Fear and Anxiety: Relationship to Noradrenergic Function

Abstract

The experiences of human fear and anxiety are discussed within the context of locus ceruleus function in animals. The rationale for studying correlates of noradrenergic function, such as 3-methoxy-4-hydroxyphenethylene glycol (MHPG), is reviewed, and data demonstrating a positive correlation between plasma free MHPG and state anxiety in normal volunteers is presented. The behavioral effects of oral caffeine (240–720 mg), intravenous clonidine (2 µg/kg), and oral yohimbine (20 mg) were studied in various psychiatric patients and normal volunteers. Caffeine and yohimbine had anxiogenic properties; conversely, clonidine reduced self-rated measures of anxiety across a wide spectrum of psychiatric conditions. These findings expand previous research indicating that noradrenergic hyperactivity may be associated with many types of human fear and anxiety.

Neural Activation Profile Elicited by Cues Associated with the Anxiogenic Drug Yohimbine Differs from That Observed for Reward-Paired Cues

“…It is thought that yohimbine's antagonist action at the a-2 adrenergic receptor causes an increase in the firing of norepinephrine-containing locus coeruleus neurons (Uhde et al, 1984;Pellow et al, 1985;Chopin et al, 1986). In humans, yohimbine increases self-reports of anxiety (Charney et al, 1983;Uhde et al, 1984) as well as facilitating acoustic startle reflex (Morgan et al, 1993).…”

“…It is thought that yohimbine's antagonist action at the a-2 adrenergic receptor causes an increase in the firing of norepinephrine-containing locus coeruleus neurons (Uhde et al, 1984;Pellow et al, 1985;Chopin et al, 1986). In humans, yohimbine increases self-reports of anxiety (Charney et al, 1983;Uhde et al, 1984) as well as facilitating acoustic startle reflex (Morgan et al, 1993). Animals treated with yohimbine exhibit increased anxiety and fearful behavior, including conditioned place aversion, decreased social interaction, decreased exploration and potentiated startle (Davis et al, 1979;Pellow et al, 1985;Chopin et al, 1986;File, 1986;Bhattacharya et al, 1997).…”

“…Instead of pairing an injection of a rewarding drug with a specific environment, an environment was paired with an injection of yohimbine, an anxiogenic a-2 adrenergic receptor antagonist. Yohimbine causes an increase in the firing of central nervous system noradrenergic neurons and, in humans, increases subjective reports of anxiety (Charney et al, 1983;Uhde et al, 1984;Sanger, 1988). Similarly, in animal studies, yohimbine has been shown in multiple paradigms to be apparently anxiogenic, causing conditioned place aversion, potentiated startle, decreased social interaction and decreased exploration (Davis et al, 1979;Pellow et al, 1985;Chopin et al, 1986;File, 1986;Bhattacharya et al, 1997).…”

A re‐evaluation of the role of α2‐adrenoceptors in the anxiogenic effects of yohimbine, using the selective antagonist delequamine in the rat

“…Yohimbine has therefore proved useful in teasing out humans. In normal subjects the effect tends to be mild anxiety sub-groups of responders, but this is only of value from an (Uhde et al, 1984;Mattila et al, 1988;Krystal et al, 1992); in aetiological point of view if its precise pharmacological mepatients with agoraphobia or panic disorder the agent induces chanism of action is understood. an enhanced anxiety response or panic (Charney et al, 1987), Following the discovery of presynaptic a2-adrenoceptors and in patients with post-traumatic stress disorder, yohimbine (see Langer, 1974) located both terminally and somato-dencan induce panic and flashbacks (Southwick et a!., 1993).…”

Role of Norepinephrine in Modulating Inhibitory Avoidance Memory Storage: Critical Involvement of the Basolateral Amygdala

“…yohimbine) results in increased anxiety [69][70][71][72], probably as a result of the potentiation of this excitatory pathway from the LC to the amygdala. In addition to a role in anxiety, the LC projection to the amygdala may also play a role in forming and retrieving emotional memories [73,74].…”