- Email: [email protected]
Influence of an alternative reinforcer on human cocaine self-administration
Life Sciences, Vol. 55, No. 3, pp. 179-187, 1994 Copyright © 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0024-3205/94 $6.00 + .00
Pergamon
0024-3205(94)00102-2 INFLUENCE
Stephen Departments
OF AN
ALTERNATIVE REINFORCER SELF-ADMINISTRATION
T. Higgins,
Warren
K. Bickel,
ON HUMAN
& John R. Hughes
of P s y c h i a t r y and Psychology, U n i v e r s i t y 38 F l e t c h e r Place, Burlington, VT 05401 ( R e c e i v e d in final f o r m
COCAINE
of Vermont,
May 3, 1994)
Summary Identifying factors that m o d u l a t e c o c a i n e selfadministration is f u n d a m e n t a l to the d e v e l o p m e n t of effective strategies to treat and prevent cocaine abuse. In the p r e s e n t study, the i n f l u e n c e of an a l t e r n a t i v e reinforcer on the p r o b a b i l i t y of c o c a i n e use w a s examined in four adult humans under controlled laboratory conditions. D u r i n g e l e v e n test sessions, subjects chose between cocaine hydrochloride vs. placebo or b e t w e e n c o c a i n e vs. v a r y i n g a m o u n t s of m o n e y (0$2.00/choice). Subjects made a m a x i m u m of I0 e x c l u s i v e choices per session. Cocaine and placebo were administered intranasally in I0 mg unit doses u n d e r double-blind conditions. S u b j e c t s e x c l u s i v e l y chose cocaine over placebo demonstrating that the drug f u n c t i o n e d as a reinforcer. D u r i n g sessions c o m p a r i n g c o c a i n e vs. money, choice of cocaine d e c r e a s e d as the amount of m o n e y available in the m o n e t a r y option increased, w i t h all subjects e x c l u s i v e l y c h o o s i n g the monetary o p t i o n in the $2.00 p e r c h o i c e c o n d i t i o n . These results systematically r e p l i c a t e and e x t e n d to humans prior findings in laboratory animals demonstrating that the a v a i l a b i l i t y of a l t e r n a t i v e , n o n d r u g r e i n f o r c e r s can s i g n i f i c a n t l y d e c r e a s e cocaine use.
K~ Wor~: ~ i n e ,
drugabuse, beha~oralpharmacolo~,cocainesel~administration
Recreational cocaine use in the U.S. has decreased s u b s t a n t i a l l y since the m i d 1980s, but p a t t e r n s of r e g u l a r use i n d i c a t i v e of d e p e n d e n c e and use among certain s u b g r o u p s (e.g., criminals) have b e e n r e s i s t a n t to c h a n g e (1,2,3). Moreover, measures of adverse consequences of cocaine use such as the number of e m e r g e n c y room m e n t i o n s of cocaine use, p r e v a l e n c e of recent cocaine use among arrestees, and number of persons entering public t r e a t m e n t f a c i l i t i e s for t r e a t m e n t of cocaine abuse all indicate an e n t r e n c h e d cocaine abuse p r o b l e m (e.g., 4). Identifying factors that m o d u l a t e cocaine's reinforcing effects is of f u n d a m e n t a l importance to the d e v e l o p m e n t of effective interventions for the t r e a t m e n t and p r e v e n t i o n of c o c a i n e abuse. C o n t r o l l e d l a b o r a t o r y s t u d i e s in a v a r i e t y of species i n c l u d i n g humans provide c o m p e l l i n g evidence that cocaine functions as a potent p o s i t i v e r e i n f o r c e r (5). Indeed, cocaine's Corresponding author: Stephen T. Higgins, Ph.D., Human Behavioral P h a r m a c o l o g y Laboratory, D e p a r t m e n t of Psychiatry, U n i v e r s i t y of Vermont, 38 F l e t c h e r Place, Burlington, VT 05401, USA.
180
Human Cocaine Self-administration
Vol. 55, No. 3, 1994
reinforcing e f f e c t s c a n g a i n s u c h a h i g h d e g r e e of b e h a v i o r a l c o n t r o l that, u n d e r c e r t a i n c i r c u m s t a n c e s , l a b o r a t o r y a n i m a l s will forego basic sustenance in o r d e r to m a i n t a i n a c c e s s to c o c a i n e (6). Also clear from the basic-science literature is t h a t t h e reinforcing e f f e c t s of c o c a i n e are n o t i m m u t a b l e . Rather, the acquisition and maintenance of c o c a i n e - r e i n f o r c e d behavior is dependent on a v a r i e t y of p h a r m a c o l o g i c a l and environmental f a c t o r s s u c h as d r u g dose, schedule of r e i n f o r c e m e n t , and the a v a i l a b i l i t y of a l t e r n a t i v e r e i n f o r c e r s (7-10). It is t h i s l a t t e r factor, t h e a v a i l a b i l i t y of a l t e r n a t i v e reinforcers, t h a t is the focus of the p r e s e n t report. In rats, for example, the a v a i l a b i l i t y of a g l u c o s e a n d s a c c h a r i n s o l u t i o n can d e l a y or p r e v e n t the a c q u i s i t i o n a n d d e c r e a s e o n g o i n g rates of intravenous cocaine self-administration (9). Similarly, in nonhuman primates, preference for i n t r a v e n o u s injections of cocaine decreases as an o r d e r l y function of i n c r e a s e s in the magnitude of f o o d a v a i l a b l e in an e x c l u s i v e - c h o i c e arrangement (i0) . Such findings have important basic-science and clinical implications. However, to o u r k n o w l e d g e , whether they have generality to h u m a n cocaine self-administration h a s not b e e n examined under controlled laboratory conditions. The p u r p o s e of t h e p r e s e n t s t u d y w a s to e x a m i n e t h a t q u e s t i o n in h u m a n s selfadministering c o c a i n e in a l a b o r a t o r y setting. Methods
Subjects Three healthy males and one female were recruited via newspaper ads a n d flyers posted on p u b l i c bulletin boards. Subjects received monetary compensation at an h o u r l y r a t e of $5.50. Additional earnings were possible as o u t l i n e d below. A v e r a g e age a n d b o d y w e i g h t w e r e 24.8 yrs. (range = 21-32) and 75.5 kg (range = 59-82). All subjects were Caucasian. Average educational level was 13.8 yrs. (range = 12-16) . Subjects completed questionnaires assessing d r u g use, psychiatric and m e d i c a l histories, and w e r e i n t e r v i e w e d by a l i c e n s e d p s y c h o l o g i s t prior to participation. They also received a physical examination, laboratory screenings, i0 hrs. of c o n t i n u o u s EKG monitoring, and provided written informed consent prior to participating in the study. I n d i v i d u a l s w h o r e p o r t e d e v i d e n c e of current or p a s t d r u g d e p e n d e n c e other than nicotine, or w h o r e p o r t e d other c u r r e n t or past p s y c h i a t r i c p r o b l e m s were excluded. Medical problems contraindicating psychomotor s t i m u l a n t use w e r e also g r o u n d s for exclusion. S u b j e c t s w i t h less t h a n a h i g h school education were excluded, unless they could demonstrate basic literacy. A l l s u b j e c t s w e r e recent, b u t o c c a s i o n a l , u s e r s of c o c a i n e . T h e y r e p o r t e d an a v e r a g e of 4.3 w e e k s (range = 1-8) s i n c e t h e i r last i n s t a n c e of c o c a i n e use. All used cocaine intranasally. Three r e p o r t e d c u r r e n t m a r i j u a n a use, w i t h an a v e r a g e of 5.3 weeks s i n c e last u s e (range = 1-14 w e e k s ) ; one r e p o r t e d c u r r e n t use of hallucinogens (14 w e e k s since last use); one r e p o r t e d c u r r e n t use of a m p h e t a m i n e (4 w e e k s since last use); n o n e r e p o r t e d d a i l y u s e of c a f f e i n a t e d b e v e r a g e s ; all w e r e c u r r e n t c i g a r e t t e s m o k e r s
Vol. 55, No. 3, 1994
Human Cocaine Self-administration
averaging 21.3 cigarettes/day (range = 10-40), and all c u r r e n t d r i n k e r s a v e r a g i n g 17 a l c o h o l i c d r i n k s / w e e k (range 24) .
181
were = 9-
Drug C o c a i n e h y d r o c h l o r i d e (Mallinckrodt, Inc., St. Louis, MO) was administered intranasally in t e n I0 m g u n i t d o s e s . Doses were c a l c u l a t e d on t h e b a s i s o f t h e salt. An active placebo was used t h a t a l s o w a s a d m i n i s t e r e d i n t r a n a s a l l y in I0 m g u n i t d o s e s t h a t consisted o f 0.4 m g c o c a i n e h y d r o c h l o r i d e m i x e d w i t h 9.6 m g of lactose. A m a x i m u m of i0 a d m i n i s t r a t i o n s of c o c a i n e or p l a c e b o w e r e a d m i n i s t e r e d p e r s e s s i o n for t o t a l m a x i m u m c u m u l a t i v e d o s e s of i00 m g a n d 4 m g c o c a i n e p e r session. A 4 m g dose p r o d u c e s some nasal numbing but no d i s c e r n i b l e blood levels and is u s e d routinely as t h e p l a c e b o d o s e in s t u d i e s of h u m a n i n t r a n a s a l c o c a i n e u s e (11-13). A m i n i m u m 2-min. i n t e r - t r i a l i n t e r v a l (ITI) w a s r e q u i r e d b e t w e e n s u c c e s s i v e d r u g or p l a c e b o a d m i n i s t r a t i o n s . S u b j e c t s p r e p a r e d t h e p o w d e r e d d r u g in "lines", u s i n g a s t r a i g h t e d g e r a z o r on a m i r r o r , a n d w h e n i n s t r u c t e d b y t h e nurse, i n h a l e d e a c h u n i t d o s e v i a a s t r a w w i t h i n 20 sec. S t a f f w e r e i n f o r m e d t h a t c o c a i n e w a s b e i n g studied, but w e r e b l i n d t o a c t i v e vs. p l a c e b o d r u g in s e s s i o n s when both were available. S u b j e c t s w e r e i n f o r m e d t h a t t h e p u r p o s e of t h e s t u d y w a s to e x a m i n e h o w s t i m u l a n t m e d i c a t i o n s affected behavior and physiology, that they might receive ~-amphetamine, nicotine, cocaine, caffeine, or p l a c e b o , a n d t h a t t h e y w o u l d not r e c e i v e c o c a i n e if t h e y r e p o r t e d h a v i n g n e v e r t a k e n it b e f o r e . Subjects were not informed which drug they actually received in t h e experiment. R e f e r e n c e s to " d r u g " h e r e a f t e r r e f e r to t h e a c t i v e c o c a i n e dose. General
Procedure
S u b j e c t s p a r t i c i p a t e d as o u t p a t i e n t s in t h e G e n e r a l C l i n i c a l Research Center of the Medical Center Hospital of Vermont. S e s s i o n s g e n e r a l l y w e r e c o n d u c t e d at the same time of day for e a c h s u b j e c t , w e e k d a y s only, w i t h at l e a s t 48 hrs. b e t w e e n s e s s i o n s . Subjects were instructed to refrain from all illicit and p r e s c r i p t i o n d r u g u s e for t h e d u r a t i o n of t h e study, f r o m a l c o h o l for 12 hrs., a n d f r o m c a f f e i n e and s o l i d foods for 4 hrs. p r i o r to their scheduled sessions. C i g a r e t t e s m o k i n g w a s p e r m i t t e d on an ad-lib basis between experimental sessions. Subjects were r e q u i r e d to l i g h t a c i g a r e t t e 60 min. p r i o r to t h e s t a r t of t h e c h o i c e s e s s i o n s , a n d w e r e p e r m i t t e d to s m o k e as m u c h or as l i t t l e o f t h a t c i g a r e t t e as d e s i r e d ; no f u r t h e r s m o k i n g w a s p e r m i t t e d until after choice sessions were completed. To m o n i t o r c o m p l i a n c e with restrictions on a l c o h o l use, b r e a t h a l c o h o l l e v e l s (BALS) were measured (via I n t o x i m e t e r ) p r i o r to e a c h s e s s i o n . Urine s p e c i m e n s w e r e c o l l e c t e d p r i o r to e a c h s e s s i o n for d r u g s c r e e n i n g . Test r e s u l t s c o n f i r m e d c o m p l i a n c e w i t h our i n s t r u c t i o n s in all but one s u b j e c t (WK) . He t e s t e d p o s i t i v e for c o c a i n e ( b e n z o y l e c g o n i n e ) on f i v e of t h e s t u d y days. His p r e s e s s i o n p h y s i o l o g i c m e a s u r e s , EKG, a n d p e r f o r m a n c e of a f i e l d s o b r i e t y c h e c k w e r e c o m p a r a b l e to t h o s e o f s e s s i o n s c o n d u c t e d f o l l o w i n g n e g a t i v e u r i n e screens, a n d no s i g n s of a c u t e c o c a i n e e f f e c t s w e r e o b s e r v e d . Thus, s e s s i o n s w e r e c o n d u c t e d as s c h e d u l e d w i t h t h a t s u b j e c t .
182
Human Cocaine Self-administration
Vol. 55, No. 3, 1994
S e s s i o n s w e r e 5.5 hrs. in d u r a t i o n a n d w e r e c o n d u c t e d in a quiet room with a maximum of two subjects participating simultaneously and a research nurse present. Each experimental s t a t i o n w a s e q u i p p e d w i t h a r e s p o n s e c o n s o l e c o n s i s t i n g of t h r e e L i n d s l e y p l u n g e r s ( G e r b r a n d s # G6310) l o c a t e d h o r i z o n t a l l y (left, center, a n d right) a n d a t t a c h e d t o an A p p l e IIe m i c r o c o m p u t e r (Apple C o m p u t e r , C u p e r t i n o , CA) a n d v i d e o m o n i t o r . The n u m b e r of c h o i c e s made, t h e ITI, a n d s e s s i o n - t i m e r e m a i n i n g w e r e d i s p l a y e d to s u b j e c t s on t h e v i d e o m o n i t o r . Blood pressure and heart rate w e r e r e c o r d e d e v e r y 5 min. v i a a S e n t r y II A u t o m a t i c M o n i t o r (NBS Medical, Costa Mesa, CA). Skin temperature was measured continuously via a skin surface thermister (Yellow Springs I n s t r u m e n t Co., Y e l l o w Springs, OH) t a p e d to the t i p of the m i d d l e finger. B l o o d p r e s s u r e , HR, a n d E C G w e r e m o n i t o r e d v i s u a l l y by the research nurse throughout test sessions. C o n t i n u o u s E C G also was collected each session via holter-monitor recordings.
Experimental Sessions Subjects r e m a i n e d s e a t e d d u r i n g s e s s i o n s e x c e p t for b r i e f v i s i t s to t h e b a t h r o o m . The first 0.5 hr. w a s d e v o t e d to s u b j e c t preparation, the next 0.5 hr. to collection of baseline p h y s i o l o g i c m e a s u r e s , a n d the n e x t 2.0 hrs. to d r u g a d m i n i s t r a t i o n a n d p h y s i o l o g i c m o n i t o r i n g a c c o r d i n g to t h e s c h e d u l e n o t e d above. T h e f i n a l 2.0 hr. p e r i o d w a s d e v o t e d t o s u b j e c t r e c o v e r y and physiologic monitoring. Subjects participated in 12 s e s s i o n s . The first session p r o v i d e d a c c l i m a t i o n to t h e p h y s i o l o g i c m o n i t o r i n g e q u i p m e n t a n d familiarized subjects with the general experimental procedures. S e s s i o n s 2 a n d 3 w e r e e x p o s u r e days d u r i n g w h i c h s u b j e c t s r e c e i v e d t e n I0 m g u n i t d o s e s of a c t i v e d r u g on o n e d a y a n d t e n d o s e s of p l a c e b o on t h e o t h e r day. D r u g a n d p l a c e b o w e r e d e s c r i b e d to s u b j e c t s as D r u g A a n d D r u g B. O r d e r of e x p o s u r e to d r u g a n d placebo and whether they were designated as D r u g A or B w a s counterbalanced across subjects. Subjects were provided a paper and p e n c i l a n d e n c o u r a g e d to r e c o r d t h e i r i m p r e s s i o n s of e a c h d r u g during exposure sessions. T h e y w e r e i n s t r u c t e d to n o t e w h a t e a c h d r u g w a s l i k e a n d to p a y c l o s e a t t e n t i o n b e c a u s e t h e y w o u l d be m a k i n g c h o i c e s b e t w e e n the two d r u g s in a s u b s e q u e n t s e s s i o n . S e s s i o n 4 w a s a c h o i c e d a y w h e r e i n s u b j e c t s w e r e a l l o w e d to c h o o s e e i t h e r D r u g A or D r u g B, up to a t o t a l of i0 choices, w i t h a m i n i m u m 2 - m i n . ITI b e t w e e n c h o i c e s as n o t e d a b o v e . Subjects w e r e i n f o r m e d t h a t t h e y a l s o c o u l d c h o o s e to t a k e n e i t h e r D r u g A or B. Subjects registered their choices by completing ten responses on t h e l e f t - or r i g h t - m o s t Lindsley plungers; i.e., fixed-ratio (FR) I0 s c h e d u l e s of r e i n f o r c e m e n t . The center p l u n g e r w a s i n o p e r a t i v e a n d s u b j e c t s w e r e i n s t r u c t e d t h a t w a s the case. E a c h of t h e a c t i v e p l u n g e r s was d e s i g n a t e d as D r u g A or B v i a a s i g n a t t a c h e d i m m e d i a t e l y a b o v e it; w h e t h e r d r u g or p l a c e b o w a s p a i r e d w i t h t h e r i g h t or left p l u n g e r s w a s c o u n t e r b a l a n c e d across subjects. O n c e a r e s p o n s e w a s r e g i s t e r e d on e i t h e r of the plungers, the other option was unavailable u n t i l t h e F R i0 w a s completed and the 2-min. ITI e l a p s e d . As was noted above, completion of t h e F R a n d ITI w a s i n d i c a t e d to s u b j e c t s v i a the video screen. S e s s i o n s e n d e d a f t e r s u b j e c t s m a d e i0 c h o i c e s or a f t e r 2 hrs. e l a p s e d , w h i c h e v e r o c c u r r e d first. Subjects were
Vol. 55, No. 3, 1994
Human Cocaine Self-administration
183
i n s t r u c t e d a b o u t t h e s e p a r a m e t e r s a n d the s h e e t s on w h i c h t h e y h a d r e c o r d e d t h e i r i m p r e s s i o n s of D r u g s A a n d B d u r i n g e x p o s u r e days w e r e a v a i l a b l e to t h e m to a s s i s t in m a k i n g t h e i r c h o i c e s d u r i n g this choice session. O n l y s u b j e c t s w h o c h o s e d r u g 8 or m o r e t i m e s (~ 80%) d u r i n g S e s s i o n 4 c o n t i n u e d in t h e e x p e r i m e n t . S u b j e c t s w e r e not i n f o r m e d of t h i s m i n i m u m cocaine self-administration criterion. The r a t i o n a l e for it w a s t h a t we w a n t e d to s t u d y o n l y t h o s e s u b j e c t s for w h o m c o c a i n e f u n c t i o n e d as a r e i n f o r c e r . A l l s u b j e c t s met this criterion. The p l a c e b o o p t i o n was r e p l a c e d w i t h v a r y i n g a m o u n t s of m o n e y in t h e s u b s e q u e n t e i g h t t e s t s e s s i o n s a n d s u b j e c t s c h o s e b e t w e e n cocaine and money. C o c a i n e w a s a v a i l a b l e as d e s c r i b e d a b o v e a n d s t i l l d e s i g n a t e d b y t h e l e t t e r c o d e w i t h w h i c h it w a s p a i r e d in the p r i o r s e s s i o n s . S u b j e c t s w e r e l i m i t e d to m a k i n g t e n e x c l u s i v e choices between the drug and monetary options during these sessions, w i t h a m i n i m u m 2-min. ITI b e t w e e n c h o i c e s . Sessions e n d e d a f t e r t e n c h o i c e s w e r e m a d e or 2 hrs. e l a p s e d , w h i c h e v e r o c c u r r e d first. C h o i c e s w e r e r e g i s t e r e d v i a t h e left a n d r i g h t L i n d s l e y p l u n g e r s t h a t w e r e p a i r e d w i t h s i g n s i n d i c a t i n g it w a s the drug or m o n e t a r y plunger, and both drug and money were a v a i l a b l e u n d e r F R i0 s c h e d u l e s of r e i n f o r c e m e n t . As n o t e d above, o n c e a c h o i c e w a s r e g i s t e r e d on one o p t i o n the o t h e r o p t i o n was i n a c t i v e u n t i l t h e F R i0 a n d 2-min. ITI w e r e c o m p l e t e d on t h e chosen option. The f o l l o w i n g four m o n e t a r y a m o u n t s w e r e s t u d i e d in s e p a r a t e s e s s i o n s : $0.00, $0.50, $I.00, a n d $2.00 p e r c h o i c e for a m a x i m u m of $0.00, $5.00, $ i 0 . 0 0 or $ 2 0 . 0 0 p e r s e s s i o n . S u b j e c t s w e r e e x p o s e d t w i c e to e a c h m o n e t a r y a m o u n t ; t h e y w e r e e x p o s e d to e a c h of t h e a m o u n t s b e f o r e any w e r e r e p e a t e d . O r d e r of e x p o s u r e to t h e m o n e t a r y a m o u n t s w a s b a l a n c e d a c r o s s s u b j e c t s v i a a Latin-square design. M o n e y e a r n e d in e a c h s e s s i o n w a s paid, by check, at t h e e n d of t h a t s e s s i o n .
Subject Instructions Subjects were instructed that they were participating in a s t u d y d e s i g n e d to e x a m i n e h o w s t i m u l a n t m e d i c a t i o n s a f f e c t e d t h e i r b e h a v i o r , mood, a n d p h y s i o l o g i c a l functions. They w e r e i n s t r u c t e d r e g a r d i n g t h e f o r m a t of t h e a c c l i m a t i o n , e x p o s u r e , d r u g vs. drug, a n d d r u g vs. m o n e y s e s s i o n s , b u t w e r e p r o v i d e d no r a t i o n a l e or p u r p o s e for t h e s e s e s s i o n s b e y o n d the g e n e r a l p u r p o s e n o t e d above. It w a s e m p h a s i z e d t h a t in all c h o i c e s e s s i o n s s u b j e c t s w e r e to c h o o s e a c c o r d i n g to t h e i r o w n p r e f e r e n c e s . They were informed t h a t t h e o n l y l i m i t a t i o n s d u r i n g c h o i c e s e s s i o n s w e r e t h e 2-min. ITI, t h e m a x i m u m of i0 c h o i c e s p e r s e s s i o n , t h e 2-hr. s e s s i o n d u r a t i o n a n d t h a t o n c e an F R w a s i n i t i a t e d t h e a l t e r n a t e o p t i o n was unavailable u n t i l t h a t p a r t i c u l a r F R w a s c o m p l e t e d a n d a 2min. ITI e l a p s e d . W r i t t e n c o p i e s of the i n s t r u c t i o n s p r o v i d e d to s u b j e c t s c a n b e o b t a i n e d b y w r i t i n g the first a u t h o r .
Data Analysis T h e m a i n p u r p o s e of t h e s t u d y w a s to a s s e s s t h e i n f l u e n c e of providing an a l t e r n a t i v e monetary reinforcer on p r e f e r e n c e for cocaine. To a d d r e s s that question, data were analyzed as a r e p l i c a t e d L a t i n - S q u a r e d e s i g n w i t h t h r e e f a c t o r s ( m o n e t a r y value,
184
Human Cocaine Self-administration
Vol. 55, No. 3, 1994
subject, a n d o r d e r of p r e s e n t a t i o n of the m o n e t a r y v a l u e s ) ; e a c h of t h e f a c t o r s h a d four levels. The e f f e c t of m o n e t a r y v a l u e was further partitioned u s i n g o r t h o g o n a l p o l y n o m i a l s to d e s c r i b e the s h a p e of the f u n c t i o n o b s e r v e d b e t w e e n n u m b e r of c o c a i n e c h o i c e s a n d m o n e t a r y v a l u e (e.g., linear, q u a d r a t i c , etc.). Results
During sessions assessing preference between c o c a i n e vs. placebo, c o c a i n e was c h o s e n e x c l u s i v e l y by all subjects; moreover, all s u b j e c t s s e l f - a d m i n i s t e r e d the m a x i m u m t e n d o s e s of d r u g that were available (Fig. i) . P r e f e r e n c e for c o c a i n e d e c r e a s e d s i g n i f i c a n t l y as a f u n c t i o n of i n c r e a s i n g m o n e t a r y v a l u e (F(I,21) = 67.9, p < .0001; Fig. 2), and, although individual subjects showed various non-linear p a t t e r n s in t h i s r e l a t i o n s h i p , t h e r e was no s y s t e m a t i c d e v i a t i o n from linearity across subjects (F(2,21) = 1.47, p = .25). When the v a l u e in t h e m o n e t a r y o p t i o n w a s $0.00, s u b j e c t s e x c l u s i v e l y chose the cocaine option a n d in all b u t one i n s t a n c e selfadministered the maximum number of drug doses available. Preference for c o c a i n e vs. m o n e y v a r i e d b e t w e e n s u b j e c t s at the intermediate m o n e t a r y v a l u e s of $0.50 a n d $i.00 p e r choice. At the $ 2 . 0 0 p e r c h o i c e value, all s u b j e c t s e x c l u s i v e l y c h o s e the m o n e t a r y option. T h e r e w e r e no s i g n i f i c a n t changes in c o c a i n e preference across the first and second exposures to t h e v a r y i n g m o n e t a r y values (F(I,21) = 0.95, p = .34; Fig. 2). The only notable exceptions discernible in t h e r e s u l t s of i n d i v i d u a l subjects a c r o s s t h e t w o e x p o s u r e s w e r e o b s e r v e d w i t h S u b j e c t s DE a n d LC. For both subjects, preference for c o c a i n e w a s less in the first t h a n t h e s e c o n d e x p o s u r e to the $0.50 c o n d i t i o n .
The p r e s e n t r e s u l t s are c o n s i s t e n t w i t h a r o b u s t s c i e n t i f i c literature demonstrating t h a t c o c a i n e u s e is an o r d e r l y f o r m of o p e r a n t b e h a v i o r t h a t is m a i n t a i n e d by the r e i n f o r c i n g e f f e c t s of the drug (5-10). The reinforcing effects of c o c a i n e were demonstrated in the p r e s e n t s t u d y v i a the c l e a r p r e f e r e n c e shown for c o c a i n e o v e r placebo, a n d by the fact that s u b j e c t s g e n e r a l l y self-administered all of t h e a v a i l a b l e cocaine doses in t h e c o n d i t i o n s c o m p a r i n g c o c a i n e vs. p l a c e b o a n d c o c a i n e vs. the zero m o n e t a r y value. Importantly, the behavioral control exerted by cocaine's reinforcing effects was altered significantly b y i n c r e a s i n g the a v a i l a b i l i t y of a n o n d r u g r e i n f o r c e r (i.e., money). P r i o r studies h a v e d e m o n s t r a t e d t h i s in l a b o r a t o r y a n i m a l s u s i n g u n c o n d i t i o n e d , consumable reinforcers (e.g., 9, i0) . The p r e s e n t s t u d y e x t e n d s those p r i o r f i n d i n g s to h u m a n s and to the use of a n o n - c o n s u m a b l e , conditioned reinforcer. These observations are c o n s i s t e n t w i t h behavioral-economic a n a l y s e s of c h o i c e s h o w i n g t h a t d r u g i n g e s t i o n d e c r e a s e s as the cost, or loss, i n v o l v e d in c o n t i n u i n g to c h o o s e the d r u g o p t i o n i n c r e a s e s (14). The p r e s e n t r e s u l t s also p r o v i d e a d d i t i o n a l s c i e n t i f i c s u p p o r t for the p o s i t i v e f i n d i n g s o b t a i n e d in recent clinical trials in cocaine-dependent patients demonstrating that the provision of alternative, nondrug r e i n f o r c e r s in c o m b i n a t i o n w i t h i n t e n s i v e b e h a v i o r t h e r a p y
Vol. 55, No. 3, 1994
Human Cocaine Self-administration
RDB
t~ G)
.o_ O ..¢=
LC
=It=
WK
Drug Placebo
Drug Placebo
Fig. 1. Number of choices of cocaine and placebo during test sessions in which subjects made a maximum of ten choices between the two substances. Data are shown separately for the four individual subjects. 10
•
DE
Q1i ~ • O ::It:
0
.50
146 ~
RDB
LCl i ~ =2
1 10~
o0
.50
1
2
GroupA~m~le
el,l'"
a FirstExposure
6
• SecondExposure
0 0
.50
1
2
Money ($) Fig. 2. Number of cocaine choices are plotted as a function of the value of money available per choice in the monetary option. Subjects made a maximum of ten choices between cocaine vs. money each session. Data are presented for each of the four individual subjects and as a group average. Results from the first and second exposures to the different monetary values are shown separately.
185
186
Human Cocaine Self-administration
Vol. 55, No. 3, 1994
increases cocaine abstinence (15-17). Such c o n s i s t e n c y across different s p e c i e s and across l a b o r a t o r y and c l i n i c a l s e t t i n g s p r o v i d e s c o m p e l l i n g s c i e n t i f i c support for the fundamental role of reinforcement in the g e n e s i s and m a i n t e n a n c e of c o c a i n e use. S y s t e m a t i c a t t e n t i o n to and i n t e g r a t i o n of this b a s i c b e h a v i o r a l p r i n c i p l e into p r e v e n t i o n and t r e a t m e n t p r a c t i c e s should enhance the e f f i c a c y of current efforts to curb cocaine abuse. The consistency between these laboratory findings and results from c l i n i c a l t r i a l s also i l l u s t r a t e s that c l i n i c a l l y - r e l e v a n t issues m a y be f r u i t f u l l y r e s e a r c h e d u s i n g l a b o r a t o r y settings. Laboratory studies are clearly less expensive than clinical trials and a f f o r d a g r e a t e r d e g r e e of e x p e r i m e n t a l c o n t r o l t h a n is possible in c l i n i c a l settings. The p r e s e n t arrangement, for example, c o u l d be u s e d to e x a m i n e the i n f l u e n c e of v a r i o u s independent variables including drug pretreatment on the probability of c o c a i n e use. For example, one c o u l d e x a m i n e whether alcohol, marijuana and other drugs decrease the sensitivity of cocaine s e l f - a d m i n i s t r a t i o n to the influence of the m o n e t a r y r e i n f o r c e r (e.g., r i g h t w a r d shifts in the curve relating preference b e t w e e n c o c a i n e and m o n e y ) . Similarly, one c o u l d examine whether potential treatment medications increase the sensitivity of cocaine self-administration to the influence of the m o n e t a r y a l t e r n a t i v e (i.e., leftward shifts in the curve relating c o c a i n e and m o n e t a r y p r e f e r e n c e ) . Finally, the r e l a t i v e l y high d e g r e e of s t a b i l i t y o b s e r v e d w i t h i n and across s u b j e c t s in the p r e s e n t study are important p o s i t i v e features in c o n s i d e r i n g use of a l a b o r a t o r y a r r a n g e m e n t for such research purposes. The p r e s e n t study examined a single cocaine dose, an i n t r a n a s a l route of drug a d m i n i s t r a t i o n and n o n - d e p e n d e n t users. How changes in t h e s e f a c t o r s w o u l d a l t e r the r e s u l t s is an i m p o r t a n t e m p i r i c a l question. However, the g e n e r a l i t y o b s e r v e d a c r o s s the r e s u l t s of this study and t h o s e c o n d u c t e d b o t h in l a b o r a t o r y settings with n o n h u m a n s and in clinical settings with d e p e n d e n t users s u g g e s t s that q u a n t i t a t i v e or p a r a m e t r i c rather than qualitative differences are l i k e l y to e m e r g e from such parametric manipulations. For e x a m p l e , a larger magnitude alternative reinforcer is l i k e l y to be n e c e s s a r y to c o m p e t e e f f e c t i v e l y w i t h a larger dose of cocaine than was u s e d in the present study. However, the nature of the functional relationship observed between drug preference and the a v a i l a b i l i t y of the a l t e r n a t i v e r e i n f o r c e r is likely to remain intact. In s u m m a r y , the results of the present study provide a d d i t i o n a l e v i d e n c e u n d e r c o n t r o l l e d l a b o r a t o r y c o n d i t i o n s that h u m a n cocaine use is an orderly form of operant b e h a v i o r that is determined, in part, by the availability and magnitude of alternative reinforcers. In the p r e s e n t study, the d e g r e e of behavioral control exerted by cocaine varied from complete to none as an o r d e r l y function of the m a g n i t u d e of the a l t e r n a t i v e r e i n f o r c e r available.
Vol. 55, No. 3, 1994
Human Cocaine Self-administration
187
Acknowledaments S u p p o r t e d in p a r t by g r a n t s DA08076, D A 0 6 1 1 3 N a t i o n a l I n s t i t u t e on D r u g A b u s e a n d R R - 1 0 9
and K 0 2 0 0 1 0 9 from the f r o m the N a t i o n a l
Institutes of Health. The authors thank Mary Lynn, M o r t e n s e n a n d G a r y B a d g e r for a s s i s t a n c e in c o n d u c t i n g the data analysis and manuscript preparation.
Aaron study,
References i.
N a t i o n a l I n s t i t u t e on D r u g Abuse. H o u s e h o l d S u r v e y on D r u g A b u s e : M a i n F i n d i n a s 1990. W a s h i n g t o n , DC: D H H S p u b l i c a t i o n A D M 9 1 - 1 7 8 8 (1991). 2. N a t i o n a l I n s t i t u t e on D r u g Abuse. N a t i o n a l H o u s e h o l d S u r v e y on Drug Abuse: Population Estimates. 1991. W a s h i n g t o n , DC: D H H S p u b l i c a t i o n A D M 92-1887 (1991). 3. L.D. H A R R I S O N , Int J A d d i c t . 2 7 8 1 7 - 8 4 7 (1992). 4. J.C. G F R O E R E R A N D M.D. B R O D S K Y (1993), A m J P u b l i c H e a l t h 83 1149-1154 (1993). 5. C.E. J O H A N S O N A N D M.W. F I S C H M A N , P h a r m a c o l . Rev. 4_!13-52 (1989). 6. T.G. A I G N E R A N D R.L. BALSTER, S c i e n c e 2 Q 1 5 3 4 - 5 3 5 (1978). 7. C. I G L A U E R A N D J.H. WOODS, J. Exp. Anal. Behav. 2__22179-196 (1974) . 8. R.D. SPEALMAN, S c i e n c e 2 0 4 1 2 3 1 - 1 2 3 3 (1979). 9. M.E. CARROLL, S.T. LAC, A N D S.L. NYGAARD, P s y c h o p h a r m a c o l o g y 97 2 3 - 2 9 (1989). I0 M.A. N A D E R A N D W.L. W O O L V E R T O N , P s y c h o p h a r m a c o l o g y 105169-174 (1991). ii J.I. JAVAID, M.W. FISCHMAN, C.R. SCHUSTER, H. D E K I R M E N J I A N AND J.M. DAVIS, S c i e n c e 2 0 2 2 2 7 - 2 2 8 (1978). 12 R.W. F O L T I N A N D M.W. FISCHMAN, P h a r m a c o l B i o c h e m B e h a v 3_!1877883 (1988). 13 S.T. H I G G I N S , W.K. BICKEL, J.R. HUGHES, M. LYNN, M.A. C A P E L E S S A N D J.W. F E N W I C K , P s y c h o p h a r m a c o l o g y 102451-458 (1990). 14 W.K. BICKEL, R.J. D e G R A N D P R E , A N D S.T. HIGGINS, D r u g A l c o h o l Depend 33173-192 (1993). 15 S.T. H I G G I N S , D.D. DELANEY, A.J. BUDNEY, W.K. BICKEL, J.R. HUGHES, F. FOERG, A N D J.W. FENWICK, Am. J. P s y c h i a t r y 148 1218-1224 (1991). 16. S.T. H I G G I N S , A.J. BUDNEY, W.K. BICKEL, J.R. HUGHES, F. FOERG, A N D G. BADGER, Am. J. P s y c h i a t r y 1 5 0 7 6 3 - 7 6 9 (1993). 17. S.T. H I G G I N S , A.J. BUDNEY, W.K. BICKEL, F.E. FOERG, R. DONHAM, A N D G.J. BADGER, Arch. Gen. P s y c h i a t r y in press.
Pergamon
0024-3205(94)00102-2 INFLUENCE
Stephen Departments
OF AN
ALTERNATIVE REINFORCER SELF-ADMINISTRATION
T. Higgins,
Warren
K. Bickel,
ON HUMAN
& John R. Hughes
of P s y c h i a t r y and Psychology, U n i v e r s i t y 38 F l e t c h e r Place, Burlington, VT 05401 ( R e c e i v e d in final f o r m
COCAINE
of Vermont,
May 3, 1994)
Summary Identifying factors that m o d u l a t e c o c a i n e selfadministration is f u n d a m e n t a l to the d e v e l o p m e n t of effective strategies to treat and prevent cocaine abuse. In the p r e s e n t study, the i n f l u e n c e of an a l t e r n a t i v e reinforcer on the p r o b a b i l i t y of c o c a i n e use w a s examined in four adult humans under controlled laboratory conditions. D u r i n g e l e v e n test sessions, subjects chose between cocaine hydrochloride vs. placebo or b e t w e e n c o c a i n e vs. v a r y i n g a m o u n t s of m o n e y (0$2.00/choice). Subjects made a m a x i m u m of I0 e x c l u s i v e choices per session. Cocaine and placebo were administered intranasally in I0 mg unit doses u n d e r double-blind conditions. S u b j e c t s e x c l u s i v e l y chose cocaine over placebo demonstrating that the drug f u n c t i o n e d as a reinforcer. D u r i n g sessions c o m p a r i n g c o c a i n e vs. money, choice of cocaine d e c r e a s e d as the amount of m o n e y available in the m o n e t a r y option increased, w i t h all subjects e x c l u s i v e l y c h o o s i n g the monetary o p t i o n in the $2.00 p e r c h o i c e c o n d i t i o n . These results systematically r e p l i c a t e and e x t e n d to humans prior findings in laboratory animals demonstrating that the a v a i l a b i l i t y of a l t e r n a t i v e , n o n d r u g r e i n f o r c e r s can s i g n i f i c a n t l y d e c r e a s e cocaine use.
K~ Wor~: ~ i n e ,
drugabuse, beha~oralpharmacolo~,cocainesel~administration
Recreational cocaine use in the U.S. has decreased s u b s t a n t i a l l y since the m i d 1980s, but p a t t e r n s of r e g u l a r use i n d i c a t i v e of d e p e n d e n c e and use among certain s u b g r o u p s (e.g., criminals) have b e e n r e s i s t a n t to c h a n g e (1,2,3). Moreover, measures of adverse consequences of cocaine use such as the number of e m e r g e n c y room m e n t i o n s of cocaine use, p r e v a l e n c e of recent cocaine use among arrestees, and number of persons entering public t r e a t m e n t f a c i l i t i e s for t r e a t m e n t of cocaine abuse all indicate an e n t r e n c h e d cocaine abuse p r o b l e m (e.g., 4). Identifying factors that m o d u l a t e cocaine's reinforcing effects is of f u n d a m e n t a l importance to the d e v e l o p m e n t of effective interventions for the t r e a t m e n t and p r e v e n t i o n of c o c a i n e abuse. C o n t r o l l e d l a b o r a t o r y s t u d i e s in a v a r i e t y of species i n c l u d i n g humans provide c o m p e l l i n g evidence that cocaine functions as a potent p o s i t i v e r e i n f o r c e r (5). Indeed, cocaine's Corresponding author: Stephen T. Higgins, Ph.D., Human Behavioral P h a r m a c o l o g y Laboratory, D e p a r t m e n t of Psychiatry, U n i v e r s i t y of Vermont, 38 F l e t c h e r Place, Burlington, VT 05401, USA.
180
Human Cocaine Self-administration
Vol. 55, No. 3, 1994
reinforcing e f f e c t s c a n g a i n s u c h a h i g h d e g r e e of b e h a v i o r a l c o n t r o l that, u n d e r c e r t a i n c i r c u m s t a n c e s , l a b o r a t o r y a n i m a l s will forego basic sustenance in o r d e r to m a i n t a i n a c c e s s to c o c a i n e (6). Also clear from the basic-science literature is t h a t t h e reinforcing e f f e c t s of c o c a i n e are n o t i m m u t a b l e . Rather, the acquisition and maintenance of c o c a i n e - r e i n f o r c e d behavior is dependent on a v a r i e t y of p h a r m a c o l o g i c a l and environmental f a c t o r s s u c h as d r u g dose, schedule of r e i n f o r c e m e n t , and the a v a i l a b i l i t y of a l t e r n a t i v e r e i n f o r c e r s (7-10). It is t h i s l a t t e r factor, t h e a v a i l a b i l i t y of a l t e r n a t i v e reinforcers, t h a t is the focus of the p r e s e n t report. In rats, for example, the a v a i l a b i l i t y of a g l u c o s e a n d s a c c h a r i n s o l u t i o n can d e l a y or p r e v e n t the a c q u i s i t i o n a n d d e c r e a s e o n g o i n g rates of intravenous cocaine self-administration (9). Similarly, in nonhuman primates, preference for i n t r a v e n o u s injections of cocaine decreases as an o r d e r l y function of i n c r e a s e s in the magnitude of f o o d a v a i l a b l e in an e x c l u s i v e - c h o i c e arrangement (i0) . Such findings have important basic-science and clinical implications. However, to o u r k n o w l e d g e , whether they have generality to h u m a n cocaine self-administration h a s not b e e n examined under controlled laboratory conditions. The p u r p o s e of t h e p r e s e n t s t u d y w a s to e x a m i n e t h a t q u e s t i o n in h u m a n s selfadministering c o c a i n e in a l a b o r a t o r y setting. Methods
Subjects Three healthy males and one female were recruited via newspaper ads a n d flyers posted on p u b l i c bulletin boards. Subjects received monetary compensation at an h o u r l y r a t e of $5.50. Additional earnings were possible as o u t l i n e d below. A v e r a g e age a n d b o d y w e i g h t w e r e 24.8 yrs. (range = 21-32) and 75.5 kg (range = 59-82). All subjects were Caucasian. Average educational level was 13.8 yrs. (range = 12-16) . Subjects completed questionnaires assessing d r u g use, psychiatric and m e d i c a l histories, and w e r e i n t e r v i e w e d by a l i c e n s e d p s y c h o l o g i s t prior to participation. They also received a physical examination, laboratory screenings, i0 hrs. of c o n t i n u o u s EKG monitoring, and provided written informed consent prior to participating in the study. I n d i v i d u a l s w h o r e p o r t e d e v i d e n c e of current or p a s t d r u g d e p e n d e n c e other than nicotine, or w h o r e p o r t e d other c u r r e n t or past p s y c h i a t r i c p r o b l e m s were excluded. Medical problems contraindicating psychomotor s t i m u l a n t use w e r e also g r o u n d s for exclusion. S u b j e c t s w i t h less t h a n a h i g h school education were excluded, unless they could demonstrate basic literacy. A l l s u b j e c t s w e r e recent, b u t o c c a s i o n a l , u s e r s of c o c a i n e . T h e y r e p o r t e d an a v e r a g e of 4.3 w e e k s (range = 1-8) s i n c e t h e i r last i n s t a n c e of c o c a i n e use. All used cocaine intranasally. Three r e p o r t e d c u r r e n t m a r i j u a n a use, w i t h an a v e r a g e of 5.3 weeks s i n c e last u s e (range = 1-14 w e e k s ) ; one r e p o r t e d c u r r e n t use of hallucinogens (14 w e e k s since last use); one r e p o r t e d c u r r e n t use of a m p h e t a m i n e (4 w e e k s since last use); n o n e r e p o r t e d d a i l y u s e of c a f f e i n a t e d b e v e r a g e s ; all w e r e c u r r e n t c i g a r e t t e s m o k e r s
Vol. 55, No. 3, 1994
Human Cocaine Self-administration
averaging 21.3 cigarettes/day (range = 10-40), and all c u r r e n t d r i n k e r s a v e r a g i n g 17 a l c o h o l i c d r i n k s / w e e k (range 24) .
181
were = 9-
Drug C o c a i n e h y d r o c h l o r i d e (Mallinckrodt, Inc., St. Louis, MO) was administered intranasally in t e n I0 m g u n i t d o s e s . Doses were c a l c u l a t e d on t h e b a s i s o f t h e salt. An active placebo was used t h a t a l s o w a s a d m i n i s t e r e d i n t r a n a s a l l y in I0 m g u n i t d o s e s t h a t consisted o f 0.4 m g c o c a i n e h y d r o c h l o r i d e m i x e d w i t h 9.6 m g of lactose. A m a x i m u m of i0 a d m i n i s t r a t i o n s of c o c a i n e or p l a c e b o w e r e a d m i n i s t e r e d p e r s e s s i o n for t o t a l m a x i m u m c u m u l a t i v e d o s e s of i00 m g a n d 4 m g c o c a i n e p e r session. A 4 m g dose p r o d u c e s some nasal numbing but no d i s c e r n i b l e blood levels and is u s e d routinely as t h e p l a c e b o d o s e in s t u d i e s of h u m a n i n t r a n a s a l c o c a i n e u s e (11-13). A m i n i m u m 2-min. i n t e r - t r i a l i n t e r v a l (ITI) w a s r e q u i r e d b e t w e e n s u c c e s s i v e d r u g or p l a c e b o a d m i n i s t r a t i o n s . S u b j e c t s p r e p a r e d t h e p o w d e r e d d r u g in "lines", u s i n g a s t r a i g h t e d g e r a z o r on a m i r r o r , a n d w h e n i n s t r u c t e d b y t h e nurse, i n h a l e d e a c h u n i t d o s e v i a a s t r a w w i t h i n 20 sec. S t a f f w e r e i n f o r m e d t h a t c o c a i n e w a s b e i n g studied, but w e r e b l i n d t o a c t i v e vs. p l a c e b o d r u g in s e s s i o n s when both were available. S u b j e c t s w e r e i n f o r m e d t h a t t h e p u r p o s e of t h e s t u d y w a s to e x a m i n e h o w s t i m u l a n t m e d i c a t i o n s affected behavior and physiology, that they might receive ~-amphetamine, nicotine, cocaine, caffeine, or p l a c e b o , a n d t h a t t h e y w o u l d not r e c e i v e c o c a i n e if t h e y r e p o r t e d h a v i n g n e v e r t a k e n it b e f o r e . Subjects were not informed which drug they actually received in t h e experiment. R e f e r e n c e s to " d r u g " h e r e a f t e r r e f e r to t h e a c t i v e c o c a i n e dose. General
Procedure
S u b j e c t s p a r t i c i p a t e d as o u t p a t i e n t s in t h e G e n e r a l C l i n i c a l Research Center of the Medical Center Hospital of Vermont. S e s s i o n s g e n e r a l l y w e r e c o n d u c t e d at the same time of day for e a c h s u b j e c t , w e e k d a y s only, w i t h at l e a s t 48 hrs. b e t w e e n s e s s i o n s . Subjects were instructed to refrain from all illicit and p r e s c r i p t i o n d r u g u s e for t h e d u r a t i o n of t h e study, f r o m a l c o h o l for 12 hrs., a n d f r o m c a f f e i n e and s o l i d foods for 4 hrs. p r i o r to their scheduled sessions. C i g a r e t t e s m o k i n g w a s p e r m i t t e d on an ad-lib basis between experimental sessions. Subjects were r e q u i r e d to l i g h t a c i g a r e t t e 60 min. p r i o r to t h e s t a r t of t h e c h o i c e s e s s i o n s , a n d w e r e p e r m i t t e d to s m o k e as m u c h or as l i t t l e o f t h a t c i g a r e t t e as d e s i r e d ; no f u r t h e r s m o k i n g w a s p e r m i t t e d until after choice sessions were completed. To m o n i t o r c o m p l i a n c e with restrictions on a l c o h o l use, b r e a t h a l c o h o l l e v e l s (BALS) were measured (via I n t o x i m e t e r ) p r i o r to e a c h s e s s i o n . Urine s p e c i m e n s w e r e c o l l e c t e d p r i o r to e a c h s e s s i o n for d r u g s c r e e n i n g . Test r e s u l t s c o n f i r m e d c o m p l i a n c e w i t h our i n s t r u c t i o n s in all but one s u b j e c t (WK) . He t e s t e d p o s i t i v e for c o c a i n e ( b e n z o y l e c g o n i n e ) on f i v e of t h e s t u d y days. His p r e s e s s i o n p h y s i o l o g i c m e a s u r e s , EKG, a n d p e r f o r m a n c e of a f i e l d s o b r i e t y c h e c k w e r e c o m p a r a b l e to t h o s e o f s e s s i o n s c o n d u c t e d f o l l o w i n g n e g a t i v e u r i n e screens, a n d no s i g n s of a c u t e c o c a i n e e f f e c t s w e r e o b s e r v e d . Thus, s e s s i o n s w e r e c o n d u c t e d as s c h e d u l e d w i t h t h a t s u b j e c t .
182
Human Cocaine Self-administration
Vol. 55, No. 3, 1994
S e s s i o n s w e r e 5.5 hrs. in d u r a t i o n a n d w e r e c o n d u c t e d in a quiet room with a maximum of two subjects participating simultaneously and a research nurse present. Each experimental s t a t i o n w a s e q u i p p e d w i t h a r e s p o n s e c o n s o l e c o n s i s t i n g of t h r e e L i n d s l e y p l u n g e r s ( G e r b r a n d s # G6310) l o c a t e d h o r i z o n t a l l y (left, center, a n d right) a n d a t t a c h e d t o an A p p l e IIe m i c r o c o m p u t e r (Apple C o m p u t e r , C u p e r t i n o , CA) a n d v i d e o m o n i t o r . The n u m b e r of c h o i c e s made, t h e ITI, a n d s e s s i o n - t i m e r e m a i n i n g w e r e d i s p l a y e d to s u b j e c t s on t h e v i d e o m o n i t o r . Blood pressure and heart rate w e r e r e c o r d e d e v e r y 5 min. v i a a S e n t r y II A u t o m a t i c M o n i t o r (NBS Medical, Costa Mesa, CA). Skin temperature was measured continuously via a skin surface thermister (Yellow Springs I n s t r u m e n t Co., Y e l l o w Springs, OH) t a p e d to the t i p of the m i d d l e finger. B l o o d p r e s s u r e , HR, a n d E C G w e r e m o n i t o r e d v i s u a l l y by the research nurse throughout test sessions. C o n t i n u o u s E C G also was collected each session via holter-monitor recordings.
Experimental Sessions Subjects r e m a i n e d s e a t e d d u r i n g s e s s i o n s e x c e p t for b r i e f v i s i t s to t h e b a t h r o o m . The first 0.5 hr. w a s d e v o t e d to s u b j e c t preparation, the next 0.5 hr. to collection of baseline p h y s i o l o g i c m e a s u r e s , a n d the n e x t 2.0 hrs. to d r u g a d m i n i s t r a t i o n a n d p h y s i o l o g i c m o n i t o r i n g a c c o r d i n g to t h e s c h e d u l e n o t e d above. T h e f i n a l 2.0 hr. p e r i o d w a s d e v o t e d t o s u b j e c t r e c o v e r y and physiologic monitoring. Subjects participated in 12 s e s s i o n s . The first session p r o v i d e d a c c l i m a t i o n to t h e p h y s i o l o g i c m o n i t o r i n g e q u i p m e n t a n d familiarized subjects with the general experimental procedures. S e s s i o n s 2 a n d 3 w e r e e x p o s u r e days d u r i n g w h i c h s u b j e c t s r e c e i v e d t e n I0 m g u n i t d o s e s of a c t i v e d r u g on o n e d a y a n d t e n d o s e s of p l a c e b o on t h e o t h e r day. D r u g a n d p l a c e b o w e r e d e s c r i b e d to s u b j e c t s as D r u g A a n d D r u g B. O r d e r of e x p o s u r e to d r u g a n d placebo and whether they were designated as D r u g A or B w a s counterbalanced across subjects. Subjects were provided a paper and p e n c i l a n d e n c o u r a g e d to r e c o r d t h e i r i m p r e s s i o n s of e a c h d r u g during exposure sessions. T h e y w e r e i n s t r u c t e d to n o t e w h a t e a c h d r u g w a s l i k e a n d to p a y c l o s e a t t e n t i o n b e c a u s e t h e y w o u l d be m a k i n g c h o i c e s b e t w e e n the two d r u g s in a s u b s e q u e n t s e s s i o n . S e s s i o n 4 w a s a c h o i c e d a y w h e r e i n s u b j e c t s w e r e a l l o w e d to c h o o s e e i t h e r D r u g A or D r u g B, up to a t o t a l of i0 choices, w i t h a m i n i m u m 2 - m i n . ITI b e t w e e n c h o i c e s as n o t e d a b o v e . Subjects w e r e i n f o r m e d t h a t t h e y a l s o c o u l d c h o o s e to t a k e n e i t h e r D r u g A or B. Subjects registered their choices by completing ten responses on t h e l e f t - or r i g h t - m o s t Lindsley plungers; i.e., fixed-ratio (FR) I0 s c h e d u l e s of r e i n f o r c e m e n t . The center p l u n g e r w a s i n o p e r a t i v e a n d s u b j e c t s w e r e i n s t r u c t e d t h a t w a s the case. E a c h of t h e a c t i v e p l u n g e r s was d e s i g n a t e d as D r u g A or B v i a a s i g n a t t a c h e d i m m e d i a t e l y a b o v e it; w h e t h e r d r u g or p l a c e b o w a s p a i r e d w i t h t h e r i g h t or left p l u n g e r s w a s c o u n t e r b a l a n c e d across subjects. O n c e a r e s p o n s e w a s r e g i s t e r e d on e i t h e r of the plungers, the other option was unavailable u n t i l t h e F R i0 w a s completed and the 2-min. ITI e l a p s e d . As was noted above, completion of t h e F R a n d ITI w a s i n d i c a t e d to s u b j e c t s v i a the video screen. S e s s i o n s e n d e d a f t e r s u b j e c t s m a d e i0 c h o i c e s or a f t e r 2 hrs. e l a p s e d , w h i c h e v e r o c c u r r e d first. Subjects were
Vol. 55, No. 3, 1994
Human Cocaine Self-administration
183
i n s t r u c t e d a b o u t t h e s e p a r a m e t e r s a n d the s h e e t s on w h i c h t h e y h a d r e c o r d e d t h e i r i m p r e s s i o n s of D r u g s A a n d B d u r i n g e x p o s u r e days w e r e a v a i l a b l e to t h e m to a s s i s t in m a k i n g t h e i r c h o i c e s d u r i n g this choice session. O n l y s u b j e c t s w h o c h o s e d r u g 8 or m o r e t i m e s (~ 80%) d u r i n g S e s s i o n 4 c o n t i n u e d in t h e e x p e r i m e n t . S u b j e c t s w e r e not i n f o r m e d of t h i s m i n i m u m cocaine self-administration criterion. The r a t i o n a l e for it w a s t h a t we w a n t e d to s t u d y o n l y t h o s e s u b j e c t s for w h o m c o c a i n e f u n c t i o n e d as a r e i n f o r c e r . A l l s u b j e c t s met this criterion. The p l a c e b o o p t i o n was r e p l a c e d w i t h v a r y i n g a m o u n t s of m o n e y in t h e s u b s e q u e n t e i g h t t e s t s e s s i o n s a n d s u b j e c t s c h o s e b e t w e e n cocaine and money. C o c a i n e w a s a v a i l a b l e as d e s c r i b e d a b o v e a n d s t i l l d e s i g n a t e d b y t h e l e t t e r c o d e w i t h w h i c h it w a s p a i r e d in the p r i o r s e s s i o n s . S u b j e c t s w e r e l i m i t e d to m a k i n g t e n e x c l u s i v e choices between the drug and monetary options during these sessions, w i t h a m i n i m u m 2-min. ITI b e t w e e n c h o i c e s . Sessions e n d e d a f t e r t e n c h o i c e s w e r e m a d e or 2 hrs. e l a p s e d , w h i c h e v e r o c c u r r e d first. C h o i c e s w e r e r e g i s t e r e d v i a t h e left a n d r i g h t L i n d s l e y p l u n g e r s t h a t w e r e p a i r e d w i t h s i g n s i n d i c a t i n g it w a s the drug or m o n e t a r y plunger, and both drug and money were a v a i l a b l e u n d e r F R i0 s c h e d u l e s of r e i n f o r c e m e n t . As n o t e d above, o n c e a c h o i c e w a s r e g i s t e r e d on one o p t i o n the o t h e r o p t i o n was i n a c t i v e u n t i l t h e F R i0 a n d 2-min. ITI w e r e c o m p l e t e d on t h e chosen option. The f o l l o w i n g four m o n e t a r y a m o u n t s w e r e s t u d i e d in s e p a r a t e s e s s i o n s : $0.00, $0.50, $I.00, a n d $2.00 p e r c h o i c e for a m a x i m u m of $0.00, $5.00, $ i 0 . 0 0 or $ 2 0 . 0 0 p e r s e s s i o n . S u b j e c t s w e r e e x p o s e d t w i c e to e a c h m o n e t a r y a m o u n t ; t h e y w e r e e x p o s e d to e a c h of t h e a m o u n t s b e f o r e any w e r e r e p e a t e d . O r d e r of e x p o s u r e to t h e m o n e t a r y a m o u n t s w a s b a l a n c e d a c r o s s s u b j e c t s v i a a Latin-square design. M o n e y e a r n e d in e a c h s e s s i o n w a s paid, by check, at t h e e n d of t h a t s e s s i o n .
Subject Instructions Subjects were instructed that they were participating in a s t u d y d e s i g n e d to e x a m i n e h o w s t i m u l a n t m e d i c a t i o n s a f f e c t e d t h e i r b e h a v i o r , mood, a n d p h y s i o l o g i c a l functions. They w e r e i n s t r u c t e d r e g a r d i n g t h e f o r m a t of t h e a c c l i m a t i o n , e x p o s u r e , d r u g vs. drug, a n d d r u g vs. m o n e y s e s s i o n s , b u t w e r e p r o v i d e d no r a t i o n a l e or p u r p o s e for t h e s e s e s s i o n s b e y o n d the g e n e r a l p u r p o s e n o t e d above. It w a s e m p h a s i z e d t h a t in all c h o i c e s e s s i o n s s u b j e c t s w e r e to c h o o s e a c c o r d i n g to t h e i r o w n p r e f e r e n c e s . They were informed t h a t t h e o n l y l i m i t a t i o n s d u r i n g c h o i c e s e s s i o n s w e r e t h e 2-min. ITI, t h e m a x i m u m of i0 c h o i c e s p e r s e s s i o n , t h e 2-hr. s e s s i o n d u r a t i o n a n d t h a t o n c e an F R w a s i n i t i a t e d t h e a l t e r n a t e o p t i o n was unavailable u n t i l t h a t p a r t i c u l a r F R w a s c o m p l e t e d a n d a 2min. ITI e l a p s e d . W r i t t e n c o p i e s of the i n s t r u c t i o n s p r o v i d e d to s u b j e c t s c a n b e o b t a i n e d b y w r i t i n g the first a u t h o r .
Data Analysis T h e m a i n p u r p o s e of t h e s t u d y w a s to a s s e s s t h e i n f l u e n c e of providing an a l t e r n a t i v e monetary reinforcer on p r e f e r e n c e for cocaine. To a d d r e s s that question, data were analyzed as a r e p l i c a t e d L a t i n - S q u a r e d e s i g n w i t h t h r e e f a c t o r s ( m o n e t a r y value,
184
Human Cocaine Self-administration
Vol. 55, No. 3, 1994
subject, a n d o r d e r of p r e s e n t a t i o n of the m o n e t a r y v a l u e s ) ; e a c h of t h e f a c t o r s h a d four levels. The e f f e c t of m o n e t a r y v a l u e was further partitioned u s i n g o r t h o g o n a l p o l y n o m i a l s to d e s c r i b e the s h a p e of the f u n c t i o n o b s e r v e d b e t w e e n n u m b e r of c o c a i n e c h o i c e s a n d m o n e t a r y v a l u e (e.g., linear, q u a d r a t i c , etc.). Results
During sessions assessing preference between c o c a i n e vs. placebo, c o c a i n e was c h o s e n e x c l u s i v e l y by all subjects; moreover, all s u b j e c t s s e l f - a d m i n i s t e r e d the m a x i m u m t e n d o s e s of d r u g that were available (Fig. i) . P r e f e r e n c e for c o c a i n e d e c r e a s e d s i g n i f i c a n t l y as a f u n c t i o n of i n c r e a s i n g m o n e t a r y v a l u e (F(I,21) = 67.9, p < .0001; Fig. 2), and, although individual subjects showed various non-linear p a t t e r n s in t h i s r e l a t i o n s h i p , t h e r e was no s y s t e m a t i c d e v i a t i o n from linearity across subjects (F(2,21) = 1.47, p = .25). When the v a l u e in t h e m o n e t a r y o p t i o n w a s $0.00, s u b j e c t s e x c l u s i v e l y chose the cocaine option a n d in all b u t one i n s t a n c e selfadministered the maximum number of drug doses available. Preference for c o c a i n e vs. m o n e y v a r i e d b e t w e e n s u b j e c t s at the intermediate m o n e t a r y v a l u e s of $0.50 a n d $i.00 p e r choice. At the $ 2 . 0 0 p e r c h o i c e value, all s u b j e c t s e x c l u s i v e l y c h o s e the m o n e t a r y option. T h e r e w e r e no s i g n i f i c a n t changes in c o c a i n e preference across the first and second exposures to t h e v a r y i n g m o n e t a r y values (F(I,21) = 0.95, p = .34; Fig. 2). The only notable exceptions discernible in t h e r e s u l t s of i n d i v i d u a l subjects a c r o s s t h e t w o e x p o s u r e s w e r e o b s e r v e d w i t h S u b j e c t s DE a n d LC. For both subjects, preference for c o c a i n e w a s less in the first t h a n t h e s e c o n d e x p o s u r e to the $0.50 c o n d i t i o n .
The p r e s e n t r e s u l t s are c o n s i s t e n t w i t h a r o b u s t s c i e n t i f i c literature demonstrating t h a t c o c a i n e u s e is an o r d e r l y f o r m of o p e r a n t b e h a v i o r t h a t is m a i n t a i n e d by the r e i n f o r c i n g e f f e c t s of the drug (5-10). The reinforcing effects of c o c a i n e were demonstrated in the p r e s e n t s t u d y v i a the c l e a r p r e f e r e n c e shown for c o c a i n e o v e r placebo, a n d by the fact that s u b j e c t s g e n e r a l l y self-administered all of t h e a v a i l a b l e cocaine doses in t h e c o n d i t i o n s c o m p a r i n g c o c a i n e vs. p l a c e b o a n d c o c a i n e vs. the zero m o n e t a r y value. Importantly, the behavioral control exerted by cocaine's reinforcing effects was altered significantly b y i n c r e a s i n g the a v a i l a b i l i t y of a n o n d r u g r e i n f o r c e r (i.e., money). P r i o r studies h a v e d e m o n s t r a t e d t h i s in l a b o r a t o r y a n i m a l s u s i n g u n c o n d i t i o n e d , consumable reinforcers (e.g., 9, i0) . The p r e s e n t s t u d y e x t e n d s those p r i o r f i n d i n g s to h u m a n s and to the use of a n o n - c o n s u m a b l e , conditioned reinforcer. These observations are c o n s i s t e n t w i t h behavioral-economic a n a l y s e s of c h o i c e s h o w i n g t h a t d r u g i n g e s t i o n d e c r e a s e s as the cost, or loss, i n v o l v e d in c o n t i n u i n g to c h o o s e the d r u g o p t i o n i n c r e a s e s (14). The p r e s e n t r e s u l t s also p r o v i d e a d d i t i o n a l s c i e n t i f i c s u p p o r t for the p o s i t i v e f i n d i n g s o b t a i n e d in recent clinical trials in cocaine-dependent patients demonstrating that the provision of alternative, nondrug r e i n f o r c e r s in c o m b i n a t i o n w i t h i n t e n s i v e b e h a v i o r t h e r a p y
Vol. 55, No. 3, 1994
Human Cocaine Self-administration
RDB
t~ G)
.o_ O ..¢=
LC
=It=
WK
Drug Placebo
Drug Placebo
Fig. 1. Number of choices of cocaine and placebo during test sessions in which subjects made a maximum of ten choices between the two substances. Data are shown separately for the four individual subjects. 10
•
DE
Q1i ~ • O ::It:
0
.50
146 ~
RDB
LCl i ~ =2
1 10~
o0
.50
1
2
GroupA~m~le
el,l'"
a FirstExposure
6
• SecondExposure
0 0
.50
1
2
Money ($) Fig. 2. Number of cocaine choices are plotted as a function of the value of money available per choice in the monetary option. Subjects made a maximum of ten choices between cocaine vs. money each session. Data are presented for each of the four individual subjects and as a group average. Results from the first and second exposures to the different monetary values are shown separately.
185
186
Human Cocaine Self-administration
Vol. 55, No. 3, 1994
increases cocaine abstinence (15-17). Such c o n s i s t e n c y across different s p e c i e s and across l a b o r a t o r y and c l i n i c a l s e t t i n g s p r o v i d e s c o m p e l l i n g s c i e n t i f i c support for the fundamental role of reinforcement in the g e n e s i s and m a i n t e n a n c e of c o c a i n e use. S y s t e m a t i c a t t e n t i o n to and i n t e g r a t i o n of this b a s i c b e h a v i o r a l p r i n c i p l e into p r e v e n t i o n and t r e a t m e n t p r a c t i c e s should enhance the e f f i c a c y of current efforts to curb cocaine abuse. The consistency between these laboratory findings and results from c l i n i c a l t r i a l s also i l l u s t r a t e s that c l i n i c a l l y - r e l e v a n t issues m a y be f r u i t f u l l y r e s e a r c h e d u s i n g l a b o r a t o r y settings. Laboratory studies are clearly less expensive than clinical trials and a f f o r d a g r e a t e r d e g r e e of e x p e r i m e n t a l c o n t r o l t h a n is possible in c l i n i c a l settings. The p r e s e n t arrangement, for example, c o u l d be u s e d to e x a m i n e the i n f l u e n c e of v a r i o u s independent variables including drug pretreatment on the probability of c o c a i n e use. For example, one c o u l d e x a m i n e whether alcohol, marijuana and other drugs decrease the sensitivity of cocaine s e l f - a d m i n i s t r a t i o n to the influence of the m o n e t a r y r e i n f o r c e r (e.g., r i g h t w a r d shifts in the curve relating preference b e t w e e n c o c a i n e and m o n e y ) . Similarly, one c o u l d examine whether potential treatment medications increase the sensitivity of cocaine self-administration to the influence of the m o n e t a r y a l t e r n a t i v e (i.e., leftward shifts in the curve relating c o c a i n e and m o n e t a r y p r e f e r e n c e ) . Finally, the r e l a t i v e l y high d e g r e e of s t a b i l i t y o b s e r v e d w i t h i n and across s u b j e c t s in the p r e s e n t study are important p o s i t i v e features in c o n s i d e r i n g use of a l a b o r a t o r y a r r a n g e m e n t for such research purposes. The p r e s e n t study examined a single cocaine dose, an i n t r a n a s a l route of drug a d m i n i s t r a t i o n and n o n - d e p e n d e n t users. How changes in t h e s e f a c t o r s w o u l d a l t e r the r e s u l t s is an i m p o r t a n t e m p i r i c a l question. However, the g e n e r a l i t y o b s e r v e d a c r o s s the r e s u l t s of this study and t h o s e c o n d u c t e d b o t h in l a b o r a t o r y settings with n o n h u m a n s and in clinical settings with d e p e n d e n t users s u g g e s t s that q u a n t i t a t i v e or p a r a m e t r i c rather than qualitative differences are l i k e l y to e m e r g e from such parametric manipulations. For e x a m p l e , a larger magnitude alternative reinforcer is l i k e l y to be n e c e s s a r y to c o m p e t e e f f e c t i v e l y w i t h a larger dose of cocaine than was u s e d in the present study. However, the nature of the functional relationship observed between drug preference and the a v a i l a b i l i t y of the a l t e r n a t i v e r e i n f o r c e r is likely to remain intact. In s u m m a r y , the results of the present study provide a d d i t i o n a l e v i d e n c e u n d e r c o n t r o l l e d l a b o r a t o r y c o n d i t i o n s that h u m a n cocaine use is an orderly form of operant b e h a v i o r that is determined, in part, by the availability and magnitude of alternative reinforcers. In the p r e s e n t study, the d e g r e e of behavioral control exerted by cocaine varied from complete to none as an o r d e r l y function of the m a g n i t u d e of the a l t e r n a t i v e r e i n f o r c e r available.
Vol. 55, No. 3, 1994
Human Cocaine Self-administration
187
Acknowledaments S u p p o r t e d in p a r t by g r a n t s DA08076, D A 0 6 1 1 3 N a t i o n a l I n s t i t u t e on D r u g A b u s e a n d R R - 1 0 9
and K 0 2 0 0 1 0 9 from the f r o m the N a t i o n a l
Institutes of Health. The authors thank Mary Lynn, M o r t e n s e n a n d G a r y B a d g e r for a s s i s t a n c e in c o n d u c t i n g the data analysis and manuscript preparation.
Aaron study,
References i.
N a t i o n a l I n s t i t u t e on D r u g Abuse. H o u s e h o l d S u r v e y on D r u g A b u s e : M a i n F i n d i n a s 1990. W a s h i n g t o n , DC: D H H S p u b l i c a t i o n A D M 9 1 - 1 7 8 8 (1991). 2. N a t i o n a l I n s t i t u t e on D r u g Abuse. N a t i o n a l H o u s e h o l d S u r v e y on Drug Abuse: Population Estimates. 1991. W a s h i n g t o n , DC: D H H S p u b l i c a t i o n A D M 92-1887 (1991). 3. L.D. H A R R I S O N , Int J A d d i c t . 2 7 8 1 7 - 8 4 7 (1992). 4. J.C. G F R O E R E R A N D M.D. B R O D S K Y (1993), A m J P u b l i c H e a l t h 83 1149-1154 (1993). 5. C.E. J O H A N S O N A N D M.W. F I S C H M A N , P h a r m a c o l . Rev. 4_!13-52 (1989). 6. T.G. A I G N E R A N D R.L. BALSTER, S c i e n c e 2 Q 1 5 3 4 - 5 3 5 (1978). 7. C. I G L A U E R A N D J.H. WOODS, J. Exp. Anal. Behav. 2__22179-196 (1974) . 8. R.D. SPEALMAN, S c i e n c e 2 0 4 1 2 3 1 - 1 2 3 3 (1979). 9. M.E. CARROLL, S.T. LAC, A N D S.L. NYGAARD, P s y c h o p h a r m a c o l o g y 97 2 3 - 2 9 (1989). I0 M.A. N A D E R A N D W.L. W O O L V E R T O N , P s y c h o p h a r m a c o l o g y 105169-174 (1991). ii J.I. JAVAID, M.W. FISCHMAN, C.R. SCHUSTER, H. D E K I R M E N J I A N AND J.M. DAVIS, S c i e n c e 2 0 2 2 2 7 - 2 2 8 (1978). 12 R.W. F O L T I N A N D M.W. FISCHMAN, P h a r m a c o l B i o c h e m B e h a v 3_!1877883 (1988). 13 S.T. H I G G I N S , W.K. BICKEL, J.R. HUGHES, M. LYNN, M.A. C A P E L E S S A N D J.W. F E N W I C K , P s y c h o p h a r m a c o l o g y 102451-458 (1990). 14 W.K. BICKEL, R.J. D e G R A N D P R E , A N D S.T. HIGGINS, D r u g A l c o h o l Depend 33173-192 (1993). 15 S.T. H I G G I N S , D.D. DELANEY, A.J. BUDNEY, W.K. BICKEL, J.R. HUGHES, F. FOERG, A N D J.W. FENWICK, Am. J. P s y c h i a t r y 148 1218-1224 (1991). 16. S.T. H I G G I N S , A.J. BUDNEY, W.K. BICKEL, J.R. HUGHES, F. FOERG, A N D G. BADGER, Am. J. P s y c h i a t r y 1 5 0 7 6 3 - 7 6 9 (1993). 17. S.T. H I G G I N S , A.J. BUDNEY, W.K. BICKEL, F.E. FOERG, R. DONHAM, A N D G.J. BADGER, Arch. Gen. P s y c h i a t r y in press.