Synaptic gating and ADHD: a biological theory of comorbidity of ADHD and anxiety.

To derive a biologically based theory of comorbidity in Attention Deficit Hyperactivity Disorder (ADHD). Theoretical concepts and empirical studies were reviewed to determine whether the behavioral inhibition concept provided an understanding of biological processes involved in comorbidity in ADHD. Empirical studies of ADHD have shown comorbidity of ADHD and anxiety, while studies of behavioral inhibition tend to suggest independent disruptive and anxiety traits. This paradox can be resolved by an understanding of the dynamics of mesolimbic dopamine (DA) systems, where reward and delay of reinforcement are determined by tonic/phasic DA relationships, resulting in impulsive 'fearless' responses when impaired. On the other hand, comorbid anxiety is related to impaired synaptic processes, which selectively gate fear (or aggressive) responses from the amygdala at the accumbens. Monosynaptic convergence between prefrontal, hippocampal, and amygdala projection neurons at the accumbens allows the operation of a synaptic gating mechanism between prefrontal cortex (PFC), hippocampus, and amygdala. Impairment of this mechanism by lowered PFC inhibition allows greater amygdala input, and anxiety-related processes more impact, over the accumbens. In conclusion, a dual theory incorporating long-term tonic/phasic mesolimbic DA relationships and secondly impairment of PFC and hippocampal inputs to synaptic gating of anxiety at the accumbens has implications for comorbidity in ADHD, as well as for possible pharmacological interventions, utilizing either stimulant or axiolytic interventions. The use of DA partial agonists may also be of interest.