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Background: The compulsive and inflexible behaviors that are present in many psychiatric disorders, particularly behavioral addictions and obsessive-compulsive disorder, may be due to neurochemical dysfunction within the circuitry that enables goal-directed behaviors. Experimental removal of serotonin or dopamine within the orbitofrontal cortex or dorsal striatum, respectively, impairs flexible responding in a reversal learning test, suggesting that these neurochemical systems exert important modulatory influences on goal-directed behaviors. Nevertheless, the behavioral impairments present in psychiatric disorders are likely due to subtle neurochemical differences, and it remains unknown whether naturally occurring variation in neurochemical levels associate with individual differences in flexible, reward-directed behaviors., Methods: The current study assessed the ability of 24 individual juvenile monkeys to acquire, retain, and reverse discrimination problems and examined whether monoamine levels in the orbitofrontal cortex, caudate nucleus, and putamen could explain variance in behavior., Results: The interaction between dopamine levels in the putamen and serotonin levels in the orbitofrontal cortex explained 61% of the variance in a measure of behavioral flexibility but not measures of associative learning or memory. The interaction mirrored that of a hyperbolic function, with reversal learning performance being poorest in either monkeys with relatively low levels of orbitofrontal serotonin and putamen dopamine or in monkeys with relatively high levels of orbitofrontal serotonin and putamen dopamine levels., Conclusions: These results support the hypothesis that subcortical and cortical neuromodulatory systems interact to guide aspects of goal-directed behavior, providing insight into the neurochemical dysfunction that may underlie the inflexible and compulsive behaviors present in psychiatric disorders., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

We have evaluated, with the use of vertical microdialysis, the effects of fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) on the increase in serotonin and norepinephrine output elicited in rats prefrontal cortex by exposure to footshock stress. Exposure to footshock stress induced a marked increase in the cortical extracellular concentration of both serotonin and norepinephrine (+70% and +100%, respectively) in control rats. Long term, but not acute administration of fluvoxamine (10 mg/kg, i.p. once a days for 21 days) completely antagonized the stress induced increase in cortical serotonin extracellular concentration, while failed to modify the sensitivity of cortical noradrenergic neurons to the same stressful stimulus. Our results have shown that it is possible to independently modulate the sensitivity of cortical serotonergic neurons to stressful stimuli without altering the responsiveness of noradrenergic neurons to the same stress. Given the different role played by serotonin and norepinephrine in the modulation of the stress response, the availability of drugs able to selectively modulate the plastic response of serotonergic neurons to stress in specific brain areas might be important for the pharmacotherapy of anxiety disorders.

Background: Chronic exposure to stressful events precipitates or exacerbates many neuropsychiatric disorders, including depression and schizophrenia. Evidence suggests that treatment with the atypical antipsychotic drugs olanzapine or clozapine results in a superior amelioration of the anxious and depressive symptoms that accompany schizophrenia relative to therapy with classical antipsychotics such as haloperidol. Moreover, olanzapine and clozapine, but not haloperidol, increase the brain content of neuroactive steroids. The effects of olanzapine and clozapine on the stress-induced increase in dopamine output in the rat cerebral cortex have now been compared with that of haloperidol., Methods: Rats chronically treated (3 weeks, once a day) with each drug were exposed to foot-shock stress or injected with a single dose of the anxiogenic benzodiazepine receptor ligand FG7142, and dopamine release was then measured in the prefrontal cortex by vertical microdialysis., Results: Long-term administration of olanzapine or clozapine prevented or markedly inhibited, respectively, the increase in the extracellular dopamine concentration induced by foot shock; haloperidol had no such effect. Chronic olanzapine treatment also blocked the effect of FG7142 on dopamine output., Conclusions: The reduction in the sensitivity of cortical dopaminergic neurons to stress shown to be elicited by treatment with olanzapine or clozapine may contribute to the anxiolytic actions of these drugs.