Dopamine vs Noradrenaline: Inverted-U Effects and ADHD Theories

Abstract

The aim of the present study was to review the dopamine theory of attention-deficit-hyperactivity disorder (ADHD), in light of recent use of noradrenergic therapies. A historical review of pharmacological theories of ADHD was conducted, including inverted-U, spatial working memory and neural circuit aspects. Pharmacological advances, including animal and human studies of dopaminergic and noradrenergic mechanisms at the prefrontal cortex (PFC), indicate that alpha-2A adrenoreceptor stimulation results in increased dendritic firing during delay periods for preferred directions, while moderate levels of D1 receptor stimulation result in reduction of delay-related firing to non-preferred directions, allowing representational control in the PFC. Recent studies of the COMT val/met gene and stimulant medication response may help explain variation in inverted-U responses in individuals. Further studies utilizing delay-related firing paradigms should be useful in the investigation of attentional syndromes, and responses to newer pharmacological treatments.

Gene–Gene Interaction Between COMT and MAOA Potentially Predicts the Intelligence of Attention-Deficit Hyperactivity Disorder Boys in China

“…Malone et al (1994) hypothesized that the behavioral disturbances of ADHD are the result of an imbalance between noradrenergic and dopaminergic systems in the prefrontal cortex, with inhibitory dopaminergic activity being decreased and noradrenergic activity increased relative to controls. There was some supportive evidence for this hypothesis from studies demonstrating changes in NA and DA metabolism in ADHD children (Levy 2009;Hechtman 1994). Also, the spontaneously hypertensive rat model for ADHD shows hypodopaminergic and hypernoradrenergic activity in prefrontal cortex slices (Russell 2002).…”

“…Due to the mechanism of action of ADHD medications, several researchers have speculated that the dysregulation of dopamine and norepinephrine circuits underlies the pathophysiology of ADHD (Levy 2009;Prince 2008). Prefrontal cortical (PFC) function, which plays an important role in individual cognitive abilities (Gevins and Smith 2000;Duncan et al 2000;Brennan and Arnsten 2008), is modulated by catecholamines (Brennan and Arnsten 2008).…”

Altered circadian profiles in attention-deficit/hyperactivity disorder: An integrative review and theoretical framework for future studies

“…First, neurotransmitter systems do not operate independently, and the interaction between NE, dopamine, and serotonin is probably important in psychopathology (Harvey et al, 2011). In addition to the noradrenergic circuitry described above, dopaminergic and serotonergic dysfunctions may additionally link circadian alterations to ADHD as these neurotransmitters are themselves influenced by the circadian rhythm system and considered to be pathophysiologically involved in ADHD (Faraone and Khan, 2005;Levy, 2009;Paclt et al, 2005;Pattij and Vanderschuren, 2008;van der Kooij and Glennon, 2007). Second, complex interactions between neurotransmitters, clock genes, and circadian neurobiological structures have been described.…”

Attention deficit and hyperactivity disorder in people with epilepsy: diagnosis and implications to the treatment

“…Evidence obtained through pharmacological, neuroimaging, and brain damage studies suggests that the catecholamines, dopamine and norepinephrine, play a important role 14,15 . However, despite this greater involvement of catecholamines, it is likely that an imbalance occurs between the various neurotransmitter systems that interact among themselves, determining the different phenotypes observed 14,16 .…”