Orbitofrontal cortex and amygdalar over-activity is associated with an inability to use the value of expected outcomes to guide behaviour in serotonin transporter knockout rats.

Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Dept. of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21, 6525 GA Nijmegen, The Netherlands.
Neurobiology of Learning and Memory (Impact Factor: 4.04). 04/2010; 94(1):65-72. DOI: 10.1016/j.nlm.2010.04.002
Source: PubMed

ABSTRACT A disturbance in 5-HT signalling can lead to maladaptive and disruptive behavioural changes seen in neuropsychiatric disorders, potentially by 5-HT's role in cognitive control over behaviour. 5-HT levels are tightly controlled by the serotonin transporter (5-HTT). We and others have observed that 5-HTT availability affects reversal learning. Here we investigated the role of 5-HT in another type of cognitive control, which is the ability to use the value of expected outcomes to guide behaviour. 5-HTT knockout (5-HTT(-/-)) rats and wild-type (5-HTT(+/+)) controls were subjected to a Pavlovian reinforcer devaluation paradigm, which assesses the ability of an appetitive conditioned stimulus (CS) to gain access to the motivational properties of an upcoming aversive unconditioned stimulus (US). Neural correlates were evaluated using c-Fos immunohistochemistry, in brains of animals sacrificed 90min following the start of the probe test. Results show that conditioned responding was decreased in 5-HTT(+/+), but not 5-HTT(-/-), rats after US devaluation. In addition, OFC and basolateral amygdala (BLA) c-Fos immunoreactivity was increased in non-devalued 5-HTT(-/-) rats compared to non-devalued 5-HTT(+/+) rats. Whereas US devaluation increased c-Fos immunoreactivity in the OFC and BLA of 5-HTT(+/+) rats, there was no further increase in c-Fos immunoreactivity in the OFC and BLA of 5-HTT(-/-) rats. Taken together, 5-HTT(-/-) rats are unable to use the value of expected outcomes to guide behaviour, potentially due to over-activity of the OFC and BLA. Our findings suggest a new modulatory role of 5-HT in cognitive control over behaviour, which may have important implications for psychopathologies, like anxiety disorders and addiction.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Addiction is characterized by maladaptive decision-making, in which individuals seem unable to use adverse outcomes to modify their behavior. Adverse outcomes are often infrequent, delayed, and even rare events, especially when compared to the reliable rewarding drug-associated outcomes. As a result, recognizing and using information about their occurrence put a premium on the operation of so-called model-based systems of behavioral control, which allow one to mentally simulate outcomes of different courses of action based on knowledge of the underlying associative structure of the environment. This suggests that addiction may reflect, in part, drug-induced dysfunction in these systems. Here, we tested this hypothesis. This study aimed to test whether cocaine causes deficits in model-based behavior and learning independent of requirements for response inhibition or perception of costs or punishment. We trained rats to self-administer sucrose or cocaine for 2 weeks. Four weeks later, the rats began training on a sensory preconditioning and inferred value blocking task. Like devaluation, normal performance on this task requires representations of the underlying task structure; however, unlike devaluation, it does not require either response inhibition or adapting behavior to reflect aversive outcomes. Rats trained to self-administer cocaine failed to show conditioned responding or blocking to the preconditioned cue. These deficits were not observed in sucrose-trained rats nor did they reflect any changes in responding to cues paired directly with reward. These results imply that cocaine disrupts the operation of neural circuits that mediate model-based behavioral control.
    Psychopharmacology 08/2013; 229(3). DOI:10.1007/s00213-013-3222-6 · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alcoholism is a progressive brain disorder that is marked by increased sensitivity to the positive and negative reinforcing properties of ethanol, compulsive and habitual use despite negative consequences, and chronic relapse to alcohol drinking despite repeated attempts to reduce intake or abstain from alcohol. Emerging evidence from preclinical and clinical studies implicates serotonin (5-hydroxytryptamaine; 5-HT) systems in the pathophysiology of alcohol dependence, suggesting that drugs targeting 5-HT systems may have utility in the treatment of alcohol use disorders. In this review, we discuss the role of 5-HT systems in alcohol dependence with a focus on 5-HT interactions with neural circuits that govern all three stages of the addiction cycle. We attempt to clarify how 5-HT influences circuit function at these different stages with the goal of identifying neural targets for pharmacological treatment of this debilitating disorder.
    ACS Chemical Neuroscience 02/2015; DOI:10.1021/cn5003573 · 4.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In order to evaluate the influence of changes in affective state on light-enhanced startle, the effects of positive affect, induced by acute cocaine administration, and the effect of negative affect, induced by spontaneous cocaine withdrawal-induced anxiety, were studied. Acute cocaine administration decreased LES, whereas withdrawal from chronic cocaine administration exacerbated LES 24h after withdrawal, an effect indicative of increased anxiety. This exacerbated LES was reduced, but not back to normal, 4 days after withdrawal. The finding that both cocaine-induced positive and negative affect can be detected in LES, suggests that this may be a valuable tool in studying affect regulation in rodents.
    Behavioural brain research 11/2010; 213(1):117-20. DOI:10.1016/j.bbr.2010.04.022 · 3.39 Impact Factor