Various pharmacological agents may be effective in modifying the disinhibited behavior of patients with orbitofrontal circuit dysfunction, although no agent is uniformly Protease Inhibitor Library cell assay reliable.121 Potentially useful drugs include the major and minor tranquilizers, propranolol, buspirone, carbamazepine, sodium valproate, lithium, and clonidine. In addition to their dopaminergic activity,

neuroleptics may have a serotonergic mode of action in the treatment of impulsive aggression by binding to and downregulating the serotonin (5-HT)2 receptors,122 Inhibitors,research,lifescience,medical a 5-HT receptor subtype that is represented in intermediate levels in the nucleus accumbens and striatum. Lithium’s mood-stabilizing action may be mediated by effects both on the 5-HT system and on phosphoinositide,123 which is selectively concentrated Inhibitors,research,lifescience,medical in striosomes (the striatum is organized as two separate systems, the striosomes and the matrix) of the medial and

ventral striatum124 – regions that receive dense orbitofrontal input. More specific serotonergic agonists, including clomipramine and fluoxetine, may also be effective for Inhibitors,research,lifescience,medical impulsive, aggressive, or sexually disinhibited behaviors.125,126 This may reflect serotonergic modulation of orbitofrontal circuit dysfunction and is consistent with data linking behavioral disinhibition with central serotonergic deficiency.122,126 Certain 5-HT1A agonists Inhibitors,research,lifescience,medical (“serenics”), whose effects may be mediated by postsynaptic 5-HT1A receptors, exert a dose-dependent decrease in aggression with a concomitant increase in social interest in animal paradigms.14 Both propranolol and pindolol bind to somatodendritic 5-HT1A receptors, present in limbic brain regions,127 and appear to have 5-HT1 agonist properties at dosages in the range of those used in the treatment of aggressive behavior in humans.128 Similarly, the partial 5-HT1A agonist buspirone may be effective in the treatment of aggression

in a variety of neuropsychiatrie conditions. Inhibitors,research,lifescience,medical An orbitofrontal syndrome with mania may be seen oxyclozanide with bilateral orbitofrontal contusions, and may respond rapidly to clonidine,118 and α2-noradrenergic agonist that reduces central noradrenergic transmission by stimulating presynaptic autoreceptors.129,130 The response to clonidine in such cases may be related to reduction in noradrenergic overactivity induced by lesions of prefrontal areas projecting to noradrenergic systems131 which in turn innervate prefrontal cortex and modulate its function.72,132 Clonidine may ameliorate symptoms characteristic of orbitofrontal circuit dysfunction, including inattention, distractibility, impulsivity, and emotional lability, in patients with attention-deficit/hyper activity disorder and Tourette’s syndrome.