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.
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.
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ABSTRACT: Conditioned fear plays a key role in anxiety disorders as well as depression and other neuropsychiatric conditions. Understanding how neuromodulators drive the associated learning and memory processes, including memory consolidation, retrieval/expression, and extinction (recall), is essential in the understanding of (individual differences in vulnerability to) these disorders and their treatment. The human and rodent studies I review here together reveal, amongst others, that acute selective serotonin reuptake inhibitor (SSRI) treatment facilitates fear conditioning, reduces contextual fear, and increases cued fear, chronic SSRI treatment reduces both contextual and cued fear, 5-HT1A receptors inhibit the acquisition and expression of contextual fear, 5-HT2A receptors facilitates the consolidation of cued and contextual fear, inactivation of 5-HT2C receptors facilitate the retrieval of cued fear memory, the 5-HT3 receptor mediates contextual fear, genetically induced increases in serotonin levels are associated with increased fear conditioning, impaired cued fear extinction, or impaired extinction recall, and that genetically induced 5-HT depletion increases fear conditioning and contextual fear. Several explanations are presented to reconcile seemingly paradoxical relationships between serotonin levels and conditioned fear.Scientifica. 01/2012; 2012:821549.
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ABSTRACT: Nogo-A is an important neurite growth-regulatory protein in the adult and developing nervous system. Mice lacking Nogo-A, or rats with neuronal Nogo-A deficiency, exhibit behavioral abnormalities such as impaired short-term memory, decreased pre-pulse inhibition, and behavioral inflexibility. In the current study, we extended the behavioral profile of the Nogo-A deficient rat line with respect to reward sensitivity and motivation, and determined the concentrations of the monoamines dopamine and serotonin in the prefrontal cortex (PFC), dorsal striatum (dSTR), and nucleus accumbens (NAcc). Using a limited access consumption task, we found similar intake of a sweet condensed milk solution following ad libitum or restricted feeding in wild-type and Nogo-A deficient rats, indicating normal reward sensitivity and translation of hunger into feeding behavior. When tested for motivation in a spontaneous progressive ratio task, Nogo-A deficient rats exhibited lower break points and tended to have lower "highest completed ratios." Further, under extinction conditions responding ceased substantially earlier in these rats. Finally, in the PFC we found increased tissue levels of serotonin, while dopamine was unaltered. Dopamine and serotonin levels were also unaltered in the dSTR and the NAcc. In summary, these results suggest a role for Nogo-A regulated processes in motivated behavior and related neurochemistry. The behavioral pattern observed resembles aspects of the negative symptomatology of schizophrenia.Frontiers in Behavioral Neuroscience 01/2014; 8:10. · 4.16 Impact Factor
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ABSTRACT: The use of psychoactive drugs is a wide spread behaviour in human societies. The systematic use of a drug requires the establishment of different drug use-associated behaviours which need to be learned and controlled. However, controlled drug use may develop into compulsive drug use and addiction, a major psychiatric disorder with severe consequences for the individual and society. Here we review the role of the serotonergic (5-HT) system in the establishment of drug use-associated behaviours on the one hand and the transition and maintenance of addiction on the other hand for the drugs: cocaine, amphetamine, methamphetamine, MDMA (ecstasy), morphine/heroin, cannabis, alcohol, and nicotine. Results show a crucial, but distinct involvement of the 5-HT system in both processes with considerable overlap between psychostimulant and opioidergic drugs and alcohol. A new functional model suggests specific adaptations in the 5-HT system, which coincide with the establishment of controlled drug use-associated behaviours. These serotonergic adaptations render the nervous system susceptible to the transition to compulsive drug use behaviours and often overlap with genetic risk factors for addiction. Altogether we suggest a new trajectory by which serotonergic neuroadaptations induced by first drug exposure pave the way for the establishment of addiction.Behavioural brain research 04/2014; · 3.22 Impact Factor