Stimulants: Therapeutic Actions in ADHD

Abstract

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.

Methylphenidate Enhances the Abuse-Related Behavioral Effects of Nicotine in Rats: Intravenous Self-Administration, Drug Discrimination, and Locomotor Cross-Sensitization

“…From a clinical perspective, it is interesting to note that methylphenidate (Ritalin s ) is the most commonly prescribed pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD), a behavioral disorder characterized by excessive levels of activity, impulsivity, and inattention (Arnsten, 2006;Solanto et al, 2001;Volkow et al, 2005). Methylphenidate is an effective treatment for the behavioral and cognitive deficits associated with ADHD when administered orally at therapeutic doses (Greenhill, 2001;Volkow and Swanson, 2003;Biederman et al, 2004).…”

The neuropsychopharmacology of action inhibition: cross-species translation of the stop-signal and go/no-go tasks

“…(Arnsten 2006;Arnsten and Li 2005;Cardinal 2006;Cardinal et al 2004;Dalley et al 2004;Davids et al 2003;Evenden and Ryan 1996;Robbins 2002;Robbins and Everitt 1987;Winstanley et al 2006). However, to a large degree, our knowledge of catecholaminergic mediation of action inhibition has come from studying the action of psychostimulants, which act in general as indirect catecholamine agonists.…”

Regional differences in cerebral perfusion associated with the α-2A-adrenergic receptor genotypes in attention deficit hyperactivity disorder

“…These processes are the basis of executive functions, which include the regulation of attention, planning, impulse control and the initiation or monitoring of action. 2 Prefrontal cortical dysfunction contributes to neuropsychologic deficits, such as working memory and focused attention impairments, and in-hibitory control deficits in ADHD. 7 Furthermore, it has been suggested that genetic changes in catecholamine pathways might contribute to the dysregulation of prefrontal cortex circuits in ADHD.…”

“…1,2 Furthermore, guanfacine, an α-2A agonist, is believed to improve various prefrontal cortical functions, such as working memory, attention regulation and response inhibition. 3,4 Recent single-photon emission computed tomography (SPECT) studies have shown that the administration of guanfacine activates the dorsolateral prefrontal cortex in monkeys performing working memory tasks.…”