Tacrine Effects on Cocaine Self-Administration and Pharmacokinetics

Background Reinforcing effects of cocaine are believed to arise through release of
dopamine (DA) at the nucleus accumbens by neurons in the ventral tegmental area. Activation
of cholinergic receptors on the cell bodies of these neurons can enhance DA release.
Elevated levels of acetylcholine (ACh) in the nucleus accumbens may also serve to inhibit
appetitive behaviors. Cholinesterase inhibitors such as tacrine increase synaptic levels of
ACh by preventing its inactivation by acetylcholinesterase (AChE) or butyrylcholinesterase
(BuChE), and can improve learning and memory. In animals, cholinesterase inhibitors can
attenuate cocaine self-administration and conditioned place preference. Tacrine is a
centrally acting, reversible inhibitor of AChE and BuChE that is approved for treatment of
Alzheimer's disease. In addition to its effects on the cholinergic system, tacrine can
potentiate the actions of monoamines, including DA. Although use of tacrine has declined
because of requirements for monitoring of potential liver toxicity and pharmacokinetics that
necessitate multiple daily doses, it is more potent than other cholinesterase inhibitors in
attenuating cocaine self-administration in animals. Pretreatment with tacrine can produce
long-lasting reductions in cocaine-reinforced behavior in rats, described as persistent
attenuation (cocaine self-administration is decreased by more than 80% over a period of
three days during which no additional cholinesterase inhibitor is administered, see Figure
1). No previous studies have evaluated whether tacrine can modify the effects of cocaine in
humans.

Rationale To our knowledge, tacrine is the only compound that can produce persistent
attenuation in rats treated with clinically relevant doses. If similar effects were
observed in humans, this would lead to an important paradigm shift for substance abuse
treatment, in that large reductions in cocaine-reinforced behavior could be produced without
the need for continuous dosing with a medication. This scenario could remove the
requirement for continued compliance with oral dosing in some patients with its associated
potential for toxicity.

Specific Aims:

1. Evaluate whether tacrine treatment causes persistent attenuation of cocaine-reinforced
behavior in humans.

2. Determine the effectiveness of pretreatment with tacrine in attenuating cocaine-induced
craving.

3. Evaluate plasma levels of cocaine and characterize the bioavailability of tacrine in
individual patients.

Methods This is a randomized, double-blind, double-dummy, placebo-controlled, inpatient,
single-center, parallel-group evaluation of the potential for oral tacrine to modify cocaine
self-administration, cocaine-induced craving, and the pharmacokinetics of cocaine and
tacrine. To evaluate the occurrence of persistent attenuation, the subjective and
reinforcing effects of intravenous cocaine will be determined during oral treatment and
three days following its discontinuation.

Inclusion Criteria:

- Meets DSM-IV-TR criteria for cocaine abuse or dependence, with at least one
cocaine-positive urine specimen within the six weeks prior to enrollment.

- Has used cocaine for a duration of at least 6 months, with at least weekly use during
the last 30 days by a rapid route of administration (either smoked or intravenous
injection).

- Is male or female, between 21 and 50 years old.

Exclusion Criteria:

- Has a history of a medical adverse reaction to cocaine or other psychostimulants,
including loss of consciousness, chest pain, cardiac ischemia, or seizure.

- Has any current Axis I psychiatric disorder other than drug abuse or dependence.

- Meets DSM-IV-TR criteria for dependence on opiates, benzodiazepines, alcohol, or
other sedative-hypnotics.