Lack of effect of acute dopamine precursor depletion in nicotine-dependent smokers Kevin F. Casey, Chawki Benkelfat, Simon N. Young, Marco Leyton * Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1 Received 12 April 2005; received in revised form 26 January 2006; accepted 2 February 2006 Abstract Rationale: Nicotine increases dopamine (DA) release but its role in nicotine dependence remains unclear. Objective: To assess the role of DA in nicotine craving and self-administration using acute phenylalanine/tyrosine depletion (APTD). Methods: Fifteen nicotine-dependent men ingested, a minimum of 3 days apart, a nutritionally balanced amino acid (AA) mixture (BAL), a mixture deficient in the catecholamine precursors, phenylalanine and tyrosine, and APTD followed by the immediate DA precursor, l-DOPA. Beginning 3h after ingestion of the AA mixture, subjects smoked 4 cigarettes. Craving, mood, and other aspects of subjective state were assessed with self-report scales. Smoking puff topography was measured with a computerized flowmeter. Results: APTD did not change smoking puff topography, cigarette craving, or subjective effects of smoking. Conclusions: The findings suggest that in nicotine- dependent smokers craving for cigarettes, subjective effects of nicotine, and the self- administration of freely available cigarettes are largely unrelated to acute changes in DA neurotransmission. D 2006 Elsevier B.V. and ECNP. All rights reserved. 1. Introduction The neurobiology of substance dependence in humans is poorly understood. In animal models the best-studied mechanism is the ascending midbrain dopamine (DA) system. Across pharmacological classes, drugs of abuse increase extracellular DA levels (Di Chiara and Imperato, 1988), while DA receptor antagonists and selective DA lesions decrease drug self-administration (Yokel and Wise, 1976; De Wit and Wise, 1977; Roberts et al., 1977; Roberts and Koob, 1982). In humans the relation between DA and drug use is less clear. Functional neuroimaging studies have demonstrated evidence of drug-induced increases in extra- cellular DA for a range of abused substances (Laruelle et al., 1995; Schlaepfer et al., 1997; Leyton et al., 2002; Boileau et al., 2003; Brody et al., 2004), but DA antagonists do not reliably decrease the subjective effects of abused drugs 0924-977X/$ - see front matter D 2006 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2006.02.002 * Corresponding author. Tel.: +1 514 398 5804; fax: +1 514 398 4866. E-mail address: marco.leyton@mcgill.ca (M. Leyton). KEYWORDS Smoking; Addiction; Motivation; Reward; Nicotine; Dopamine European Neuropsychopharmacology (2006) 16, 512—520 www.elsevier.com/locate/euroneuro