Thursday, March 30, 2023
processing....
DA pathways in the brain arise primarily from the ventral tegmentum and have multiple cortical projections through pathways involved in conscious and intentional control of movement and in brain regions that mediate emotion and sensitivity to rewards. The reward pathway is predominantly based in the nucleus accumbens. This connection is related to interest that is highly integrated with attention. ADHD individuals typically describe that they can pay attention to topics or information that interest them, but have great difficulty sustaining focus on important information that is not intrinsically interesting. The DA projections to the mesocortex are relevant to the ability to attach attention and to relate attention to working memory and problem solving. DA projections to mesocortical areas mediate prefrontal cortical processes that enable active suppression of distractions and inhibit inappropriate behavioral expressions of tangential thoughts, ideas, or behaviors. Many ADHD individuals appear unable to inhibit or delay reacting -- even when their response might have dire consequences. They cannot remain quiet; they blurt out thoughts and ideas independent of their social or cognitive relevance. In parallel to their high level of motor restlessness, they often describe themselves as having "wiggly minds" or "grasshopper thoughts" that jump from one topic to another. The inhibition of excessive fidgetiness and functionally random thoughts are among the most beneficial effects of psychostimulant treatment. The mesodorsal-lateral DA projections are more involved in working memory -- the ability to hold an idea in conscious awareness and analyze it thoroughly before making decisions. The capacity for executive function involved in reasoning, planning, and problem solving necessitates a sustained working memory that requires activation of these dorsolateral projections to DRD2 receptors.
Thus, these dopaminergic areas are engaged in attention to detail and increase perseveration of thinking -- the ability to sustain working memory. This pathway, when overly activated, may decrease cognitive flexibility and enhance perseveration of thought while decreasing cognitive flexibility in seeking alternative solutions or responses to a problem or situation. By contrast, the meso-orbital DA projections impact the ability to make thoughtful interpersonal decisions and to inhibit excessive reactivity or impulsive social responding. This inhibitory control extends to social functioning related to the ability to inhibit overreacting, blurting out, and impulsive responding. This pattern of impulsive behavior, excessive talking, and emotional lability can be a manifestation of deficits in meso-orbital DA pathways. In addition, it is corrected by psychostimulants that diminish not only overactivity, but irritability and impulsivity that often underlie the social and interpersonal difficulties experienced by ADHD individuals.
Catecholamines not only facilitate attention, they are essential to executive function. The prefrontal cortex directs behaviors, thoughts, and feelings represented in working memory. This representational knowledge is essential to fundamental cognitive abilities that compromise executive functions. These encompass the ability to (1) inhibit inappropriate behaviors and thoughts, (2) regulate our attention, (3) monitor our actions, and (4) plan and organize for the future. Difficulties with these prefrontal cortex functions are evident in neuropsychological and imaging studies of ADHD patients and account for many of the common behavioral symptoms. Measures of prefrontal cortical functioning in animals indicate that these functions are sensitive to small changes in catecholamine modulation of prefrontal cortex cells that can produce profound effects on the ability of the prefrontal cortex to guide behavior. Optimal levels of NE acting at postsynaptic alpha2A-adrenoceptors and dopamine acting at D1 receptors are essential to prefrontal cortex function. Blockade of norepinephrine alpha2-adrenoceptors in prefrontal cortex markedly impairs prefrontal cortex function and mimics most of the symptoms of ADHD, including impulsivity and locomotor hyperactivity. Conversely, stimulation of prefrontal cortical alpha2-adrenoceptors strengthens prefrontal cortex regulation of behavior and reduces distractibility. Thus, effective treatments for ADHD facilitate catecholamine transmission and apparently have their therapeutic actions by optimizing catecholamine actions in the prefrontal cortex.[19]
In some of the previous studies, DA and its metabolite HVA were measured concurrently with NE. In their study of urinary catecholamines, Shekim and colleagues[20] found that the ADHD boys who responded to d-amphetamine treatment, including those with normal MHPG, excreted lower amounts of HVA than control boys. Conversely, those with normal HVA excreted low amounts of MHPG; d-amphetamine decreased HVA in drug responders who exhibited normal HVA levels at baseline. Castellanos and associates[18] found that HVA in CSF was positively correlated with several measures of hyperactivity and with behavioral measures of aggression. Collectively, studies of catecholamines suggest that ADHD symptoms are not the prerogative of an alternation in a single neurotransmitter system, but may reflect the relative functioning of both NE and DA systems. Further, the impact of psychostimulant treatment on catecholamines may depend on their baseline pretreatment levels.
Wigal and associates[14] found that exercise increased DA excretion in controls, but not in ADHD subjects, suggesting a decrease in dopaminergic response in ADHD. These data suggest that catecholamine excretion after exercise is increased in controls, but not in ADHD patients.
The implications of these underlying catecholaminergic mechanisms for treatment of ADHD/ADD suggest that medications that increase catecholamines may fasciculate attention.[21] The major effect of methylphenidate is to increase synaptic concentration of dopamine by blocking presynaptic DA reuptake. Amphetamines also block DA reuptake but have 2 additional effects of increased production of both DA and NE.[22] While both medications increase attention, the noradrenergic effects of amphetamine may contribute to increased energy and enhanced executive function. DA may be more essential to attaching attention; NE may contribute more to executive function. Atomoxetine, through acting primarily on NE, has secondary effects of increasing prefrontal cortical DA. Modafinil may enhance attention predominantly by increasing arousal and alertness in patients with low-energy ADHD.[23,24]
