthixol and chlordiazepoxide generally decreased preference for the delayed reinforcer; flupenthixol reduced the cue's effects, but chlordiazepoxide did not interact with the cue condition., Conclusions: Signals present during a delay can enhance the ability of amphetamine to promote choice of delayed rewards.