Dysfunctional Attitudes and 5-HT 2 Receptors During Depression and Self-Harm

124

The development of new therapies for the treatment of psychiatric disorders requires an in-depth knowledge of the molecular bases underlying these pathologies, which remain largely unknown. Alterations in adrenoceptors, serotonin receptors, and other G proteincoupled receptors (GPCRs) have been associated with suicide and depression. However, to date, there is little information about mRNA expression of the GPCRs in the frontal cortex of suicide victims. Our goal was to study the expression in the brain of these receptors. For this purpose, we measured mRNA levels by RT-PCR. We found that the expressions of a 2A -adrenoceptors, 5-HT 1A , 5-HT 2A serotonin receptors, and m-opioid receptors were elevated in the post-mortem brains of these suicide victims with respect to matched controls. Moreover, in the case of a 2A -adrenoceptors (the only for which these data were available), a significant correlation was observed between the level of mRNA and protein quantified in the brain of the same subjects, indicating that protein synthesis of this receptor was not influenced by post-translational regulatory mechanisms. In addition, the degree of adrenoceptor and 5-HT receptor expressions appeared to be correlated in the brains of suicide victims and control subjects. Alterations in the expression of adrenoceptors, serotonin, and opioid receptors indicate that these signaling proteins might be related to the etiopathology of suicidal and depressive behaviors. Alternatively, such changes may represent adaptive mechanisms to compensate for other as yet unknown alterations. The results also suggest that these receptors could share common regulatory mechanisms.

Section: Altered 5-ht Receptor Expression In the Brains Of Suicide VIsupporting

confidence: 92%

Increased mRNA Expression of α2A-Adrenoceptors, Serotonin Receptors and μ-Opioid Receptors in the Brains of Suicide Victims

Escribá

Ozaita

Garcı́a-Sevilla

2004

124

“…Facial expressions of emotion elicit significantly greater activation in the left amygdala in subjects with BPD compared with normal controls (Donegan et al, 2003). Levels of pessimistic attitudes correlate directly with 5-HT2 receptor binding potential in depressed subjects, but not in those with BPD (Meyer et al, 2003). This does not rule out 5-HT dysfunction in BPD mediated by other 5-HT receptors.…”

Section: Pfcmentioning

confidence: 79%

Dopamine Dysfunction in Borderline Personality Disorder: A Hypothesis

Friedel

2004

123

Research on the biological basis of borderline personality disorder (BPD) has focused primarily on the serotonin model of impulsive aggression. However, there is evidence that dopamine (DA) dysfunction may also be associated with BPD. Pertinent research and review articles, identified by Medline searches of relevant topics, books, references from bibliographies, and conference proceedings from 1975 to 2003, were reviewed. Evidence of DA dysfunction in BPD derives from the efficacy of traditional and atypical antipsychotic agents in BPD, and from provocative challenges with amphetamine and methylphenidate of subjects with the disorder. In addition, human and animal studies indicate that DA activity plays an important role in emotion information processing, impulse control, and cognition. The results of this review suggest that DA dysfunction is associated with three dimensions of BPD, that is, emotional dysregulation, impulsivity, and cognitive-perceptual impairment. The main limitation of this hypothesis is that the evidence reviewed is circumstantial. There is no study that directly demonstrates DA dysfunction in BPD. In addition, the therapeutic effects of antipsychotic agents observed in BPD may be mediated by non-DA mechanisms of action. If the stated hypothesis is correct, DA dysfunction in BPD may result from genetic, developmental, or environmental factors directly affecting specific DA pathways. Alternatively, DA dysfunction in BPD may be a compensatory response to alterations in the primary neural systems that control emotion, impulse control, and cognition, and that are mediated by the brain's main neurotransmitters, glutamate, and GABA, or in one or more other neuromodulatory pathways such as serotonin, acetylcholine, and norepinephrine.

“…A recent study by Bhagwagar et al (2006), in un-medicated, euthymic patients recovered from depression, support that a higher frontolimbic 5-HT 2A receptor level may be a trait factor of the susceptibility to develop depression and correlate positively with measures of negativistic thinking. Moreover, Meyer et al, 2003 found that in currently depressed patients, cortical, predominantly frontal, 5-HT 2 receptor binding was correlated to dysfunctional attitudes (pessimistic, negativistic thinking), whereas only the subgroup of patients with the most prominent negativistic thinking had a higher frontal 5-HT 2 receptor binding than healthy controls. As such, even in the depressed state, a positive association between negativistic thinking and frontal 5-HT 2A receptor binding seems to exist.…”

Section: Discussionmentioning

confidence: 95%

“…Additional evidence for 5-HT 2A receptor changes in depression comes from post-mortem studies in the subset of depressed patients that commit suicide of which the majority report that 5-HT 2A receptor binding is increased in dorsolateral prefrontal cortex (Stockmeier, 2003). Although initial findings of in vivo receptor imaging studies were contradictory, two recent studies have confirmed that frontal cortex 5-HT 2A receptor binding is increased, both in recovered, un-medicated patients with a history of major depression (Bhagwagar et al, 2006), and in un-medicated patients with severe depression (Meyer et al, 2003). Interestingly, negativistic thinking and 5-HT 2A receptor binding is correlated both in depressed patients (Bhagwagar et al, 2006;Meyer et al, 2003) and in healthy individuals (Frokjaer et al, 2008) in terms of dysfunctional attitudes and neuroticism scores, respectively.…”

Section: Introductionmentioning

confidence: 99%

Familial Risk for Mood Disorder and the Personality Risk Factor, Neuroticism, Interact in Their Association with Frontolimbic Serotonin 2A Receptor Binding

Frøkjær¹,

Vinberg

Erritzoe³

et al. 2009

Life stress is a robust risk factor for later development of mood disorders, particularly for individuals at familial risk. Likewise, scoring high on the personality trait neuroticism is associated with an increased risk for mood disorders. Neuroticism partly reflects stress vulnerability and is positively correlated to frontolimbic serotonin 2A (5-HT 2A ) receptor binding. Here, we investigate whether neuroticism interacts with familial risk in relation to frontolimbic 5-HT 2A receptor binding. Twenty-one healthy twins with a co-twin history of mood disorder and 16 healthy twins without a co-twin history of mood disorder were included. They answered self-report personality questionnaires and underwent [ 18 F]altanserin positron emission tomography. We found a significant interaction between neuroticism and familial risk in predicting the frontolimbic 5-HT 2A receptor binding (p ¼ 0.026) in an analysis adjusting for age and body mass index. Within the high-risk group only, neuroticism and frontolimbic 5-HT 2A receptor binding was positively associated (p ¼ 0.0037). In conclusion, our data indicate that familial risk and neuroticism interact in their relation to frontolimbic 5-HT 2A receptor binding. These findings point at a plausible neurobiological link between genetic and personality risk factors and vulnerability to developing mood disorders. It contributes to our understanding of why some people at high risk develop mood disorders while others do not. We speculate that an increased stress reactivity in individuals at high familial risk for mood disorders might enhance the effect of neuroticism in shaping the impact of potential environmental stress and thereby influence serotonergic neurotransmission.