cAMP anorexigenic effect
cAMP Anorexia
cAMP regulation by hormones
Adrenaline
adrenaline regulation by COMT
Pre-Frontal Cortex Effects of polymorphism Val158Met
The differences in dopamine levels and presumed neural efficiency between alternative alleles of the val158met polymorphism are thought to underlie observed phenotypic differences in cognition and behavior. The val158met polymorphism has also been associated with individual differences in cognitive performance. Explicitly manipulating the effects of the polymorphism in mice disrupted attentional set-shifting abilities, and impaired working and recognition memory for mice with an overexpressed val allele In humans, individuals homozygous for the val allele have shown decrements in memory, executive functioning, and inhibitory control, although not all behavioral studies support this association.
Such elevated DA tone associated with the Met allele has been shown to confer an advantage for tasks involving sustained attention and memory and in contrast, a disadvantage for tasks involving cognitive flexibility.
Human neuroimaging studies have suggested that val/val individuals compensate for lower tonic levels of prefrontal DA with increased brain activity during executive cognitive tasks. Specifically, val/val individuals show greater activity in fronto-parietal regions such as the anterior cingulate, dorsolateral prefrontal cortex, inferior frontal sulcus, and pre-SMA during tasks involving working memory attentional control, and response inhibition. These differences in brain activity have been found to be independent of differences in behavioral performance. Consequently, the increased neural activity in val/val individuals may reflect lower neural efficiency as a result of lower tonic DA levels, which requires increased neural activity to stay on-task.
However, DA does not always enhance cognitive performance.
An inverted U-shaped curve characterizes the relationship between DA levels and cognitive performance, and both reduced and excessive DA activity impair prefrontal functions. These effects may be mediated by the differential effects of D1 and D2 receptor binding. Tonic stimulation of D1 receptors is associated with stabilization of mental representation in active memory, whereas phasic D2 receptor binding allows flexible adjustment of processing and updating of active memory. Decreased COMT activity in Met carriers leads to increased DA in the PFC, which diffuses from the synaptic cleft to activate extrasynaptic D1 receptors (high D1:D2 ratio). In contrast, increased COMT activity in Val carriers limits DA diffusion from the synapse, favouring activation of intrasynaptic D2 receptors (low D1:D2 ratio). In the former case, the effects include not only enhanced maintenance of information, but also great inflexibility; in the latter, participants are more flexible, but are also more easily distracted.
Implications in Anorexia nervosa
Anorexia nervosa is an eating disorder characterized by immoderate food restriction and irrational fear of gaining weight, as well as a distorted body self-perception. It typically involves excessive weight loss and is usually found more in females than in males. Due to the fear of gaining weight, people with this disorder restrict the amount of food they consume. This restriction of food intake causes metabolic and hormonal disorders.
It was found evidence that the COMT genotype affects both executive performance, in terms of inflexibility, and PFC functional connectivity in starving patients with anorexia nervosa.
Underweight Met homozygous patients with anorexia nervosa displayed the highest levels of perseveration, whereas among healthy women this genotype was associated with the best performance on the WCST . Cognitive performance measured by the WCST in the underweight women with anorexia nervosa was consistent with the U-shaped curve as the effect of the COMT polymorphism, situations characterized by increased PFC dopaminergic activity. There is growing evidence of a dysfunction of dopaminergic systems in patients with anorexia nervosa. Patients with anorexia nervosa display increased D2/D3 receptor binding in the ventral striatum, alteration of reward-related processes and altered growth hormone response to apomorphine stimulation. However, the effects of the COMT genotype are usually appreciable only on PFC function, probably because of the presence of more efficient DA transporters in subcortical areas. Decreased motivation, compulsive exercising and loss of appetitive responses are considered to be a consequence of dopaminergic dysfunction, although the biological mechanisms underlying these symptoms are not clear. Some form of DA dysregulation occurs in both the acute stage of anorexia nervosa and in patients who have recovered from the illness, but clinical characteristics, such as low motivation and compulsive exercise, typically tend to exacerbate with weight loss.
In contrast with previous studies that investigated mainly subcortical functions, our findings on WCST performance are consistent with excessive DA signalling in the PFC of underweight patients with anorexia nervosa. Generally, exposure to both acute and chronic stress increases DA release in the PFC together with activation of the hypothalamic– pituitary–adrenal axis. In these situations, interruption of top–down control mechanisms by the PFC and a shift to bottom–up control by the sensory cortices and subcortical structures have been observed. This results in impairment on tasks that require PFC operations (flexible thinking, error monitoring), whereas mental functions relying on basal ganglia circuits are spared or enhanced (fear conditioning and habits). Starving patients with anorexia nervosa show alterations of the hypothalamic–pituitary–adrenal axis that are characteristic of stress, and their clinical symptoms clearly reflect a dysfunction of top–down control, showing impaired executive functioning, high levels of inflexibility, harm avoidance and compulsive behaviour.
Catechol-O-methyltransferase genotype modifies executive functioning and prefrontal functional connectivity in women with anorexia nervosa. 2012
Estrogens inhibit mRNA COMT transcription
Another reason why the COMT polymorphism is particularly interesting in anorexia nervosa is that it allows us to explore its effects in women in various conditions of exposure to estrogens. There is a role for estrogen in cognitive functioning and an influence on dopaminergic function in striatum. Estradiol is synthesized in the brain via steroidogenic enzymes localized in the brain. Estrogen functions as a multipurpose brain messenger that can interact with neurotransmitter systems at critical brain nuclei and facilitate neuronal function via gene expression and transmitter-gated ion channels. Estrogen action is mediated through estrogen receptors α and β, which are widely distributed throughout the brain and located in regions associated with cognitive functions. Receptors for estrogen have been localized in the prefrontal cortex, and have been considered to this region of the brain as the site of estrogen's effect on cognition. There are two estrogen response elements in the COMT promoter and that estrogen at physiological concentrations inhibits COMT mRNA expression in cells expressing estrogen receptors.
Since estrogen levels decrease greatly in starvation, underweight patients with anorexia nervosa represent a unique opportunity to analyze the convergence between estrogen levels and the COMT genotype.
Low levels of estrogens, like those observed in underweight women with anorexia nervosa, fail to exert their well-known inhibitory effects on COMT.
Executive functions and selective attention are favored in middle-aged healthy women carriers of the Val/Val genotype of the catechol-o-methyltransferase gene: a behavioral genetic study 2010
| Giuliana Barcellona e Bianca Granozzi |
