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Studies about the role of NE in psychiatric disorders often rely on the measurement of plasma or urinary levels of NE and its neuronal metabolites (MHPG and

DHPG), which represents the most direct method available to measure noradrenergic activity in living human subjects. However, the variations in these levels more probably correspond to NE released by the sympathetic system rather than to NE released in the brain. Alternative methods have been considered (MAO activity of platelets, platelet density of a2-adrenergic receptors, growth hormone release in response to clonidine), but results are still contaminated by noradrenergic activity at the periphery. The limitation of such approaches has always led to debate. Central noradrenergic activity can easily be measured in animals, but animal models of psychiatric disorders are subject to controversy. The most convincing arguments often arise from the pharmacological properties of psychotropic drugs and, conversely, the psychotropic effects of noradrenergic agents.

1. Anxiety: Panic Disorders and Posttraumatic Stress Disorder (PTSD)

Anxiety is phenomenologically similar to states of fear, with the difference that fear is related to real threat, whereas anxiety is an excessive response when little or no real danger is present. There is considerable evidence for a relationship between noradrenergic brain systems and behaviors associated with stress and anxiety. In animals, behaviors that are characteristically observed in situations of stress and fear are associated with an increase in activation of LC-NE systems. Similarly, in healthy human subjects, many studies found significant correlations between states of anxiety and plasma or urinary levels of MHPG. Conversely, stimulating NE transmission induces fear reactions. Infusion of NE into the hypothalamus of cats results in defensive-aggressive behaviors such as hissing, growling, and ear retraction. Stimulation of LC in monkeys induces behavior seen in the wild when the animal is threatened. Panic attacks are induced by yohimbine, an a2-adrenergic antagonist that increases LC firing, in approximately 60-70% of patients with panic disorders.

In animals, chronic stress is associated with a sensitization of both behavioral and NE responses after reexposure to a subsequent stress. This stress sensitization might be relevant to the neurobiology of disorders such as panic disorders or PTSD, in which patients have had a history of previous exposure to stress. This suggests that panic disorders and PTSD may result from abnormally high LC activity. Indeed, some studies have demonstrated increased urinary NE and blunted growth hormone response to clonidine in both patients with panic disorders and those with PTSD. Studies on other anxiety disorders, such as generalized anxiety disorder and obsessive-compulsive disorder, do not support an important role for NE brain systems.

Finally, the therapeutic efficacy of tricyclic drugs or monoamine oxidase inhibitors, usually considered as antidepressants, may result from their actions on the noradrenergic system. Benzodiazepines that are highly efficient in reducing panic disorders also reduce LC firing.

2. Depression

In 1965, Joseph Schildkraut initially proposed the hypothesis that noradrenergic systems would play a role in depression and be the major site of action of antidepressant drugs. Although more recent data clearly indicate that other neurotransmissions, such as serotonergic and dopaminergic ones, are also implicated, the role of noradrenergic systems nevertheless remains prominent. For example, in bipolar patients, urinary MHPG levels are lower during the depressed phase and higher during the manic phase than during periods of euthymia. Furthermore, unipolar and bipolar depressive patients demonstrate greater increases in plasma NE after moving to an upright position than do controls. Finally, post mortem studies have reported higher b-receptor densities in the brains of suicide victims than in controls.

Since the demonstration that most antidepressants decrease b1-adrenergic receptor transduction in the cerebral cortex of the rat, this parameter has generally been considered as a biochemical correlate of therapeutic activity. This observation is noteworthy not only because it seems to be a common consequence of chronic treatments with most antidepressants whatever their mechanism but also because its development parallels clinical improvements. Indeed, in animal studies, down-regulation of bl-adrenergic receptors only appears following 10-20 days of chronic treatment, a delay that corresponds to clinical observations. Not all antidepressants, however, induce desensitization of b-adrenergic receptors. A reactivation of serotonin transmission, which can be obtained by some antidepressants such as SSRIs (specific serotonin re-uptake inhibitors), can hamper the development of b-adrenergic receptor desensitization even when noradrenergic transmission is also reactivated. The lack of a response by b-adrenergic receptors has been proposed to be due to past receptor events at the level of phosphorylations mediated by PKA and PKC.

b-Adrenergic receptors are not the only receptors desensitized by antidepressants. A serotonin receptor subtype, 5-HT2, is also frequently affected. This should not imply, however, that an up-regulation of b1-adrenergic or 5-HT2 receptors is responsible for the disease and that, consequently, down-regulation of these receptors is the goal to achieve. These observations rather suggest that both types of receptors, b1-adrenergic and 5-HT2, are very sensitive to any modification of their respective neurotransmissions and that an activation of the latter occurs following chronic treatment with antidepressants. According to that view, a deactivation of serotonergic and/or noradrenergic neurons is probably the main biochemical characteristic of depression.

It can be added that tricyclic antidepressants are generally considered to have better clinical therapeutic efficacy than SSRIs in major depression. Both groups share the property of inhibiting the re-uptake of NE and serotonin, but tricyclic antidepressants are, in contrast to SSRIs, potent cholinergic and al-adrener-gic receptor antagonists. Although a1-adrenergic antagonism may represent an adverse side effect because of its hypotensive action, it cannot be excluded that the blockade of central a1-adrenergic receptors at least partly explains the better clinical efficacy of tricyclics.

3. Schizophrenia

Since the early 1970s, the dopamine hypothesis has been at the forefront of explanations for the pathogenesis of schizophrenia. This was founded on the fact that classical neuroleptics are potent dopaminergic antagonists. However, estimation of NE and its metabolite MHPG post mortem and in cerebrospinal fluid has produced more consistent findings than similar studies on dopaminergic systems.

Moreover, psychophysiological abnormalities observed in schizophrenic patients, such as dysfunction in smooth pursuit eye movement (smooth pursuit being replaced by stepwise pursuit or spiky pursuit) or in skin conductance responses to novel sensory stimuli (absence of response or failure of its habituation), which may reflect under- or overarousal, are also observed as a consequence of noradrenergic system sub- or super-sensitivity.

The interest in noradrenergic systems was renewed with the apparition of atypical antipsychotic agents such as clozapine. Clozapine is one of the first agents demonstrating superior efficacy compared with classical neuroleptics (particularly on negative symptoms)

and, perhaps because it has a relatively low affinity for dopaminergic receptors of the D2 subtype, is devoid of extrapyramidal side effects. It has also been found that chronic clozapine treatment increases plasma DHPG levels in a manner that is correlated with clinical improvement. This study is in agreement with experiments in rats showing that chronic clozapine increases the firing rate of LC neurons. Like other atypical neuroleptics, clozapine is a potent al-adrenergic receptor antagonist. If we assume, as previously mentioned, that the coupling between noradrenergic and dopaminergic systems is due to the stimulation of a1-adrenergic receptors, it may explain that blockade of the latter can moderate the increased dopaminergic subcortical activity generally considered as one of the main biochemical features of schizophrenia. Finally, clonidine, an a2-adrenergic agonist that decreases LC neuron firing, shows a strong therapeutic effect on positive symptoms in acute treatment but is not used because tolerance develops rapidly with chronic medication and provokes a rebound exacerbation of the symptoms after withdrawal.

4. Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) is a childhood psychiatric disorder characterized by inattention, impulsivity, and overactivity. Children with ADHD have difficulty completing tasks, they make careless mistakes, do not listen, lose things, and avoid tasks that require concentration, and they are forgetful and disorganized. The behavioral deficits ADHD are estimated to be present in 3-5% of all school-aged children and are believed to arise in early childhood. The neurotransmitter systems most commonly implicated in the pathophysiology of ADHD are the catecholamines, dopamine and NE. Virtually all medications that are effective in the treatment of ADHD, in particular psychostimulants such as me-thylphenidate, affect catecholamine transmission, and medications that do not interact with catecholamine transmission are rarely effective in the treatment of ADHD, thus indicating the possibility of a biological etiology. A relatively early model has postulated that a noradrenergic dysfunction in the LC produces the deficits in vigilance and sustained attention observed in children with ADHD. However, although studies employing peripheral measures to assess catecholami-nergic function in ADHD are plentiful, they are highly inconsistent in their findings. Urinary MHPG levels, for example, were either higher, not changed, or lower in children with ADHD than in normal controls.

The prefrontal cortex and the basal ganglia play prominent roles in a complex neural system that serves to regulate motor function and behavior via working memory. There are different indications suggesting that working memory in the prefrontal cortex is under the control of the stimulation of D1-dopaminergic receptor subtype, whereas activation of cortical a1-adrenergic receptors inhibits the effects of D1-receptor stimulation. Complex interactions between prefronto-cortical Dl, D2, and a1-adrenergic receptors have been demonstrated, and it cannot be excluded that ADHD corresponds to some dysfunction of these interactions, which, in turn, are responsible for the expression of subcortical functions.

5. Pharmacodependence

Although multiple lines of research have implicated the mesolimbic dopaminergic system in drug reward, the role of noradrenergic systems in pharmacodepen-dence processes should not, however, be overlooked. Indeed, virtually all classes of abused drugs affect LC discharge characteristics at doses that are in the range of those abused by humans. These include hallucinogens, psychostimulants, opiates, alcohol, nicotine, and benzodiazepines. Much of the work on the LC concerning substance abuse has focused on physical dependence and withdrawal symptoms. This is due to the fact that a2-adrenergic agonists such as clonidine, which suppresses LC activity, partly alleviate withdrawal symptoms for several dependence-producing substances. Indeed, the cessation of drug use in chronic opiate abusers produces a severe withdrawal syndrome that is highly aversive. Although increased NE in the brain has long been implicated in opiate withdrawal, it was not clear whether noradrenergic systems were involved until studies, performed in the rat, were completed to indicate that the noradrenergic inputs to the bed nucleus of the stria terminalis arising from noradrenergic cell groups of the caudal medulla are critically involved in the aversiveness of opiate withdrawal.

As mentioned earlier, LC receives a prominent enkephalinergic input associated with a high density of opioid receptors in that region. Opioid antagonists have no effect on LC activity by themselves, but produce a dramatic long-lasting excitation in rats that have chronically received opiates. It is this effect that has been the basis for rationalizing the use of clonidine, which inhibits LC discharge, in the treatment of opiate withdrawal.

The case of nicotine is also interesting because it produces a potent activation of LC neurons when administered systemically. Surprisingly, evidence indicates that this effect of nicotine is not mediated in the LC, or even initiated in the brain, but results from nicotine activation of primary sensory C-fiber afferents. In addition to increasing LC discharge, nicotine induces an increase in the frequency of burst activity, suggesting that the net effect of nicotine is to elicit more NE release in targets and produce short-lasting periods of enhanced arousal.

Dopaminergic systems are, however, more generally considered as the main targets of drugs of abuse than noradrenergic ones because it is believed that psychostimulants, such as amphetamine and cocaine, or opiates, such as morphine and heroin, cause addiction in humans and induce locomotor hyperactivity in rodents through increased release of dopamine in a subcortical structure, the nucleus accumbens. Nevertheless, as noted earlier, experiments performed on rats have indicated that prazosin, an a1-adrenergic antagonist, could hamper the locomotor hyperactivity induced by D-amphetamine. Similarly, we have previously mentioned that mice lacking the a1B-adrenergic receptor were considerably less sensitive to the locomotor effects of amphetamine and cocaine than their corresponding controls. This suggests that, in addition to its role in drug withdrawal, NE, via the stimulation of a1B-adrenergic receptors, may enhance the release of subcortical dopamine and, therefore, amplify the rewarding effects of drugs of abuse. Such a role for NE may provide some new insight into the problem concerning the great variability in the sensitivity to drugs of abuse observed in humans and animals. Indeed, because LC cells are extremely sensitive to environmental stimuli, small genetic or epigenetic variations in the reactivity of noradrenergic neurons to environmental cues may affect the activation of mesencephalic dopaminergic neurons and, more generally, the sensitivity to drugs of abuse.

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