The Effects of Doxazosin on the Cardiovascular and Subjective Effects of Cocaine

Human Laboratory Trial of Doxazosin for Cocaine Dependence: Accumulating evidence implicates
noradrenergic (NE) systems in mediating the effects of stimulants (1-8). Mice lacking NE £\
-1 receptor mice show reduced sensitivity to cocaine and amphetamine (8, 9). Local depletion
of prefrontal cortex (PFC) NE reduced rewarding effects of amphetamine and reduced
amphetamine-induced dopamine (DA) release in the PFC and accumbens (7), suggesting that PFC
NE contributes to the rewarding effects of stimulants. Treatment with the NE Ą-1 antagonist
prazosin has been shown to antagonize a variety of effects produced by cocaine and
amphetamine. In rats, prazosin (1-2 mg/kg) significantly attenuated the locomotor activating
effects produced by cocaine (10-12) and for amphetamine (4, 13, 14). Similar findings have
been observed for the discriminative stimulus effects produced by cocaine and amphetamine in
mice (15) and for food-maintained responding in pigeons (16). More recently, prazosin (0.3
mg/kg) reduced reinstatement of extinguished cocaine-seeking behavior in rats without
affecting responding for food, suggesting that prazosin my blunt the motivational effects of
drug cues (5). Clinical Experience with Alpha-1 Adrenergic Antagonists: Prazosin is a
prototypical antagonist at NE £\-1 receptors. When first released the medication was thought
to produce relaxation of smooth muscles in the vasculature. Since then however it has been
determined that prazosin antagonizes norepinephrine and this mediates the antihypertensive
effect (17). The medication has been assessed extensively for the treatment of hypertension
(18). The initial dose is 1mg two or three times per day. The usual dose range is 6mg/day to
15mg/day, with some patients requiring up to 40mg/day in divided doses. The most common side
effects are: dizziness 10.3%, headache 7.8%, drowsiness 7.6%, lack of energy 6.9%, weakness
6.5%, palpitations 5.3%, and nausea 4.9%. In most instances side effects have disappeared
with continued therapy or have been tolerated with no decrease in dose of drug. More
recently, prazosin has been successfully used to treat post traumatic stress disorder (19,
20). For this indication, prazosin was initiated at 1mg at bedtime and increased as needed
to control symptoms to up to 15mg at bedtime by day 28. This approach resulted in no change
in systolic and diastolic blood pressure compared to pretreatment measurements. Several
subjects reported transient dizziness upon standing (9/14 in the prazosin group and 6/15 in
the placebo group), but none reported syncope. Prazosin has a relatively short elimination
half-life of 3.5 h (21). Longer-lasting cogeners (e.g. terazosin and doxazosin) are
available, but there is no experience using these medications as treatments for cocaine
dependence. The purpose of this study is to evaluate the effects of doxazosin on the
cardiovascular and subjective effects of cocaine in a human laboratory study. Doxazosin was
selected because it has a longer elimination half-life (22h) compared to terazosin (12h).
The side-effect profile of doxazosin closely resembles that of prazosin.