Imaging the Neurobiology of a Behavioral Treatment for Cocaine Dependence

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 fMRI and spectroscopy studies in
order to asses differences in neuronal integrity, learning, and impulse control.

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