Dextroamphetamine Modulates the Response of the Human Amygdala

Abstract

Amphetamine, a potent monoaminergic agonist, has pronounced effects on emotional behavior in humans, including the generation of fear and anxiety. Recent animal studies have demonstrated the importance of monoamines, especially dopamine, in modulating the response of the amygdala, a key brain region involved in the perception of fearful and threatening stimuli, and the generation of appropriate physiological and behavioral responses. We have explored the possibility that the anxiogenic effect of amphetamine in humans reflectsRecent work in both animal and human subjects has implicated limbic-based circuitry, centered on the amygdala, in the generation and regulation of normal fearful responses as well as pathological anxiety (Damasio 1994;LeDoux 1997). Likewise, amphetamine and other dopaminergic psychostimulants have been shown to produce pronounced effects on emotional behavior, including the generation of fear and anxiety (Angrist and Gershon 1970;Ellinwood et al. 1973;Hall et al. 1988). Studies in animals suggest that such anxiogenic effects may reflect dopamine (DA) augmentation of amygdala activity (Willick and Kokkinidis 1995;Harmer et al. 1997; Harmer and Phillips 1999a,b;Rosenkranz and Grace 1999. These convergent findings lead to the intriguing possibility that the emotion enhancing properties of amphetamine may be related to effects on the amygdala. We used dextroamphetamine (DEX), a potent monoaminergic agonist and anxiogenic, in a double-blind placebo controlled functional magnetic resonance imaging (fMRI) study to explore this possibility in human subjects. METHODSTwelve healthy subjects (five males and seven females, mean age ϭ 33 years) gave written informed consent according to the guidelines of the National Institute of Mental Health Institutional Review Board. Each subject Approximately 120 min before each session, subjects received an oral dose of either placebo (PBO) or DEX (0.25 mg/kg body weight) in a double-blind manner. The order of drug administration was counterbalanced across subjects by the pharmacy. Blood was drawn at the beginning of each session and serum DEX levels were measured using gas chromatography. During each session, subjects completed a blocked fMRI paradigm consisting of two tasks. Subject performance (accuracy and reaction time) was monitored during all scans. In an emotion task, subjects were required to match the expression (either angry or afraid) of one of two faces to that of a simultaneously presented target face (Figure 1, panel A). These stimuli were employed because previous neuroimaging studies have revealed that facial expressions, especially those of negative affect, elicit a robust amygdala response (Davis and Whalen 2001). As a sensorimotor control task, subjects were required to match one of two geometric shapes with a simultaneously presented target shape (Figure 1, panel B). We employed simple geometric shapes and not neutral facial expressions as control stimuli because subjects may perceive such "neutral" faces ambiguously and thus elicit an amygdala...

A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity

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Gene–gene effects on central processing of aversive stimuli

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Progesterone selectively increases amygdala reactivity in women

“…This paradigm has been used previously to investigate drug effects on amygdala reactivity. 26,27 It robustly engages the amygdala, by contrasting the response to simultaneously presented angry and fearful face stimuli (http:// www.macbrain.org) with the response to ellipses (that consisted of scrambles of the same face stimuli). The results therefore do not show emotion-specific effects, but rather a general response to salient, biologically relevant stimuli.…”