CPDD 72nd Annual Meeting • Scottsdale, Arizona - The College on ...

133
URB597, A FATTY ACID AMIDE HYDROLASE METABOLISM
INHIBITOR, EFFECTS LOCOMOTOR ACTIVITY
IMMEDIATELY AFTER THE FORCED SWIM TEST.
Tyechia Culmer 1 , L A Dykstra 1,2 ; 1 Pharmacology, University of North Carolina
at Chapel Hill, Chapel Hill, NC, 2 Psychology, University of North Carolina at
Chapel Hill, Chapel Hill, NC
Aims: <strong>The</strong> effects of CB1 receptor activation in the forced swim test (FST) and
on locomotor activity (LMA) were examined by manipulating the endogenous
receptor agonist anandamide with URB597. URB597 inhibits the enzymatic
activity of fatty acid amide hydrolase (FAAH) and thereby increases the concentration
of anandamide and activates the CB1 receptor.
Methods: C57Bl/6 mice (n=9-10) were exposed to the FST (6 min in 25° C
water) following an intraperitoneal (i.p.) injection of vehicle or a dose of 0.03
mg/kg or 0.1 mg/kg URB597. Immediately after the FST, the mice were placed
in a locomotor activity chamber (30 min; LAC). <strong>The</strong> effect of CB1 receptor activation
and FST exposure was measured by time spent immobile (sec) in the FST
and by distance traveled (cm), the average velocity (cm/sec), total entries into the
center zone (#), and total time spent in the center zone (sec) in the LAC. LMA
was measured before the FST (Pre-FST1), immediately after the FST (Post-
FST1), and a week after the FST (LMA-FST1).
Results: Time spent immobile in the FST was similar in C57Bl/6 mice treated
with vehicle and URB597 at doses 0.03 mg/kg and 0.1 mg/kg. LMA was
reduced significantly during the Post-FST1 session compared to LMA during the
Pre-FST1. Also, a significant increase in the total time spent in the center (0-10
min) was observed in mice treated with 0.03 mg/kg URB597 compared to vehicle
in both the Post-FST1 and LMA-FST1. In addition, the average velocity
increased significantly in mice treated with 0.03 mg/kg URB597 compared to
vehicle in the Post-FST1 (20-30 min).
Conclusions: <strong>The</strong>se data suggest an interaction between CB1 receptor activation
and responses in the FST and LAC. Under these conditions, URB597 did not
decrease time spent immobile in the FST as reported with antidepressants such
as desipramine (Lucki, 2001). However, a low dose of URB597 increased time
in the center immediately after the FST in the LAC.
Financial Support: Provided by NIH grants R01-DA002749 and T32-007244.
135
DOPAMINE β HYDROXYLASE INHIBITOR SYN117
DECREASES SUBJECTIVE EFFECTS OF COCAINE.
K A Cunningham 1 , C L Carbone 1 , N C Anastasio 1 , T A Harper 1 , F G Moeller 2 ,
D L Ware 1 , M A Fuller 1 , G J Holstein 1 , K E Smith 1 , J B Jayroe 1 , S Bandak 3 , K
Reiman 3 , A Neale 3 , L Pickford 3 ; 1 Center for Addiction Research, Univ Texas
Med Branch, Galveston, TX, 2 Psychiatry Behav Sci, Univ Texas HSC, Houston,
TX, 3 Synosia <strong>The</strong>rapeutics, Inc., San Francisco, CA
Aims: <strong>The</strong> non-selective DβH inhibitor disulfiram blocks the subjective effects of
cocaine and reduces its use. We tested the hypothesis that the selective DβH
inhibitor SYN117 will reduce the positive subjective effects of cocaine in a doubleblind,
placebo-controlled, inpatient study with fewer side effects than disulfiram.
Methods: Non-treatment seeking, cocaine dependent subjects were randomized
to placebo (n=5) or placebo/80 mg/160 mg of SYN117 for 13 days (n=15). <strong>The</strong>
pharmacokinetics of cocaine and its cardiovascular and subjective effects were
measured at ascending doses of 0, 10, 20 and 40 mg of intravenous cocaine in
subjects treated with placebo or SYN117.
Results: SYN117 was well-tolerated and there was no difference in adverse
events observed after the combination of SYN117 and cocaine vs. cocaine alone.
<strong>The</strong> pharmacokinetics of cocaine was unaltered. A main effect of SYN117,
cocaine and an interaction were observed (ANOVA) for some measures on the
Visual Analogue Scale (VAS). ‘Drug effect,’ ‘high,’ ‘good effects,’ and ‘stimulated’
significantly decreased in subjects receiving SYN117 plus cocaine vs. placebo
plus cocaine. SYN117 significantly increased ratings of ‘depressed’ and ‘anxious’.
‘Craving’ did not change.
Conclusions: <strong>The</strong>se data show that SYN117 significantly alters the subjective
effects of cocaine and is well tolerated by human subjects. In comparison to
disulfiram which resulted in increased levels of plasma cocaine and decreased
cocaine clearance, SYN117 did not alter the pharmacokinetics of cocaine in
keeping the selectivity of SYN117 as a DβH inhibitor. Thus, the present phase
I analysis suggests that further examination of SYN117 for efficacy in treatment
of cocaine dependent subjects is warranted.
Financial Support: Synosia <strong>The</strong>rapeutics, Inc., UTMB Center for Addiction
Research, UTMB Clinical Research Center, DA009262, DA024157,
DA020087
<strong>CPDD</strong> <strong>72nd</strong> <strong>Annual</strong> <strong>Meeting</strong> <strong>•</strong> <strong>Scottsdale</strong>, <strong>Arizona</strong>
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134
MECHANISMS OF PRESCRIPTION DRUG DIVERSION
AMONG IMPAIRED PHYSICIANS.
Simone M Cummings, L J Merlo, L B Cottler; Psychiatry, Washington
University School of Medicine, St. Louis, MO
Aims: To investigate mechanisms of prescription drug diversion among a population
of physicians being monitored for substance abuse and to explore policy
options for preventing the specific methods of diversion uncovered. <strong>The</strong> authors
hypothesize that methods of diversion used by physicians are a function of the
access to prescription drugs that they have by virtue of their profession.
Methods: A qualitative study using focus groups was conducted to gather information
about prescription drug diversion among impaired physicians being
monitored by a state physician health program (PHP). Non-probabilistic, purposive
sampling was used to obtain a geographically diverse group of physician
participants. PHP monitors arranged the focus group sessions and recruited all
participants. Nine focus groups, which included a total of 54 physicians, were
conducted. Focus groups were anonymous. Physicians were not compensated for
participation. Audiotapes of the focus group sessions were transcribed and loaded
into Atlas.ti for coding and analysis.
Results: Physicians reported using five primary methods to divert prescription
drugs: stealing from patients; stealing from health care organizations; utilizing
samples provided by prescription drug reps; ordering large shipments of drugs
from pharmaceutical warehouses for personal use; and self-prescribing or prescribing
in the name of patients and/or friends for personal use. <strong>The</strong> most commonly
diverted drugs included prescription opioids, followed by prescription
sedatives. Many physicians reported diverting for several years before being
caught.
Conclusions: Mechanisms of prescription drug diversion used by physicians
result from their increased access to prescription drugs relative to the general
population. <strong>The</strong> development of policies to require funding of state prescription
drug monitoring programs as well as policies to restrict the distribution of drug
samples has the potential to mitigate the amount of prescription drug diversion
that occurs among physicians as well as other health care personnel.
Financial Support: This work was supported by a NIDA Diversity Supplement
to R01DA020791, LB Cottler, PI.
136
DIFFERENTIAL ANTAGONISM OF THE BEHAVIORAL
EFFECTS OF NICOTINE, VARENICLINE, AND CYTISINE
IN MICE.
Colin S Cunningham, L R McMahon; Pharmacology, UTHSCSA, San
Antonio, TX
Aims: Although nicotine replacement therapy is effective in promoting abstinence
from cigarette smoking, there is margin for improvement. Varenicline is
reported to be more effective than nicotine replacement therapy and comparatively
less is known about cytisine, a pharmacotherapy for tobacco dependence
in Europe. To examine the possibility that nicotine acetylcholine receptor subtypes
differentially mediate behavioral effects, nicotine, varenicline, and cytisine
were combined with antagonists differing in their selectivity for receptors containing
α4β2 subunits.
Methods: Male C57BL/6J mice (n=7) responding on a fixed ratio 30 schedule
of food delivery received i.p. nicotine, varenicline, and cytisine, alone and in
combination with the non-selective nicotine antagonist mecamylamine and the
α4β2 nicotine receptor-selective antagonist dihydro-β-erythroidine (DHβE).
Results: Nicotine, varenicline, and cytisine dose-dependently decreased responding;
nicotine was more potent (ED50 = 0.72 mg/kg) than varenicline (ED50 =
1.8 mg/kg) and cytisine (ED50 = 2.7 mg/kg). <strong>The</strong> agonists had a similar time
course of activity, including a rapid onset (