And Depression

Although results have differed widely across studies, 5-HT1A receptors have been implicated in both depression and anxiety disorders. Early drug challenge studies had revealed an attenuation of 5-HT1A receptor-induced hypo-thermic and neuroendocrine responses in patients with depression and panic disorder (PD), reflecting dysfunction of both pre- and postsynaptic 5-HT1A receptors (Lesch, Mayer, et al., 1990; Lesch et al., 1992). A postmortem study also found decreased 5-HT1A receptor messenger RNA (mRNA) expression and ligand binding in the raphe and hippocampus, but not in dorsal or anterior prefrontal cortical areas, in brains of depressed persons who committed suicide (Cheetham, Crompton, Katona, & Horton, 1990); these findings seem to correlate well with an attenuation of 5-HT1A receptor-mediated hypo-thermic and neuroendocrine responses (Lesch, Mayer, et al., 1990), and may thus support the notion of dysfunctional pre- and postsynaptic 5-HT1A receptors. Likewise, a decrease in 5-HT1A ligand binding elicited by positron emission tomography (PET) has been shown in forebrain areas such as the medial temporal lobe, as well as in the raphe of depressed patients (Drevets et al., 1999; Sargent et al., 2000). Investigations using 5-HT1A receptor challenge and PET imaging revealed similar deficiencies in PD (Lesch et al., 1992; Neumeister et al., 2004).

Hippocampal 5-HT1A receptor expression is under tonic inhibition by corticosteroid receptor stimulation. Both glucocorticoid administration and chronic stress (a concomitant pathophysiological factor in mood disorders) have also been demonstrated to result in down-regulation of 5-HT1A receptor density and mRNA levels in the hippocampus in the animal model (Flügge, 1995; Lopez, Chalmers, Little, & Watson, 1998; Wissink, Meijer, Pearce, van der Burg, & van der Saag, 2000). In contrast, 5-HT1A receptors in the raphe seem insensitive to circulating corticosteroids (Chalmers, Kwak, Mansour, Akil, & Watson, 1993). Abnormal 5-HT1A receptor expression in this structure may instead reflect neuromorphological abnormalities that affect 5-HT1A receptor number.

Although initial association studies of the HTR1A variations produced ambiguous results in mood disorders (Arias et al., 2002; Nishiguchi et al., 2002), Lemonde and colleagues (2003) also showed that the G variant of the HTR1A-1019 polymorphism is associated with severe depression and suicidality. Given the considerable comorbidity of depression and anxiety, as well as associations of the G variant with anxiety- and depression-related personality traits—particularly with higher scores on NEO Neuroticism and TPQ Harm Avoidance (Rothe et al., 2004; Strobel et al., 2003)—relevance of the HTR1A-1019 polymorphism in anxiety disorders such as PD is plausible.

PD typically has its onset between late adolescence and the mid-30s. Panic attacks are sudden, appear to be unprovoked, and are often disabling. They may include intense fear, fear of dying, or a sense that something unimaginably horrible is about to occur and one is powerless to prevent it. Discomfort may be accompanied by several physiological symptoms, including palpitations, chest pain, choking sensations, sweating, trembling or shaking, dizziness, lightheadedness or nausea, flushes or chills, and/or tingling or numbness in the hands. Other manifestations may include fear of losing control and doing something embarrassing, dreamlike sensations, or perceptual distortions. A panic attack typically lasts several minutes to hours and may be one of the most distressing experiences a person may experience. Panic attacks are followed by persistent concerns about having additional attacks, worry about the implications of the attack or its consequences, and significant changes in behavior related to the attacks.

After one or repeated panic attacks—for instance, while driving, shopping in a crowded store, or riding in an elevator—patients may develop an irrational fear, or phobia, about these situations and begin to avoid them. Ultimately, the pattern of avoidance and level of anxiety about another attack may reach a point where a patient with PD may be unable to drive or even to leave home. At this stage, PD is complicated by agoraphobia. The first attacks are frequently triggered by physical illnesses, psychosocial stress, or certain drug treatments or drugs of abuse that increase activity of the neural systems involved in fear and anxiety responses. Although a considerable genetic component contributes to the susceptibility to PD (for a review, see Lesch, 2003), attacks can be pharmacologically precipitated by carbon dioxide, caffeine, lac-

tate, cholecystokinin tetrapeptide, and serotonergic compounds (Lesch et al., 1992).

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