Noradrenergic hypothesis

Panic disorder begins with the eruption of full-blown panic attacks—many of which (as mentioned earlier) occur "out of the blue" in low- or no-stress situations. Some individuals with panic disorder suffer from relatively infrequent attacks (a few per month) in more severe cases, attacks can occur several times a day and oftentimes even during sleep. The noradrenergic hypothesis holds that the intense, recurring attacks are caused by hypersensitive neurons in the LC or a dysfunction in the natural braking mechanism in the LC nerve cells or both (see figure 7-F). 

The nerve axon in figure 7-F impinges back on itself and releases its neurotransmitter norepinephrine (also called noradrenaline, hence the term "noradrenergic hypothesis"). The neurotransmitter typically stimulates inhibitory receptors on the... 

Based on the modest ability of the (+)-isomers of MDMA and MBDB to inhibit the reuptake of norepinephrine (NE) into hypothalamic synaptosomes (Steele et al. 1987). it seemed possible that noradrenergic pathways might be involved in the eue. In ano er series of drug discrimination experiments designed to test this hypothesis, the specific NE uptake inhibitor (-)-tomoxctine was tested for stimulus transfer in doses up to 10 mg/kg in MDMA-trained rats. At 5 mg/kg, 67 percent of the animals responded on, the drug lever. However, pretreatment with tomoxetine in six rats trained to discriminate MDMA from saline had no effect on the discrimination of a subsequent dose of MDMA. 

There is ample support for the hypothesis of noradrenergic system dysfunction in depression however, the inconsistencies in findings rule out any simple model of increased or decreased noradrenergic activity. It is important to determine which noradrenergic system abnormalities relate specifically to the pathogenesis of mood disorders, and which are related to nonspecific effects of stress, homeostatic mechanisms, or comorbid psychopathology. More work is needed on the mood-state-depen-dence of noradrenergic function. 

HT/NE link hypothesis. This theory suggests that there is a link between 5-HT and NE activity, and that both the serotonergic and noradrenergic systems are involved in the antidepressant response. 

There is extensive clinical evidence that NE plays a role in hiunan anxiety. Well-designed psychophysiological studies have been conducted that have documented heightened autonomic or sympathetic nervous system arousal in combat veterans with chronic PTSD. Because central noradrenergic and peripheral sympathetic systems function in concert (Aston-Jones et al. 1991), the data from these psychophysiology investigations are consistent with the hypothesis that noradrenergic hyperreactivity in patients with PTSD may be associated with the conditioned or sensitized responses to specific traumatic stimuli. 

The serotonergic hypothesis of OCD was initially derived from clinical observations that pointed to the preferential response of patients with OCD to medications possessing a serotonergic profile. CMl and other SRls have been demonstrated to be superior not only to placebo in OCD, but also to other antidepressants, such as the noradrenergic tricyclic antidepressant desipramine [W. K. Goodman et al. 1990b H. L. Leonard et al. 1991 Zohar and Insel 1987] as well as nortriptyline, amitriptyline, and imipramine, with much of the same results [Ananth et al. 1981 Volavka et al. 1985). 

Beani L, Tanganelh S, Antonelh T, et al Noradrenergic modulation of cortical acetylcholine release is both direct and gamma-aminobutyric acid-mediated. J Pharmacol Exp Ther 236 230-236, 1986 Beatty WW, Butters N, Janowsky D Patterns of memory failure after scopolamine treatment implications for the chohnergic hypothesis of dementia. Behavioral and Neural Biology 45 196-211, 1986... 

Early research at our institute found that treatment with lithium decreased the b-adrenergic receptor number, consistent with the noradrenergic down-regulation hypothesis but difficult to reconcile with a complementary theory of mania ( 25). Lithium can also block dopamine receptor supersensitivity, and this is consistent with the postulate that mania is associated with an increased sensitivity of catecholamine receptors. 

This a a2-noradrenergic presynaptic receptor agonist is approved by the FDA as an antihypertensive. The rationale for using clonidine for mania is based on the original catecholamine hypothesis (21, 22), which postulates a hyperfunctionality of the noradrenergic system predisposing to mania. Because the hypothesis... 

The beneficial effect of precursors (e.g., lecithin), cholinesterase inhibitors (e.g., physostigmine, donepezil), or drugs with cholinomimetic effects (e.g., bethanechol) for actue mania was discovered in part from the work of Janowsky et al. ( 29), leading to their cholinergic—noradrenergic balance hypothesis. Interestingly, lithium is also able to raise RBC choline concentrations and CNS cholinergic activity ( 274). 

Classical Antidepressants, Serotonin Selective and Noradrenergic Reuptake Inhibitors Monoamine Hypothesis of Antkfepresssant Action on Gene Expression... 

Overactivity of noradrenergic neurons creates too much postsynaptic norepinephrine at noradrenergic receptors, particularly beta receptors (Fig. 8-14). As is consistent with the hypothesis of a state of norepinephrine excess in anxiety, it is possible to reduce symptoms of anxiety in some cases by blocking beta receptors with beta... 

Increased sensitivity to stress may be related to spontaneous recurrence of metamfetamine psychosis, triggering flashbacks. Stressful experiences, together with metamfetamine use, induce sensitization to stress associated with noradrenergic hyperactivity, involving increased dopamine release (54,55). This hypothesis has been investigated by determining plasma noradrenaline metabolite... 

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