Orbitofrontal cortex dysfunction in attention-deficit hyperactivity disorder revealed by reversal and extinction tasks

415

257

Stimulants such as methylphenidate and amphetamine are currently the most common treatment for attention deficit hyperactivity disorder (ADHD). For years, it was assumed that stimulants had paradoxical calming effects in ADHD patients, whereas stimulating 'normal' individuals and producing locomotor activation in rats. It is now known that low doses of stimulants focus attention and improve executive function in both normal and ADHD subjects. Furthermore, the seminal work of Kuczenski and Segal showed that low, oral doses of methylphenidate reduce locomotor activity in rats as well. Berridge et al have now shown that these low doses produce marked increases in norepinephrine and dopamine release in the prefrontal cortex, whereas having only subtle effects on subcortical catecholamine release. ihe prefrontal cortex regulates behavior and attention using representational knowledge, and imaging and neuropsychological studies have shown that the prefrontal cortex is weaker in subjects with ADHD. This cortical area is very sensitive to levels of catecholamines: moderate levels engage postsynaptic a2A-adrenoceptors and D1 receptors and improve prefrontal regulation of behavior and attention, while high levels impair prefrontal function via a1-adrenoceptors and excessive D1 receptor stimulation. Administering low doses of methylphenidate to rats improves the working memory and attentional functions of the prefrontal cortex, while high doses impair working memory and produce a perseverative pattern of errors similar to that seen in patients. The low dose improvement is hiocked by either an a2-adrenoceptor or Dl receptor antagonist, suggesting that both norepinephrine and dopamine contribute to the beneficial actions of stimulant medications.

Section: Prefrontal Cortical Dysfunction In Adhdmentioning

confidence: 99%

Stimulants: Therapeutic Actions in ADHD

Arnsten

2006

415

257

“…The ability to shift 'set' or response is suboptimal in a number of psychiatric disorders, namely schizophrenia, drug addiction, and attention deficit/hyperactivity disorder (Crider, 1997;Itami and Uno, 2002;Fillmore and Rush, 2006). Indeed, we have previously emphasized the face validity for impairments in the ability to stop or change ongoing responses for key psychopathological aspects of drug dependence and abuse (Jentsch and Taylor, 1999).…”

Section: Implications For Mental Disordersmentioning

confidence: 99%

Dopamine D2/D3 Receptors Play a Specific Role in the Reversal of a Learned Visual Discrimination in Monkeys

Lee

Groman

London

et al. 2007

140

123

Converging evidence supports a role for mesocorticolimbic dopaminergic systems in a subject's ability to shift behavior in response to changing stimulus-reward contingencies. To characterize the dopaminergic mechanisms involved in this function, we quantified the effects of subtype-specific dopamine (DA) receptor antagonists on acquisition, retention, and reversal of a visual discrimination task in nonhuman primates (Chlorocebus aethiops sabaeus). We used a modified Wisconsin General Test Apparatus that was equipped with three food boxes, each fitted with a lid bearing a unique visual cue; one of the cues concealed a food reward, whereas the other two concealed an empty box. The monkeys were trained first to acquire a novel discrimination (eg A + , B À , C À ) in a single session, before experiencing either a reversal of the discrimination (eg A À , B + , C À ) or the acquisition of a completely new discrimination (eg D + , E À , F À ), on the following day. Systemic administration of the D 2 /D 3 receptor antagonist raclopride (0.001-0.03 mg/kg) failed to significantly affect the performance of reversal learning when reversal sessions were run without a retention session. But, raclopride (0.03 mg/kg) significantly impaired performance under the reversal condition when reversal sessions were run right after a retention session; however, it did not affect acquisition of a novel visual discrimination. Specifically, raclopride significantly increased the number of reversal errors made before reaching the performance criterion in the reversal, but not in new learning sessions. In contrast, the D 1 /D 5 receptor antagonist SCH 23390 did not significantly modulate acquisition of a novel discrimination or reversal learning at doses (0.001-0.03 mg/kg, i.m.) that did not suppress behavior generally. In addition, none of the drug treatments affected retention of a previously learned discrimination. The results strongly suggest that D 2 /D 3 receptors, but not D 1 /D 5 receptors, selectively mediate reversal learning, without affecting the capacity to learn a new stimulus-reward association. These data support the hypothesis that phasic DA release, acting through D 2 -like receptors, mediates behavioral flexibility.

“…With regard to a possible involvement of 5-HT 2C receptors in ADHD, two studies report changes in the allelic distribution of two polymorphisms in the promoter region of the 5-HT 2C receptor gene in ADHD populations (Li et al, 2006;Xu et al, 2009), although not all studies have revealed an association (Bobb et al, 2005;Brookes et al, 2006). Although mutations resulting in the complete absence of 5-HT 2C receptor expression have not been reported in humans, the potential relevance of 2CKO mice to ADHD is further suggested by the expression of several behavioral phenotypes relevant to this syndrome, including attentional impairment, reduced behavioral flexibility, physical hyperactivity, and obesity (Tecott et al, 1995;Itami and Uno, 2002;Nonogaki et al, 2003;Dempsey et al, 2011;Cortese and Vincenzi, 2012). Thus, it is possible that insights into how a more robust genetic perturbation (knockout) of 5-HT 2C receptor function impacts executive function may facilitate attempts to understand the neural mechanisms through which common more subtle genetic alterations of 5-HT 2C receptor function impact disease pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

Impact of Serotonin (5-HT)2C Receptors On Executive Control Processes

Pennanen

Hart

et al. 2012

Although the serotonin (5-hydroxytryptamine, 5-HT) neurotransmitter system has been implicated in modulating executive control processes such as attention, response inhibition, and behavioral flexibility, the contributions of particular serotonin receptors remain unclear. Here, using operant-based behavioral paradigms, we demonstrate that mice with genetically ablated 5-HT 2C receptors (2CKO mice) display deficits in executive functions. 2CKO mice were impaired in the acquisition of a visuospatial attention task as assessed in the 5-choice serial reaction time task (5-CSRTT). In this task, 2CKO mice exhibited marked impairment of attentional processes, with normal response inhibition. We assessed dynamic changes in neurotransmitter levels within the nucleus accumbens (NAc) by in vivo microdialysis in task-performing animals. Extracellular dopamine concentrations were elevated in the NAc of 2CKO mice during task performance, indicating that 5-HT 2C receptors impact dopamine homeostasis during a visuospatial attention task. These findings raise the possibility that disinhibition of mesolimbic dopamine pathways contributes to impaired attention and perturbed task performance in 2CKO mice. Additionally, in a spatial reversal learning task, 2CKO mice failed to improve their performance over a series of reversals, indicating that intact 5-HT 2C receptor signaling is required to accurately respond to repeated changes in reward contingencies. In contrast to the 2CKO phenotype in the 5-CSRTT, wild-type mice treated with the 5-HT 2C receptor antagonist SB242084 exhibited diminished response inhibition, suggesting differing effects of acute pharmacological blockade and constitutive loss of 5-HT 2C receptor activity. Altogether, these findings provide insights into the serotonergic regulation of executive control processes and suggest that impaired 5-HT 2C receptor signaling during development may predispose to executive function disorders.