Effects of Acute Tyrosine/Phenylalanine Depletion on the Selective Processing of Smoking-Related Cues and the Relative Value of Cigarettes in Smokers
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Psychopharmacology DOI 10.1007/s00213-007-0995-5 ORIGINAL INVESTIGATION Effects of acute tyrosine/phenylalanine depletion on the selective processing of smoking-related cues and the relative value of cigarettes in smokers Brian Hitsman & James MacKillop & Anne Lingford-Hughes & Tim M. Williams & Faheem Ahmad & Sally Adams & David J. Nutt & Marcus R. Munafò Received: 16 May 2007 /Accepted: 18 October 2007 # Springer-Verlag 2007 Abstract tive mood, and expired carbon monoxide (CO) levels were Rationale Acute tyrosine/phenylalanine depletion (ATPD) is measured at various timepoints through 300 min. Participants a validated neurobiological challenge that results in reduced smoked at hourly intervals to prevent acute nicotine with- dopaminergic neurotransmission, allowing examination of drawal during testing. the effects of a hypodopaminergic state on craving-related Results The TYR/PHE-free mixture, as compared to the processes. BAL mixture, was associated with a greater increase in CO Objectives We studied 16 nonabstaining smokers (>10 levels from baseline ( p=0.01). Adjusting for the potential cigarettes/day; 9 males; age 20–33 years) to whom was confounding influence of between-condition differences in administered a tyrosine/phenylalanine-free mixture (TYR/ CO levels across time, TYR/PHE-free mixture was asso- PHE-free) and a balanced amino acid mixture (BAL) in a ciated with increased demand for cigarettes ( p=0.01) and double-blind, counterbalanced, crossover design. decreased attentional bias toward smoking-related words Methods Subjective cigarette craving, attentional bias to ( p=0.003). There were no significant differences between smoking-related word cues, relative value of cigarettes, nega- conditions in either subjective craving or depressed or anxious mood ( p values>0.05). Conclusion Among nonabstaining daily smokers, acute dopaminergic depletion via ATPD may influence smoking B. Hitsman (*) behavior and indices of smoking-related motivation, such Centers for Behavioral and Preventive Medicine, as attentional bias to smoking cues and relative cigarette The Miriam Hospital and Brown Medical School, Coro Building, Suite 500, 1 Hoppin Street, value, which are not readily captured by subjective craving. Providence, RI 02903, USA e-mail: [email protected] Keywords Cigarette smoking . Attentional bias . J. MacKillop Relative value Cigarette craving Dopamine Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA Introduction A. Lingford-Hughes : T. M. Williams : F. Ahmad : D. J. Nutt Academic Unit of Psychiatry, University of Bristol, Bristol, UK Converging evidence from animal and human studies : indicates that cigarette smoking behavior is under partial S. Adams M. R. Munafò (*) influence of dopamine-dependent mesolimbic and meso- Department of Experimental Psychology, University of Bristol, cortical brain systems. Nicotine stimulates burst firing of 12a Priory Road, Bristol BS8 1TU, UK dopaminergic neurons in animals when binding to nicotinic e-mail: [email protected] acetylcholine receptors in the midbrain tegmentum (Di Psychopharmacology Chiara 2000), which in turn enhances release of dopamine degree of attentional bias and level of subjective cigarette in the outer shell of the nucleus accumbens and prefrontal craving. Consequently, cognitive constructs such as atten- cortex (Benwell and Balfour 1992; Corrigall et al. 1994). tional bias to smoking cues may index facets of reward and The cascade of events, including changes in postsynaptic motivational processes not necessarily entirely captured by signaling, is theorized to be positively reinforcing with self-report measures of craving (Perkins et al. 1997; Tiffany strong hedonic and appetitive motivational properties and Conklin 2000). A similar distinction has been observed (Epping-Jordan et al. 1998; Koob and Le Moal 1997). in studies of the relative value of addictive substances vs The synthesis of brain dopamine is dependent on the money. Relative value has been measured by eliciting self- availability of its amino acid precursor, tyrosine, in plasma. report of the desired level of consumption of a substance Administration of an amino acid mixture that lacks tyro- under multiple (and increasing) levels of price. In general, sine, as well as its precursor phenylalanine, decreases avail- the more a person is willing to spend to obtain a substance, ability of tyrosine and phenylalanine in plasma through such as a cigarette, the greater its relative value. These processes of increased protein synthesis. This results in studies have found moderate correlations between relative increased competition for transport across the blood–brain value and subjective craving, but far from collinear rela- barrier (Oldendorf and Szabo 1976; Pardridge 1977). In tionships (e.g., Mackillop et al. 2007). More objective animals, administration of the tyrosine/phenylalanine- cognitive and behavioral indicators of motivational drive to free (TYR/PHE-free) mixture decreases the availability smoke, such as attentional bias to smoking-related cues and of tyrosine in the brain, resulting in direct action on relative value of cigarettes, may be especially sensitive to dopamine (McTavish et al. 1999b). Noradrenergic acute changes in dopaminergic neurotransmission. response to either amphetamine or idazoxan is unaffected In the current study, we investigated the influence of (McTavish et al. 1999a), suggesting a selective effect on ATPD via administration of a TYR/PHE-free mixture, as dopamine. Administration of the TYR/PHE-free mixture compared with a BAL mixture, on motivation to smoke, in humans increases prolactin levels (Harmer et al. 2001) as indexed by attentional bias for smoking-related cues, and decreases extracellular dopamine levels, as indexed by relative value of cigarettes, and subjective cigarette changes in [11C]raclopride binding (Leyton et al. 2004; craving, and mood among non-nicotine deprived male Montgomery et al. 2003). and female smokers. Based on the role of dopamine in The acute tyrosine/phenylalanine depletion (ATPD) mediating nicotine’s rewarding and motivational effects, technique represents a valuable paradigm for examining we hypothesized that administration of the TYR/PHE-free the effects of reduced dopamine availability on addictive mixture would be associated with increased attentional behaviors. Despite the promise of this approach for iden- bias for smoking-related cues and increased value of tifying core biobehavioral processes underlying chronic cigarettes. Based in part on Casey and colleagues’ (2006) addiction, to our knowledge only one study has applied it to results, we did not hypothesize an effect on subjective nicotine dependence. A recent study of 15 male smokers craving. We also did not predict effects on negative mood (Casey et al. 2006) found no effect of ATPD on self- as ATPD has been found to influence mood only in healthy reported craving or smoking topography. Subjective crav- female social drinkers and only after exposure to a ing may be distinct from other craving-related mechanisms psychological stress challenge (Leyton et al. 2000). The that contribute to relapse following acute smoking absti- TYR/PHE-free and BAL challenges were administered nence (Munafò and Hitsman 2006; Perkins et al. 1997). The 1 week apart using a double-blind, counterbalanced, incentive-sensitization model (Robinson and Berridge crossover design. 1993, 2000) asserts that repeated use of substances that enhance mesolimbic dopaminergic neurotransmission results in permanent or semipermanent changes in the Methods system. This process results in stimuli associated with substance use being assigned higher levels of incentive Participants salience (i.e., subjective “wanting” of the substance). One hypothesized consequence is an attentional bias towards Participants were 16 healthy volunteers who reported associated stimuli, which is not necessarily closely coupled smoking 10 to 25 cigarettes per day. Exclusion criteria with subjective craving. were the following: current intention to quit smoking, Numerous studies have employed the modified Stroop to defined by a score >5 on a 10-point scale of readiness to investigate attentional biases towards smoking-related cues quit (with 10=strong desire); any current illicit drug use; in daily smokers (Munafò and Hitsman 2006). In most current or past psychiatric disorder (DSM-based), including cases, only a weak correlation has been observed between substance abuse or dependence other than nicotine depen- Psychopharmacology dence; history of neurological illness; significant current nausea and sedation. The composition for males was iso- medical illness; pregnancy or lactation; current or recent leucine 15 g, leucine 22.5 g, lysine 17.5 g, methionine 5 g, (past 3 months) use of psychotropic medications (antide- valine 17.5 g, threonine 10 g, and tryptophan 2.5 g. The pressants, anxiolytics, or neuroleptics) or herbal supple- BAL mixture for males additionally contained tyrosine ments known to affect mood (e.g., St. John’s Wort); current 12.5 g and phenylalanine 12.5 g. Females received 20% use of smoking cessation pharmacotherapy; or uncorrected less by weight of each amino acid than males. The amino impaired vision or color blindness. All participants gave acids were suspended in tap water, which was flavored with their written informed consent prior to screening. lemon and lime or cherry vanilla (participant’s preference) to disguise the unpalatable taste of the mixture. Eligibility