Scientific Goals. We and others have now identified several human chromosomal regions that contain genetic markers that have been associated with vulnerability to substance abuse/dependence in several different human populations (Uhl et al, 2002). However, little is known about the biological or behavioral mechanisms by which specific molecular genetic characteristics enhance risks for drug disorders. This protocol will test hypotheses that genetically-mediated individual differences in acute responses to abused substances contribute to the mechanisms through which specific human allelic variants influence individual differences in vulnerability to drug abuse/dependence. This protocol will characterize individual differences in responses to oral methylphenidate (30 mg) (also known as Ritalin). We have chosen this agent due to a) its wide clinical use, b) its moderate to low risks which are largely well-understood as a result of this widespread use, and c) its prior usefulness to us and others as a probe for reward system activities in, for example, patients with dopaminergic brain lesions (Persico et al 1998). We have chosen this dose due to: a) our prior success with this dose, even in a brain lesioned clinical population (Persico et al 1998) b) our preliminary work with candidate gene studies in individuals administered oral doses of up to 60-70 mg (GRU et al, in preparation) c) consultations with other workers in the field who advise use of this dose and who have used doses of 0.5 mg/kg intravenously in prior work with few reported adverse events (Volkow et al, 2003).

We will study individuals who are selected based on their genotypes. We will test the hypothesis that individuals who display combinations of the abuse-associated and/or resistance-associated allelic variants at different genomic loci that we and others have reproducibly associated with substance abuse (Uhl et al 2002) will differ in their acute responses to methylphenidate administration. We will also perform exploratory analyses of these data. We will study the genotypes of individuals who display high- or low-level responses to oral methylphenidate administration. Both the hypothesis-testing and exploratory aspects of this study will allow us to identify which addiction-associated human gene variants can alter subjective and physiologic responses to administration of methylphenidate.

Method. We will study previous participants in study #148 (90-DA-N448) who have already consented to recontact from NIDA personnel. We will select individuals who are eligible for study participation based on their genotypes at markers whose alleles differ between drug abusers (those who report significant lifetime use and dependence on at least one illegal substance) and controls (individuals free from significant lifetime use of any addictive substances) as well as allelic variants in genes expressed in reward circuits. Patients will receive psychiatric and medical screening. Eligible volunteering participants will have a one-day study session in which they receive oral placebo and oral methylphenidate (30 mg) in single-blinded fashion. This design was chosen to allow study participation by a larger fraction of eligible participants than those likely to consent to inpatient stays and longer designs. Subjective methylphenidate effects, plasma levels of methylphenidate and heart rate will be assessed periodically before and for 4 hours after the drug is administered. Methylphenidate was chosen as a probe because: (1) its mechanism of action directly involves central monoaminergic reward pathways, including dopamine and norepinephrine transporter inhibition, (2) there is such broad clinical experience with the drug that significant side effects are well known to be of low frequency in broad populations (3) there are individual differences in methylphenidate subjective responses documented in several sorts of studies, including the studies of Parkinsonian patients and controls previously reported from our group.

Hypothesis. We advance a two-tailed hypothesis that subjective liking VAS responses to methylphenidate will be different in those individuals with multiple candidate genetic characteristics that are related to enhanced vulnerability to substance abuse/dependence compared to matched controls with few of these genomic characteristics. Confidence will be greatest for those associations that are consistent among both Caucasian/European American and African American participants, an internal replication built into this design.

Benefits. The results will have important implications for possible mechanisms by which genetic vulnerability to substance abuse (particularly psychostimulants) is expressed in humans. The findings will also bear on genetic predictors of the response to methylphenidate, which may be important for attention deficit hyperactivity disorder, narcolepsy and other clinical disorders in which drugs of this class are used therapeutically.

Risks. Methylphenidate is also known as Ritalin, and is commonly prescribed for a number of clinical conditions including attention deficit/hyperactivity syndrome. The drug has been used for many individuals with few serious complications. Individuals who use this drug for long periods of time may show nervousness and sleep changes. Skin rashes, appetite suppression, nausea, dizziness, heart palpitations, pulse and heart rhythm changes, headache, abnormal movements, sleepiness, chest pain, abdominal pain, liver function changes, blood cell changes and changes in thinking have also been rarely reported in individuals who use this drug chronically. A review of patients taking a treatment dose of methylphenidate for ADHD revealed serious cardiovascular adverse events in patients with underlying serious heart problems or defects, and reports of stroke and heart attack in adults with certain risk factors, (i.e. untreated high blood pressure and a history of coronary artery disease). Another review of patients taking a treatment dose of methylphenidate for ADHD revealed a slight increased risk (about 1 per 1,000) for drug-related psychiatric adverse events, such as hearing voices, becoming suspicious for no reason, or becoming manic, even in patients who did not have previous psychiatric problems. Additional modest to minimal risks to participants include the risks of venous catheterization and blood withdrawal, including pain, bruising and bleeding, and the risks of confidentiality. We will minimize each of these more than minimal risks by appropriate exclusionary criteria, medical screening, use of low/moderate drug doses, evaluation prior to discharge, availability of taxi for return home, aseptic methods, small total amounts of blood drawn, standard minimal risk recording procedures, coded, locked data and Confidentiality Certification of this work.