Evolving Behavior in the Clinical and Experimental Amphetamine (Model) Psychosis

Ellinwood, Everett H.; Sudilovsky, Abraham; Nelson, Linda M.

doi:10.1176/ajp.130.10.1088

Cited by 238 publications

(75 citation statements)

References 2 publications

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“…The absence of anxiogenic effects in the current study are not surprising given the relatively low physiological doses of DEX administered and the controlled environment. While measurable levels of DEX were detected in all subjects, ranging from 46 to 71 ng/ml (mean 57.3 ng/ml), previous work has illustrated that symptoms of intense anxiety and panic require persistent administration of amphetamine exceeding 150 mg/day (Ellinwood et al 1973). During the emotion task, subjects viewed a trio of faces and had to select one of two faces (bottom) that expressed the same emotion as the target face (top).…”

Section: Resultsmentioning

confidence: 74%

“…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.…”

Section: Amphetamine a Potent Monoaminergic Agonist Has Pronounced mentioning

confidence: 99%

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Dextroamphetamine Modulates the Response of the Human Amygdala

Hariri

Mattay

Tessitore

et al. 2002

Neuropsychopharmacology

171

114

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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...

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Section: Resultsmentioning

confidence: 74%

Section: Amphetamine a Potent Monoaminergic Agonist Has Pronounced mentioning

confidence: 99%

Dextroamphetamine Modulates the Response of the Human Amygdala

Hariri

Mattay

Tessitore

et al. 2002

Neuropsychopharmacology

171

114

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“…Human symptoms following repetitive stimulant drug use evolve gradually from intense curiosity, progressing to intense exploration of the environment, which may be displayed in repetitive stereotyped searching, sorting, and examining behaviors. This curious 'suspiciousness' of the environment later evolves into paranoia and psychotic thought (Ellinwood et al, 1973;Segal et al, 1981;Segal and Schuckit, 1983). Because pretreatment with AMPH facilitates the later acquisition of drug self-administration in rodents (Piazza et al, 1989), it has also been theorized that sensitization may underlie the development of drug craving, and thus initiate addictive behaviors seen in human drug dependence (Robinson and Berridge, 1993).…”

Section: Behavioral Characteristics Of Sensitizationmentioning

confidence: 99%

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Richtand

2006

Neuropsychopharmacol

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Behavioral sensitization, the progressive and enduring augmentation of certain behaviors following repetitive drug use, alters rodent locomotion in a long-standing manner. The same dopamine pathways playing an important role in drug dependence and psychosis also play a critical role in sensitization. Individual dopamine receptor subtypes have markedly different functional responses to stimulation, with D3 dopamine receptor stimulation inhibiting rodent locomotion. The D3 receptor has highest affinity of the dopamine receptor subtypes for dopamine, and is occupied to a greater degree following stimulant drug administration. D3 receptor activity may be regulated through the expression of an alternatively spliced, truncated receptor isoform (termed 'D3nf') altering receptor localization and function via dimerization with the full-length subunit. The expected physiological response to repetitive drug administration is tolerance. Tolerance of D3 receptor inhibition of locomotion would contribute to sensitization to stimulant drugs. We hypothesize that repetitive D3 receptor stimulation contributes to the development of behavioral sensitization through decreased responsivity of D3-receptor-mediated locomotor inhibition. Increased D3nf expression may direct altered receptor localization and subsequent release of D3-receptormediated inhibition, contributing to the expression of sensitization. These hypotheses follow directly from the affinities of the receptor subtypes for dopamine; dopamine concentrations following stimulant administration; the effects of individual dopamine receptor subtype stimulation on locomotion; and the expected homeostatic response of the system to perturbation by drug. Clarifying these mechanisms underlying sensitization may suggest new interventions for neuropsychiatric conditions in which dopamine plays an important role, including psychosis, drug dependence, and Parkinson's disease. This information may also elucidate a previously unrecognized mechanism regulating receptor trafficking and desensitization.

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“…Moreover, several studies have reported that the early onset in males was particularly evident in paranoid schizophrenia, [22][23][24] and paranoid symptoms have been specifically related to increased dopaminergic activity on the basis of amphetamine-induced psychosis. 25,26 It has been shown that amphetamine causes a reduction in DDC mRNA and 2-PE production. 27 This could be due to a homeostatic negative feedback mechanism since amphetamine is a structural analogue of 2-PE and is most likely acting as a 2-PE agonist, and DDC is the rate-limiting enzyme in the synthesis of 2-PE.…”

Section: ‫ء‬mentioning

confidence: 99%

Dopa decarboxylase genotypes may influence age at onset of schizophrenia

Børglum¹,

Hampson

Kjeldsen³

et al. 2001

Mol Psychiatry

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Several lines of evidence implicate dopa decarboxylase (DDC) with schizophrenia. By analysis of two putative functional DDC variants in 173 schizophrenic patients and 204 controls we tested the hypotheses that DDC is involved in: (1) predisposition to schizophrenia; and (2) modulation of age at disease onset. No association was observed with schizophrenia as a whole, whereas an association between DDC genotypes and age at disease onset was suggested in males (P = 0.03). This association was most pronounced in relation to genotypes of haplotypes comprising both variants, suggesting an additive model where one variant mediates early and the other late onset. Accordingly, the haplotypebased genotypes could be assigned into three groups by their possible relative effect on age at onset: an 'early', 'neutral' and 'late' group. Dividing the male schizophrenics into four groups with increasing age at onset, the 'early' genotypes were seen to decrease in frequency from 51.5% to 16.7% while the 'late' genotypes increased from 12.1% to 33.3% (P = 0.02). The difference in mean age at onset between male patients with 'early' genotypes vs patients with 'late' genotypes was close to 5 years (95% CI: 0.7-8.8). Thus, DDC may possibly act as a modulator of age at onset in male schizophrenics. Molecular Psychiatry (2001) 6, 712-717.

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Evolving Behavior in the Clinical and Experimental Amphetamine (Model) Psychosis

Cited by 238 publications

References 2 publications

Dextroamphetamine Modulates the Response of the Human Amygdala

Dextroamphetamine Modulates the Response of the Human Amygdala

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Dopa decarboxylase genotypes may influence age at onset of schizophrenia

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