Neurochemistry of Fear

Future anxiolytic drug development is dependent on further clarification of the neu-rochemical systems that control fearfulness in the brain (Davis, 1999; LeDoux, 2000; Panksepp, 1998a, 2000). The abundant BZ receptors that exist along the main "artery" of the FEAR circuit that courses between the amygdala and PAG (Fig. 16.1) provide a substrate whereby traditional minor tranquilizers (as well as alcohol and barbiturates) may inhibit anxiety (Haefely, 1990). The distinct GABA and BZ binding sites on this complex (as well as those that bind alcohol and barbiturates) synergistically facilitate neuronal inhibition (by promoting chloride flow into the cell). Thus, BZs quell anxiety by hyperpolarizing neurons that distribute fearful messages within the brain. Stimulants for BZ receptors not only directly reduce activity in the FEAR circuit, they may also directly suppress higher processing of related thoughts and appraisals through effects on abundant BZ receptors in the neocortex. BZ receptor antagonists (e.g., flumaze-nil) given alone are typically behaviorally inactive in nonanxious organisms, which suggests that endogenous anxiety molecules are generally absent at BZ receptor sites. However, these antagonists do block the effects of administered BZs as well as anxiety provoked by "inverse agonists" such as 6-carbolines (see below). Also, they increase the number of attacks in panic-prone individuals (Nutt et al., 1990).

A key question for understanding this system is: What endogenous molecules normally act on BZ receptors? A definitive answer remains elusive, but a perennial candidate has been the diazepam-binding inhibitor (DBI), an endogenous peptide that may promote anxiety when released onto BZ receptors (Ferrarese et al., 1993). DBI appears to be an "inverse agonist" at BZ receptors, actively increasing the arousability of the brain substrates for fearfulness by decreasing inhibition in the system. However, elevated DBI has not been evident in panic disorders (Payeur et al., 1992). In any event, inverse agonists such as various 6-carboline drugs exert neurophysiological effects opposite to those of BZs (i.e., actively inhibiting inflow of chloride into neurons) after interacting with the BZ-GABA complex, and the overall emotional effect is to promote anxiety. Thus, it seems reasonable that endogenous anxiogenic substances may facilitate fearful affect by blocking the activation of the BZ-GABA receptor complex.

Many other neurotransmitters are capable of promoting anxiety signals through the brain. For instance, norepinephrine (NE) and serotonin have long been touted as potential anxiogenic systems. Certain drugs that facilitate NE and serotonin activity [e.g., after the alpha2-NE receptor antagonist, yohimbine, and the 5-HT2C receptor agonist m-chlorophenylpiperazine (MCPP), respectively] do promote anxiety in humans (Charney et al., 1987). Some of these effects probably reflect modulation of general arousal rather than evocation of specific emotional responses. It is unlikely that biogenic amine systems contribute specifically to the experiences of anxiety. Rather, they do so by regulating ongoing brain activities (e.g., memory) that can prolong or shorten anxious rumination.

One fear transmitter is the simple excitatory amino acid glutamate. Intense fear responses are evoked by microinfusions of various glutamate agonists, such as kainic acid and N-methyl-D-aspartate (NMDA), into the lower ventricular system as well as various sites within the FEAR system (Carobrez et al., 2001). Such fearful episodes are counteracted by various glutamate receptor antagonists. Although one might assume that new antianxiety drugs could be created from these agents, such a strategy seems outwardly impractical because of the broad spectrum of brain functions, from sensory processes to memory, that are controlled by glutamatergic synapses. Undesirable side effects of the strong glutamate receptor antagonists are numerous, but mild glutamate antagonists have recently yielded some promising results in the treatment of depression (Skolnick et al., 2001). There is also some data that down-regulation of glu-tamatergic transmission with selective metabotropic glutamate agonists may provide therapeutically useful anxiolysis (Helton et al., 1998).

The number of drug targets among the neuropeptides is rapidly growing. In addition to DBI, the clarification of a large number of neuropeptides that modulate anxiety-like behaviors in animals has provided a cornucopia of promising candidates for further drug discovery. Most of these neuromodulators are enriched along the trajectory of the FEAR system, As detailed in Chapter 21, among the next generation of antianxiety drugs, we will certainly find corticotrophin-releasing hormone (CRH) receptor antagonists, since CRH is a major neuropeptide vector that promotes various, albeit still poorly defined, anxieties (Chalmers et al., 1996; Heilig et al., 1994, and see Chapter 4). Briefly, centrally administered CRH promotes agitated arousal and reduces all positively motivated behaviors from feeding to all sociosexual activities (Dunn and Berridge, 1990). Animals show conditioned freezing in environments where they previously experienced CRH, and CRH antagonists diminish freezing induced by normal stressors (Candor et al., 1992).

One form of anxiety that deserves special attention arises from separation distress systems in action. CRH is highly effective in promoting such instinctual responses (Panksepp and Bekkedal, 1997). The effectiveness of nonpeptide CRH antagonists on more routine animal models of anxiety has been sufficiently impressive (Chapter 4) that several are undergoing clinical evaluation. Separation anxiety should be a prime target of such therapies. Many other neuropeptides reduce separation anxiety behaviors following central administration, including opioids acting on mu receptors. Oxytocin and prolactin are very effective when centrally administered (Panksepp, 1991, 1998a).

Based on the fact that the neuropeptide a-melanocyte-stimulating hormone (a-MSH) facilitates camouflage-type color changes in reptiles (a physiological defense response), it should not be surprising that behaviorally clear freezing/hiding responses can be activated by central administration of a-MSH in organisms that no longer show those pigmentary effects (Panksepp and Abbott, 1990). Adrenocorticotrophic hormone (ACTH), derived from the same pro-opiomelanocortin (POMC) gene as a-MSH, evokes the same effects in birds, and high doses of the molecule into the PAG evoke vigorous flight in rats.

Anxiogenic peptides have also been found in the cholecystokinin (CCK) family, perhaps the most abundant peptide in the brain. Intravenous administration of certain

CCK fragments in humans can promote panic attacks and a variety of fearlike symptoms in animals (Harro et al., 1993). Unfortunately, preliminary human clinical trials with CCK antagonists have failed to demonstrate efficacy in the treatment of panic or general anxiety disorders, a characteristic that may be explained by their poor pharma-cokinetic characteristics (Pande et al., 1999) or perhaps their mixed affective effects in different neural circuits (You et al., 1998).

The affective changes evoked by most such molecules remain to be monitored using appropriate behavioral paradigms (e.g., place avoidance and conditioned freezing paradigms), but if they prove effective in such tests, it would be predicted that antagonists for such neuropeptides may ameliorate fearful inhibitions in humans. Of course, in pursuing such interpretations, we might recall that a large number of negative affects can be elaborated in the mammalian brain. Hence, many psychological subtleties will have to be considered that require careful behavioral ethological studies in animals and psychoethological ones in humans (Panksepp, 1999a,b).

As elaborated in Chapter 21, some of the forthcoming neuropeptide modulator medicines may not have robust therapeutic effects on their own. Instead, they may provide an optimal affective bias for various other environmentally based therapies to work better. Such a concept will need to be studied first in animal models, to see whether certain types of antianxiety conditioning will proceed more effectively in the presence of specific neurochemical background activities that in themselves do not modify the intensity of an animal's response to threats. Although there is little relevant data of this sort, a didactic precedent is identification of experimental agents that promote social activities if they had been experienced in affectively positive environments, while reducing such activities if the drugs had previously been administered in aversive environments (Bekkedal et al., 1999).

A goal for future research is to specify, more precisely, how the emerging antianx-iety chemistries mediate subcomponents of the overall affective process subsumed by the concept of anxiety. Do certain neuropeptides elaborate specific fears while others are more global modulators of FEAR and separation distress/PANIC responses (e.g., helping regulate the intensity and duration of emotional episodes, etc.)? Concurrent work with several animal models, hopefully using several species, may help tease apart the distinct functions of the increasing number of known neurochemistries that regulate anxiety within the mammalian brain. Also, considering that the broadcasting of information and affect in the nervous system is widespread [facilitated perhaps via ascending NE, 5-HT, and Acetylcholine (ACh) systems], the way in which learning as well as generalized arousal/attentional systems interact with specific affective processes needs to be further elucidated.

How To Win Your War Against Anxiety Disorders

How To Win Your War Against Anxiety Disorders

Tips And Tricks For Relieving Anxiety... Fast Everyone feels anxious sometimes. Whether work is getting to us or we're simply having hard time managing all that we have to do, we can feel overwhelmed and worried that we might not be able to manage it all. When these feelings hit, we don't have to suffer. By taking some simple steps, you can begin to create a calmer attitude, one that not only helps you feel better, but one that allows you the chance to make better decisions about what you need to do next.

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