Imaging the Neurobiology of a Behavioral Treatment for Cocaine Dependence (PET-CRA)

The purpose of this study is to determine whether patients with the greatest loss of dopamine transmission due to cocaine dependence at pre-treatment PET and MRI scans will be those who fail to respond to substance abuse treatment. This study will also determine whether patients who do respond to treatment will experience a recovery of dopamine function. This study includes free brain imaging and behavioral intervention. Compensation provided for the brain scans.

Previous studies have shown that cocaine dependence is associated with a decrease in dopamine release in response to a psychostimulant challenge. We have recently completed a study demonstrating that this loss of pre-synaptic dopamine function is associated with the choice to self-administer cocaine in the presence of an alternative reinforcer. This finding consistent with animal models of reinforcement and which show that dopamine transmission serves to modulate reward based behavior, and in this case, allows for a more adaptive response to be made in the presence of a competing reinforcer. The previous study was performed in non-treatment seeking cocaine dependent subjects using an inpatient laboratory model to measure the choice for cocaine. Thus, the goal of the present proposal is to investigate this association in a more realistic setting where cocaine dependent out patients face the choice between using cocaine and the alternative reinforcers presented to them in a therapeutic setting. The Community Reinforcement Approach with voucher incentives is a treatment for cocaine dependence that has been shown success in a number of controlled studies. Since the basis of this therapy is to reduce the reinforcing value of cocaine by increasing the density of alternative, healthy reinforcers, we have chosen to correlate outcome from this treatment with measures of presynaptic dopamine function. We propose to scan cocaine dependent patients with [11C]raclopride and oral methylphenidate in order to measure dopamine release. Patients will be scanned before treatment and at 12 weeks into therapy. We predict that the patients with the greatest loss of dopamine transmission at the pre-treatment scan will be those who fail to respond to treatment. Furthermore, we hypothesize that the patients who do respond to treatment will experience a recovery of dopamine function, measured at the post-treatment scan. In addition, subjects enrolled in this study will undergo functional Magnetic Resonance Imaging (fMRI) and spectroscopy studies in order to asses differences in neuronal integrity, learning, and impulse control.

A group of healthy matched comparison subjects with no DSM-IV axis I Disorder was included; they were matched for cigarette smoking, gender, and ethnicity.

Community Reinforcement Approach (CRA): The community reinforcement treatment program will be carried out in accordance with NIDA's therapy manual (13).During weeks 13 through 24, patients will meet once per week with their therapists. Sessions will focus on promoting continued change in the life areas addressed in the first 12 weeks of treatment or new components are added as needed.

The relationship between Methylphenidate-induced Dopamine Release in the Striatum (Measured by Displacement of [11C]-Raclopride by Oral Methylphenidate) and Treatment Response (Measured Using Community Reinforcement Approach and Contingency Management) was studied. Dopamine Function was assessed by evaluation of endogenous Dopamine release over the course of treatment (i.e., at 3 months as compared to baseline). Endogenous Dopamine release is inversely related to the change in binding potential (delta BPND) of [11C]raclopride, in that a negative delta BPND, or increased displacement of [11C]raclopride, reflects an increase in the release of endogenous dopamine over the course of treatment.

Inclusion Criteria: Males or females between 21 and 45 years old Fulfill DSMIV criteria for cocaine abuse or dependence Able to give informed consent and comply with study procedures Medically Healthy Exclusion Criteria: Major DSM-IV Axis I disorder other than cocaine abuse or dependence. Subjects with a history of other psychostimulant abuse/dependence or compulsive gambling will be excluded. Current use of opiates, sedative-hypnotic, and/or cannabis more than twice a week (use less than twice a week is acceptable). Current use of psychotropic medication such as antipsychotics or antidepressants. Presence or positive history of severe medical or neurological illness (including epilepsy), or any cardiovascular disease, low hemoglobin (Hb < 14 gm/dL in males, Hb < 12 gm/dL in females), or SGOT or SGPT > 2-3 times normal. Chronic active hepatitis B or C will also be an exclusion criteria. Resting SBP >150, DBP > 90 Pregnancy or lactation, lack of effective birth control during 15 days before the scans* Evidence /report of any heart abnormality during intake medical history, EKG or physical exam. Metal implants or paramagnetic objects contained within the body which may interfere with the MRI scan, as determined in consultation with a neuroradiologist and according to the guidelines set forth in the following reference book commonly used by neuroradiologists: "Guide to MR procedures and metallic objects" Shellock, PhD, Lippincott Williams and Wilkins, NY 2001. Lifetime exposure to radiation in the workplace, or history of participation in nuclear medicine procedures, including research protocols ** Positive Allen Test indicating lack of collateral blood flow to hand History of sensitivity to methylphenidate

Martinez D, Carpenter KM, Liu F, Slifstein M, Broft A, Friedman AC, Kumar D, Van Heertum R, Kleber HD, Nunes E. Imaging dopamine transmission in cocaine dependence: link between neurochemistry and response to treatment. Am J Psychiatry. 2011 Jun;168(6):634-41. doi: 10.1176/appi.ajp.2010.10050748. Epub 2011 Mar 15. Erratum In: Am J Psychiatry. 2011 May;168(5):553.