Serotonergic mechanisms of cocaine effects in humans

Sc, Aronson; Je, Black; Cj, McDougle; Be, Scanley; Jatlow, Peter; Tr, Kosten; Gr, Heninger; Lh, Price

doi:10.1007/bf02246159

Cited by 88 publications

(45 citation statements)

References 43 publications

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“…Finally, while serotonin may modulate risky choices through its influences upon learning from negative outcomes (Evers et al, 2005; see below), it is also likely that serotonin can alter choice behaviors via processing of positive reward signals when making decisions, consistent with the evidence of functional interactions between midbrain dopamine neurones and the serotonergic neurones of the raphe (Nakamura et al, 2008) and evidence that serotonin activity can facilitate aspects of dopaminemediated reward processing (Aronson et al, 1995). Thus, Rogers et al (2003) showed that tryptophan depletion reduced healthy volunteers' attentional processing of reward cues, but not probability or punishment cues, when deciding between risky actions associated with uncertain outcomes, highlighting a role for serotonin in auxiliary cognitive activitiesFthis time, attentionalFin decisionmaking functions .…”

Section: Serotonin and Risky Choicementioning

confidence: 85%

“…For example, the behavioral and reinforcing effects of cocaine in rats are potentiated by treatment with selective serotonin-reuptake blockers (SSRIs) (Cunningham and Callahan, 1991;Kleven and Koek, 1998;Sasaki-Adams and Kelley, 2001), and brain self-stimulation thresholds can also be dose dependently altered with SSRI treatment (Harrison and Markou, 2001). Similarly, tryptophan depletion can block the rewarding effects of cocaine in human subjects (Aronson et al, 1995).…”

Section: Background: Dopamine and Serotonin In Reinforcement Processingmentioning

confidence: 99%

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The Roles of Dopamine and Serotonin in Decision Making: Evidence from Pharmacological Experiments in Humans

Rogers

2010

Neuropsychopharmacol

202

130

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Neurophysiological experiments in primates, alongside neuropsychological and functional magnetic resonance investigations in humans, have significantly enhanced our understanding of the neural architecture of decision making. In this review, I consider the more limited database of experiments that have investigated how dopamine and serotonin activity influences the choices of human adults. These include those experiments that have involved the administration of drugs to healthy controls, experiments that have tested genotypic influences upon dopamine and serotonin function, and, finally, some of those experiments that have examined the effects of drugs on the decision making of clinical samples. Pharmacological experiments in humans are few in number and face considerable methodological challenges in terms of drug specificity, uncertainties about pre-vs post-synaptic modes of action, and interactions with baseline cognitive performance. However, the available data are broadly consistent with current computational models of dopamine function in decision making and highlight the dissociable roles of dopamine receptor systems in the learning about outcomes that underpins value-based decision making. Moreover, genotypic influences on (interacting) prefrontal and striatal dopamine activity are associated with changes in choice behavior that might be relevant to understanding exploratory behaviors and vulnerability to addictive disorders. Manipulations of serotonin in laboratory tests of decision making in human participants have provided less consistent results, but the information gathered to date indicates a role for serotonin in learning about bad decision outcomes, non-normative aspects of risk-seeking behavior, and social choices involving affiliation and notions of fairness. Finally, I suggest that the role played by serotonin in the regulation of cognitive biases, and representation of context in learning, point toward a role in the cortically mediated cognitive appraisal of reinforcers when selecting between actions, potentially accounting for its influence upon the processing salient aversive outcomes and social choice.

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Section: Serotonin and Risky Choicementioning

confidence: 85%

Section: Background: Dopamine and Serotonin In Reinforcement Processingmentioning

confidence: 99%

The Roles of Dopamine and Serotonin in Decision Making: Evidence from Pharmacological Experiments in Humans

Rogers

2010

Neuropsychopharmacol

202

130

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“…More directly, tryptophan depletion has been shown to diminish the euphoric effects of intravenous cocaine in cocaine addicts (Aronson et al, 1995), and to reduce the craving experienced when presented with cocaine-related paraphernalia (Satel et al, 1995). The latter finding suggests that serotonin affects the way that reward-associated signals influence behaviour; consistent with reports that fluoxetine potentiates the control of ongoing responding by available conditioned reinforcers (Sasaki-Adams and Kelley, 2001;Fletcher et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Tryptophan Depletion Alters the Decision-Making of Healthy Volunteers through Altered Processing of Reward Cues

Rogers

Tunbridge

Bhagwagar

et al. 2002

Neuropsychopharmacol

253

231

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While accumulating evidence suggests that effective real-life decision-making depends upon the functioning of the orbitofrontal cortex, much less is known about the involvement of the monoamine neurotransmitter systems and, in particular, serotonin. In the present study, we explored the impact of depleting the serotonin precursor, tryptophan, on human decision-making. Eighteen healthy volunteers consumed an amino-acid drink containing tryptophan and 18 healthy volunteers consumed an amino-acid drink without tryptophan, before choosing between simultaneously presented gambles, differing in the magnitude of expected gains (ie reward), the magnitude of expected losses (ie punishment), and the probabilities with which these outcomes were delivered. Volunteers also chose between gambles probing identified non-nomative biases in human decision-making, namely, risk-aversion when choosing between gains and riskseeking when choosing between losses. Tryptophan-depleted volunteers showed reduced discrimination between magnitudes of expected gains associated with different choices. There was little evidence that tryptophan depletion was associated with altered discrimination between the magnitudes of expected losses, or altered discrimination between the relative probabilities with which these positive or negative outcomes were delivered. Risk-averse and risk-seeking biases were also unchanged. These results suggest that serotonin mediates decision-making in healthy volunteers by modulating the processing of reward cues, perhaps represented within the orbitofrontal cortex. It is possible that such a change in the cognition mediating human choice is one mechanism associated with the onset and maintenance of anhedonia and lowered mood in psychiatric illness.

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“…When patients were exposed to cocaine-related paraphernalia (specifically intended to enhance craving), RTD diminished the subjective feelings of craving (Satel et al 1995). In another group of addicts, RTD diminished the "high" feeling after intranasal cocaine when compared with sham challenge (Aronson et al 1995). Since serotonergic raphe neurons are known to modulate mesolimbic dopaminergic reward pathways believed to mediate the rewarding properties of all known drugs of abuse (Baumgarten and Grozdanovic 1994), these findings imply that RTD directly reduces the pleasurable subjective states related to drug craving and drug reward.…”

Section: Other Psychiatric Diagnosesmentioning

confidence: 90%

Clinical and Physiological Consequences of Rapid Tryptophan Depletion

Moore

Landolt

Seifritz

et al. 2000

Neuropsychopharmacology

184

121

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We review here the rapid tryptophan depletion (RTD) methodology and its controversial association with depressive relapse. RTD has been used over the past decade to deplete serotonin (5-hydroxy-tryptamine, or 5-HT) in humans and to probe the role of the central serotonin system in a variety of psychiatric conditions. Its current popularity was stimulated by reports that RTD reversed the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) KEY WORDS : 5-HT; Serotonin; Tryptophan-free drink; Major depressionSerotonin (5-hydroxy-tryptamine, or 5-HT) is involved in many physiologic and behavioral systems and clinical disease states. Much of the information available on the function of serotonin comes from pharmacological agents which mimic or amplify endogenous serotonergic neurotransmission, such as serotonin agonists or SSRIs. Historically, methods to functionally deplete serotonin have been problematic. Even previous approaches that have been moderately successful in experimental animals -such as the 5-HT synthesis inhibitor, parachloro-phenylalanine (PCPA); the neurotoxin 5-6-dihydroxy-tryptamine; or various lesions to the serotonergic raphe nuclei of the brainstem -have been non-specific, rife with secondary effects, or clearly inapplicable to humans (e.g., Engelman et al. 1967;Koella et al. 1968;Jouvet et al. 1967). The advent of rapid tryptophan depletion (RTD) as a method to deplete central serotonin has been met with enthusiasm because of its reversibil- NO . 6 ity, its relative lack of side effects, and its merit in elucidating the pathophysiology of various psychiatric conditions. This paper reviews the RTD methodology and its reported ability to induce a depressive relapse in euthymic patients, and other physiological and clinical effects. RAPID TRYPTOPHAN DEPLETION Availability of Tryptophan and Serotonin SynthesisRTD is based on the current understanding of the 5-HT biosynthetic pathway, in which the first step is generally considered to be the rate-limiting one. The first step entails the hydroxylation of the amino acid TRP (by the enzyme TRP hydroxylase, or TRP-H) into the intermediate product 5-hydroxy-tryptophan, or 5-HTP. 5-HTP is then decarboxylated into 5-HT. Under normal conditions, TRP-H is about 50% saturated with TRP. Increasing or decreasing the availability of TRP correlates highly with the amount of 5-HT produced (e.g., Lin et al. 1969;Schaechter and Wurtman 1990). Because the body cannot synthesize TRP, reducing dietary intake of TRP reduces TRP levels in plasma and diminishes its transport from plasma into the brain.In humans, TRP depletion is accomplished by consuming a TRP-free amino acid drink (e.g., Delgado et al. 1990;Biggio et al. 1974). This drink contains 15 amino acids in the same proportion as in human milk, except that TRP, aspartic acid, and glutamic acid are omitted (see Table 1). Within a matter of hours (4 to 12), plasma TRP declines to 10-50% of baseline levels (Delgado et al. 1990(Delgado et al. , 199...

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Serotonergic mechanisms of cocaine effects in humans

Cited by 88 publications

References 43 publications

The Roles of Dopamine and Serotonin in Decision Making: Evidence from Pharmacological Experiments in Humans

The Roles of Dopamine and Serotonin in Decision Making: Evidence from Pharmacological Experiments in Humans

Tryptophan Depletion Alters the Decision-Making of Healthy Volunteers through Altered Processing of Reward Cues

Clinical and Physiological Consequences of Rapid Tryptophan Depletion

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