Triazolam as a discriminative stimulus in humans

Drug and Alcohol Dependence, 30 (1992) 133Elsevier Scientific Publishers Ireland Ltd.

Triazolam

133

142

as a discriminative

Alison H. Oliveto”, Warren

stimulus in humans

K. Bickel”‘“, John R. Hughes”‘“‘“, Stephen T. Higgins”‘” and James W. Fenwickd

Human Behavioral Pharmacology Laboratory, Departments of aPsychiatry, bPsychology, ‘Family and Statistics, University of Vermon,t, Burlington, VT (U.S.A.)

(Accepted

December

Practice and dMathematics

20, 1991)

Seven healthy normal male and female volunteers (19 - 42 years) were trained to discriminate between the benzodiazepine triazolam (0.32 mg/70 kg; e.g. drug A) and placebo (e.g. drug B). During the first four daily sessions, drug A and drug B were administered orally in capsules 60 min prior to the session on alternate days and subjects were informed of the drug label at the time of drug administration. Subsequently, drug A and drug B were administered in a randomized-block fashion and subjects identified the drug code they thought they received. Subjects were informed of the drug code post-session. Once the criterion for discrimination was met (i.e. correct drug code identification on four consecutive sessions), the dose-effect curve for triazolam (0.1-0.75 mg/70 kg) was determined. The discrimination was acquired in all subjects; triazolam (0.32 mg/70 kg) and placebo produced approximately 85 - 95% correct responding. During the dose-effect curve determination, triazolam produced dose-related increases in triazolam-appropriate responding and self-reported sedation and drug strength. These results indicate that a triazolam-placebo discrimination can be acquired and that the triazolam discriminative stimulus effect is related to dose and to self-reported sedation. Key words:

benzodiazepine;

drug

discrimination;

humans;

triazolam

Introduction

(Chait et al., 1984, 1985, 1986ab; Chait and Johanson, 1988; Heishman and Henningfield, 1991; Oliveto et al., in press). Results of these studies generally have indicated that the discriminative stimulus effects of drugs can be acquired and maintained (Bickel et al., 1989; Chait et al., 198613; Oliveto et al., in press), have pharmacological specificity (Bickel et al., 1989; Chait et al., 1985, 1986a,b; Chait and Johanson, 1988; Heishman and Henning-field, 1991; Oliveto et al., in press; Preston et al., 1987, 1989) and correlate well with self-reported drug effects (Preston et al., 1987; Bickel et al, 1989; Chait et al., 1985, 198613, 1989; Chait and Johanson, 1988; Heishman and Henningfield, 1991). Such studies demonstrate the utility of the human drug discrimination paradigm and assist in understanding the relationship between discriminative stimulus effects, self-reports and dependence potential of behaviorally-active compounds (Schuster and Johanson, 1988).

Drug discrimination procedures, considered standard neurolbehavioral pharmacological assays in non-humans, are used to characterize drugs based upon their interoceptive stimulus effects (e.g. Barry, 1974). Recently, the drug discrimination paradigm has been adapted for use in humans (e.g. Chait et al., 1984; Preston et al., 1987). To date, most human drug discrimination studies have examined the discriminative stimulus effects of opioids (Bickel et al., 1989; Preston et al., 1987, 1989, 1990) and stimulants

Correspondence to: A. Oliveto, Substance Abuse Unit, Department of Psychiatry, Yale University

Treatment School of

Medicine, 27 Sylvan Ave., New Haven, CT 06519, U.S.A. Reprint requests: W. Bickel, Human Behavioral Pharmacology Laboratory, Department of Psychiatry, University of Vermont, 38 Fletcher Place, Burlington, VT 05401-1419, U.S.A. 0376~8716/92/$05.00 Printed and Published

0

1992 Elsevier in Ireland

Scientific

Publishers

Ireland

Ltd.

134

Recently, the discriminative stimulus effects of the 1,4-benzodiazepine diazepam have been investigated in humans (Johanson, 1991a,b). In these studies, subjects were trained to discriminate between diazepam (10 mg/70 kg) and placebo via a procedure similar to that developed by Chait et al. (1984). In a given session, subjects were administered a compound in the laboratory and then allowed to leave the laboratory, filling out self-report questionnaires and telephoning the experimenters with their drug code identification at later time points. Results of these studies indicated that the diazepam-placebo discrimination can be acquired and maintained. Moreover, the diazepam discriminative stimulus was shown to have at least some pharmacological specificity, in that other benzodiazepines, as well as non-benzodiazepine anxiolytics such as pentobarbital and buspirone, produced diazepam-appropriate responding, whereas the stimulant d-amphetamine and the antihistamine tripelennamine did not. Discrimination behavior also generally correlated well with self-reported drug effects. The fact that benzodiazepines are widely prescribed (Woods et al., 1987) warrants further examination of these compounds in order to define their behavioral effects more fully. The present study examined whether another benzodiazepine, triazolam, can function as a discriminative stimulus in humans. Triazolam, a triazolo-1,4_benzodiazepine, has a different chemical structure than the traditional 1,4-benzodiazepine diazepam (Garzone and Kroboth, 1989; Hester et al., 1971; Rudzik et al., 1973). This structural difference is thought to account for differences in their pharmacokinetics, in that triazolam has a short duration of action and no clinically significant active metabolites (Eberts et al., 1981; Garzone and Kroboth, 1989; Pakes et al., 1981),whereas diazepam has a longer duration of action and active metabolites (Greenblatt et al., 1982, 1983). In this study, triazolam’s discriminative stimulus effects were examined under a drug discrimination paradigm that differs from that used by Johanson (1991a,b) to study diazepam and is very similar to the protocol developed by Preston et al.

(1987) to study opioids. In the Preston et al. (1987) procedure, each entire session is conducted in the laboratory, the administration of discrimination and self-report measures is completely automated, and subjects remain in the laboratory for the duration of the drug effect. Methods Subjects

Four male and three female volunteers (ages 19 - 42) who were recruited from newspaper ads and posters gave written informed consent to participate in this study. All subjects were nonsmokers. In terms of current alcohol use, one subject reported drinking on a weekly basis (2- 4 drinks/week), two subjects on a monthly basis (l-4 drinks/month), and four subjects reported no regular alcohol use. Five subjects reported prior, though generally limited (i.e. < 40 times over lifetime), experience with several psychoactive compounds, including marijuana, cocaine and hallucinogens. All subjects reported being drug-free for at least 6 months prior to the experiment and current abstinence was confirmed via urinalysis. On the basis of physical examination, history, routine laboratory chemistries and EKG, subjects were found to be in good health and without a history of significant psychiatric or substance use problems. Subjects were compensated monetarily for their participation. Apparatus

Commodore 64 microcomputers, located in a 113 square foot experimental room that was temperature controlled and well-ventilated, were programmed via a Macintosh computer network to present all questionnaires and performance tests in a prearranged and timed sequence. Subjects indicated their responses on manipulanda consisting of a numeric pad and three telegraph keys. Data were relayed through a Macintosh computer network to subjects’ respective files on a Macintosh SE and were also printed on an Apple ImageWriter II as each task was completed.

135

Drugs The training conditions were 0.32 mg/70 kg body weight of triazolam and lactose (i.e. placebo). Triazolam was also tested at doses of 0.10, 0.18, 0.24 and 0.75 mgl70 kg body weight. Each dose was tested once. All drugs were administered double-blind 60 min prior to the first drug assessment cycle. Triazolam and placebo were administered p.o. via two blue opaque capsules (size 00). Experimental procedure An initial session without drug administration was conducted to familiarize subjects with the procedures. Then the study proceeded in three phases and sessions were conducted 3- 5 days/week. Training. Discrimination training was conducted in sessions 1 - 4, during which the training dose of triazolam (0.32 mg/70 kg) and placebo were administered on alternate days. During these sessions, subjects were informed of the drug’s letter code at the time of drug administration and were instructed to attend carefully to the drug effect and to try to discriminate precisely between drugs. Subjects were told that in each session they could earn money by correctly identifying the administered drug by letter code. Acquisition of the Test-of-acquisition. discrimination was tested in sessions 5 - 11. The triazolam training dose and placebo were administered in a randomized block order, such that every four sessions consisted of two placebo and two triazolam tests (each training condition was never tested more than three consecutive times). During the session, subjects identified on three discrimination tasks the drug code they thought they received (described below). The drug letter code was not revealed until the end of the experimental session. The purpose of these sessions was to determine whether subjects could identify correctly the training condition/doses by letter code and to provide further training. Once criterion for discrimination was met (i.e. an average of L 85% correct respond-

ing across the three discrimination measures on four consecutive sessions), subjects were eligible to enter the testing phase. Testing. This phase consisted of approximately eight sessions, during which different doses of triazolam typically were tested in a randomized order with test-of-acquisition sessions interspersed throughout. In these test-of-acquisition sessions, training drug or placebo was tested to provide continued training and to ensure continued correct identification. The ratio of test to test-of-acquisition sessions was approximately 1:l. If a novel dose was administered, subjects were informed at the end of the session that it was a test day; otherwise, subjects were informed of the drug code. Compensation was accrued at the rate of $5.00/h. In addition, during training and test-ofacquisition sessions, monetary compensation could be earned based upon performance on three discrimination measures (see below). During tests of novel doses, subjects’ earnings were not contingent on their performance, but were equal to the average bonus earned on the last four test-of-acquisition sessions. This method of subject payment has been used successfully in other drug discrimination studies (e.g. Bickel et al., 1989). Experimental session Experimental sessions began at 12:00 h. Subjects typically remained at the facility for approximately 5 h. At the beginning of each session, blood pressure, breath alcohol levels and heart rate were recorded. Urine samples were obtained, ostensibly to verify abstention from illicit drugs. (Analyses were not performed unless drug use was suspected.) Subjects then underwent a sobriety test (i.e. test of balance, hand coordination, simple arithmetic, and recall) and completed baseline self-report questionnaires and a performance task on the computer. Capsules were then administered. Sixty and ninety minutes after drug administration, subjects completed tasks during a post-drug assessment cycle. Each assessment cycle lasted approximately 10 min and consisted of drug

136

discrimination measures, self-report measures on drug effect and a performance measure (see below). At the end of the session, heart rate and blood pressure were recorded once more and the subject underwent a sobriety test and a test of memory recall. A sealed envelope was opened for each subject, informing subject and experimenter either of the letter code identity of the administered drug or that the session had been a test day. Bonus earnings for each letter code were displayed on the computer screen. Subjects were instructed to abstain from caffeine and solid food for at least 4 h and from alcohol for at least 24 h prior to each experimental session. Subjects also were asked to abstain from all illicit drug use for the duration of the experiment. Discrimination measures. Drug discrimination data were collected during each assessment cycle using three procedures (Bickel et al., 1989; Oliveto et al., in press; Preston et al., 1987, 1989, 1990). In each procedure, only correct responses were converted to monetary reinforcement for subjects. Subjects earned up to $15.00 per session ($5.00 per procedure) for maximal correct responding. In the first procedure, subjects responded on either of two keys corresponding to the training drug and placebo according to a fixed-interval l-s schedule of point presentation. Thus, the first response made after each l-s interval elapsed increased the total number of points accumulated on a given key by one. This schedule lasted 3 min and the number of points earned on each of the two manipulanda and the overall rate of responding were recorded. The second procedure required subjects to make a discrete choice, indicating by letter code (e.g. A or B) the drug they thought they had received. In the third component, subjects were required to distribute 50 points between the two drug codes depending upon how certain they were of the identity of the drug administered. Self-report measures. Three questionnaires were completed: the Addiction Research Center Short Form (ARCI), an adjective rating scale

and visual analog scales. The ARC1 consists of 49 true/false questions that are scored as five subscales: morphine-benzedrine group (MBG), a measure of ‘euphoria’; pentobarbital-chlorpromazine-alcohol group (PCAG), a measure of ‘sedation’; lysergic acid diethylamide (LSD), a measure of ‘dysphoria’; and the benzedrine (BG) and amphetamine (A) scales, which are sensitive to amphetamine-like effects (Jasinski, 1977; Martin et al., 1971). The adjective rating scale lists 32 adjectives that are rated on a 5-point scale from 0 (no effect) to 4 (maximum effect). The items in the list are grouped into 2 subscales: (i) a sedative scale, consisting of adjectives describing sedative effects (PDR, 1991) and (ii) a stimulant scale, consisting of adjectives describing stimulant effects (e.g. Hughes et al., 1991). The visual analog scale consists of seven loo-point visual-analog scales anchored with ‘not at all’ on one end and ‘extremely’ on the other. On these scales subjects reported the extent to which they experienced the strength of the drug effect, effects similar to each training condition, drug-liking, ‘good’ drug effects, ‘bad’ drug effects, and drug-induced high. Psychomotor measures. The psychomotor test was a computerized version of the digit symbol substitution task or DSST (McLeod et al., 1982). Briefly, randomly-selected digits appear on the center of the video screen. Subjects reproduce a geometric pattern associated with a digit according to the digit code presented continuously at the top of the screen using a numeric keypad. Subjects were instructed to complete as many patterns as possible while maintaining accuracy during the 90-s presentation of the task. Data collected include the number of trials attempted and the number of correct trials completed. Data analysis

Discrimination data within each session were averaged across the two assessment cycles. Performance in sessions during test-of-acquisition (i.e. sessions 5- 11) was reported in terms of percentage of correct drug responding under the three drug discrimination procedures for each session. The results of self-report and

DSST measures from sessions during training and test-of-acquisition are reported as the mean of the scores from exposures to each drug in sessions 1 - 4 (i.e. training) and the last 4 sessions during test-of-acquisition. Visual analog scales are reported as mean scores; mean change from predrug scores are reported for ARC1 scales. Self-report and DSST performance measures obtained in six subjects during test-of-acquisition were entered into 2 x 2 x 2 x 2 repeated measures ANOVA with training condition (0.32 mg/70 kg triazolam vs. placebo), phase (training vs. acquisition), session and post-drug time point (1 vs. 2) as factors. Data for the seventh subject were not used in this analysis as there was an unequal number of triazolam and placebo sessions during the last four test-of-acquisition sessions. For the purpose of this paper, only data FI l-SEC

showing a main effect for training condition are presented. A P value of 5 0.05 was used to infer statistical significance. Results

The training and test-of-acquisition phases were completed in all seven subjects. Subsequently, three subjects chose not to continue, so the dose-effect curve for triazolam was determined in four subjects. During the test-of-acquisition phase, all seven subjects met the criterion for discrimination within an average of 5.4 sessions (range: 4 - 7) and their discrimination performance is shown in Fig. 1. Both triazolam and placebo produced 85 - 95% correct responding under all three discrimination measures; that is, the FI l-s

SCHEDULE

60

POINT

DISTRIBUTION

60

RESPONSE

RATE

DISCRETE

CHOICE

51

60 -

Fig. 1. Effects of triazolam (0.32 mg/70 kg, filled bars) and placebo (striped bars) on performance under of point presentation (left panels), the point distribution component (top right panel) and the discrete choice right panel) during the test-of-acquisition phase. Discrimination performance is expressed as percentage (top panels, bottom right panel) and rate of responding as responses per second (bottom left panel). Each mean (* S.E.M.) across seven subjects.

the FI l-s schedule component (bottom correct responding bar represents the

138

schedule of point presentation (top left panel), the point distribution component (top right panel), and the discrete choice component (bottom right panel). The training conditions did not differentially alter response rate under the FI l-s schedule (bottom left panel). On the ARCI, triazolam and placebo produced significantly different effects on the PCAG and BG scales during training and test-of-acquisition (Fig. 2, top panel). Triazolam increased ratings of sedation on the PCAG scale by more than six units relative to predrug and to placebo. Triazolam decreased ratings of stimulation on the BG scale by at least three units relative to predrug scores, whereas the placebo did not. The training conditions did not differentially alter ratings on the LSD, MBG or A scales (data not shown). On the visual analogs, triazolam and placebo produced significantly different effects on the ‘like triazolam’ and ‘like placebo’ scales (Fig. 2, middle panel). Triazolam was rated as being very much like triazolam but not at all like placebo, whereas placebo was rated as the converse. Triazolam produced marginally greater ratings of ‘drug strength’ (61.4 vs. 35) and ‘good effects’,(37.7 vs. 34.2) than placebo (0.05 < P < 0.1); otherwise the training conditions did not produce significant differential effects on the other visual analog scales (data not shown). On the DSST, triazolam significantly decreased the number of trials completed and the number of trials correct by approximately eight trials relative to placebo (Fig. 2, bottom panel). Triazolam also significantly decreased the percentage of trials completed correctly by 3% as compared with the placebo. The effects of different doses of triazolam on discrimination performance under the FI l-s schedule in four subjects are shown in Fig. 3. Since performance tended to be similar across all discrimination measures, only data from the FI component are illustrated. The lowest dose of triazolam tested (0.1 mg/70 kg) produced placebo-appropriate responding (Fig. 3, top panel). Triazolam increased triazolam-appropriate responding in a dose-related manner, such that greater than 85% of triazolam-appropriate

ARC1

PCAG

VISUAL ANALOGS 100,

-

-

LIKE PIACE

LIKE TRlAZOLAh4

DSST 50 -

100

40 -

80

3 0"

30 -

60

s ;:

20 -

40

10 -

20

O-

0

zi mp 7

TOTAL

CORRECT

CORFUTOT

Fig. 2. Effects of triazolam (0.32 mg/70 kg, filled bars) and placebo (striped bars) on selected self-report and DSST measures during the four training sessions and last four test-of acquisition sessions. Scores are expressed as change from predrug on drug on the visual measures (bottom (* S.E.M.) across

the ARC1 (top panel) or score postanalog scales (middle panel) and DSST panel). Each bar represents the mean six subjects.

responding occurred at 0.32 and 0.75 mgl70 kg. In contrast, triazolam produced no change in rate of responding up to a dose of 0.75 mgl70 kg (Fig. 3, bottom panel). The effects of different doses of triazolam on selected self-report and performance measures

139

S-

the highest doses tested (0.32 and 0.75 mg/70 kg) produced ratings of more than 60 units (bottom left panel). Conversely, the lowest triazolam dose produced ‘like placebo’ ratings of approximately 80 units, whereas the highest dose produced ratings of 20 units. Triazolam also impaired DSST performance in a dose-related manner, decreasing the number of trials completed from 48 at 0.1 mg/70 kg to 27 at 0.75 mg/70 kg (Fig. 4, top right panel). Similarly, triazolam decreased the number of correct trials from 47 at 0.1 mg/70 kg to 18 at 0.75 mg/70 kg (middle right panel). In addition, the percentage of trials that were correct at the 0.75 mgi70 kg dose of triazolam was almost half that at 0.1 mg/70 kg (bottom right panel).

4-

Discussion

FI l-SEC

SCHEDULE

100 80

-

60

-

40

-

20

-

o,+_

f

P

;:I

0.1

,

1.0

0.32

m

2

1 -

O-l-7 , P

0.1

TRIAZOLAM

I

0.32

1.0

(mgn0kg)

Fig. 3. Effects of triazolam dose on performance under the FI l-s schedule of point presentation. Discrimination performance is expressed as percentage triazolamappropriate responding (top panel). Rate of responding is expressed as responses per second (bottom panel). The points above ‘P’ represent performance after placebo administration. Each point represents the mean =t S.E.M. of the four subjects.

are shown in Fig. 4. Triazolam increased ratings of sedation on the PCAG from less than 4 units at 0.1 mg/70 kg to approximately 6.5 units at 0.75 mg/70 kg (top left panel). Ratings of drug strength were increased from approximately 20 units at 0.1 mg/70 kg to 60 units at the highest dose of triazolam tested (middle left panel). The 0.1 mg170 kg dose of triazolam produced ‘like triazolam’ ratings of less than 10 units, whereas

This study assessed the ability of triazolam to serve as a discriminative stimulus in humans and has the following findings: a triazolamplacebo discrimination was acquired, triazolam produced dose-related increases in drug-appropriate responding without altering response rate, and triazolam increased self-reported sedation and impaired performance on the DSST in a dose-related manner. These results are consistent with previous diazepam drug discrimination studies in humans (Johanson, 1991a,b) and extend these prior findings by demonstrating that another benzodiazepine, triazolam, can function as a discriminative stimulus in humans. One strength of the procedure employed in the present study was that subjects remained in the laboratory for the duration of the drug effect. Thus, higher doses of triazolam were able to be trained and tested than in procedures where subjects leave the laboratory immediately after drug administration. For instance, doses similar to the training dose of triazolam employed here (i.e. 0.32 mgl70 kg) have been shown to produce performance decrements on various repeated acquisition, recall and psychomotor tasks as well as to increase self-reported sedation (Bickel et al., 1990; Evans et al., 1990; Roache and Griffiths, 1985). The training dose is also comparable to the usual recommended therapeutic dose

140 DSST

PCAG

so-

a-

m-

OJ

Y P

o-

, 0.1

Oil2

P

1.0

al

&o.

r. doT

F T'

1 -

P

T

-1

al

LIKE TRAINING

20-

i “t ?

Od

-t

1

032

1.0

DssT

ORUG STRENGTH

T

0.32

P

1.0

CONDITION

a1

0.22

_ 7

1.0

DSSf

loo,

l

so-

w40.

1

2Q-

Od

T-

1

P TRIAZOLAM

0.1

022

1.0

(mg70kg)

Fig. 4. Effects of triazolam dose on selected self-report and DSST measures. Data are expressed as change from predrug (top left panel) or post-drug score (middle, bottom left panels and right panels). The points above ‘P’ represent performance after placebo administration. Each point represents the mean (f S.E.M.) of four subjects.

of triazolam, which is 0.25 - 0.5 mg (Physicians Desk Reference, 1991). The use of a higher training dose of triazolam is important, not only to be comparable with the therapeutic doses of this compound, but also to increase the probabil-

ity that the drug will acquire stimulus control over the behavior. Indeed, individual quantitative differences in response to drug effects for a given training dose have been reported (Chait et al., 1989). For instance, Chait and

141

associates (1989) showed that d-amphetamine produced quantitatively greater self-reported drug effects in subjects who could discriminate d-amphetamine (10 mg) from placebo than in non-discriminators. When a higher dose of damphetamine (15 mg) was employed, all of five subjects who could not discriminate the lower dose acquired the drug-placebo discrimination at the higher dose. Higher training doses also produce more pharmacologically specific discriminative stimulus effects (e.g. Colpaert et al., 1980, Mumford and Holtzman, 1991; Shannon and Holtzman, 1979). This is important when determining the pharmacological mechanism of action of triazolam and of other compounds; therefore, the triazolam dose employed here (i.e. 0.32 mg/70 kg) will be useful when examining the pharmacological specificity of triazolam’s discriminative stimulus effects. Triazolam is particularly well-suited as the training drug for several reasons. For instance, triazolam has a fast onset, a short duration of action, and no clinically significant active metabolites (Garzone and Kroboth, 1989; Eberts et al., 1981; Pakes et al., 1981). In addition, tolerance does not occur to triazolam’s effects on self-reports and psychomotor performance with repeated dosing in 48-h intervals (Roache and Griffiths, 1986). Thus, triazolam can be administered repeatedly at higher doses with minimal risk of drug accumulation and chronic behavioral toxicity. Triazolam and diazepam also have some structural dissimilarities (Hester et al., 1971; Rudzik et al., 1973) which may indicate different pharmacological activities. For instance, results of in vitro studies indicate that triazolam has antagonist- or inverse agonist-like activity whereas diazepam has agonist effects on certain benzodiazepine receptor populations (Chewh et al., 1985; Mathers and Yoshida, 1987). Therefore, triazolam discrimination studies may provide information that is at least complementary to that provided by the diazepam studies (Johanson, 1991a,b), if not unique to triazolo-benzodiazepines. Overall, the results of this study provide further evidence that benzodiazepines can ac-

quire discriminative stimulus control over human behavior, discrimination responding is an orderly function of dose, and some self-reports correlate well with dose. Acknowledgements

This work was supported by USPH Grants DA-06205 and T32-DA-07242 from the National Institute on Drug Abuse. J.R. Hughes was the recipient of Research Scientist Development Award DA-00109. S.T. Higgins was the recipient of First Independent Research Support and Transition Award DA-04545, The authors wish to express their appreciation to Charissa Wieland and Mitchell Wiegner for their expert technical assistance, Craig Rush and Dr. Jonathan Kamien for their helpful comments and Brandi Smith for her assistance with preparation of the figures. References Barry, III, H. (1974) their discriminable

Classification effects in

of drugs according rats. Fed. Proc.

to 33,

1814 - 1824. Bickel, W.K., Bigelow, G.E., Preston, K.L. and Liebson, I.A. (1989) Opioid drug discrimination in humans: Stability, specificity and relation to self-reported drug effect. J. Pharmacol. Exp. Ther. 251, 1053- 1063. Bickel, W-K., Hughes, J.R. and Higgins, S.T. (1990) Human behavioral pharmacology of benzodiazepines: Effects on repeated acquisition and performance of response chains. Drug Dev. Res. 20, 53-65. Chait, L.D. and Johanson, C.-E. (1988) Discriminative stimulus effects of caffeine and benzphetamine in amphetamine-trained volunteers. Psychopharmacology 96, 302 - 308. Chait, L.D., Uhlenhuth, E.H. and Johanson, C.-E. (1984) An experimental paradigm for studying the discriminative stimulus properties of drugs in humans. Psychopharmacology 82, 272 - 274. Chait, L.D., Uhlenhuth, E.H. and Johanson, C.-E. (1985) The discriminative stimulus and subjective effects of damphetamine in humans. Psychopharmacology 86, 307-312. Chait, L.D., Uhlenhuth, E.H. and Johanson, C.E. (1986a) The discriminative stimulus and subjective effects of phenylpropanolamine, mazindol and d-amphetamine in humans. Pharmacol. Biochem. Behav. 24, 1665 - 16’72. Chait, L.D., Uhlenhuth, E.H. and Johanson, C.-E. (1986b) The discriminative stimulus and subjective effects of damphetamine, phenmetrazine and fenfluramine in humans. Psychopharmacology 89, 301- 306.

142 Chait, L.D., Uhlenhuth, E.H. and Johanson, C.E. (1989) Individual differences in the discriminative stimulus effects of d-amphetamine in humans. Drug Dev. Res. 16: 451- 460. Chewh, A.Y., Swinyard, E.A. and Wolf. H.H. (1985) Gamma-Aminobutyric acid modulation of benzodiazepine receptor binding in vitro does not predict the pharmacological activity of all benzodiazepine receptor ligands. Neurosci. Lett. 54, 173 - 177. Colpaert, F.C., Niemeegers, C.J.E. and Janssen, P.A.J. (1980) Factors regulating drug cue sensitivity: The effect of training dose in fentanyl-saline discrimination. Neuropharmacology 19, 705 - 713. Eberts, F.S., Phiopoulos, Y., Reineke, L.M. and Vliek, R.W. (1981) Triazolam disposition. Clin. Pharmacol. Ther. 29, 81-93. Evans, S.M., Funderburk, F.R. and Griffiths, R.R. (1990) Zolpidem and triazolam in humans: Behavioral and subjective effects and abuse liability. J. Pharmacol. Exp. Ther. 225, 1246- 1255. Garzone, P.D. and Kroboth, P.D. (1989) Pharmacokinetics of the newer benzodiazepines. Clin. Pharmacokin. 16, 337-364. Greenblatt, D.J., Divoll, M., Abernathy, D.R. and Shader, R.I. (1982) Benzodiazepine hypnotics: Kinetic and therapeutic options. Sleep 5, S18 - S27. Greenblatt, D.J., Shader, R.I. and Abernathy, D.R. (1983) Current status of benzodiazepines (First of two parts). N. Engl. J. Med. 309, 354-358. Heishman, S.J. and Henningfield, J.E. (1991) Discriminative stimulus effects of d-amphetamine, methylphenidate, and diazepam in humans. Psychopharmacology 103,436 - 442. Hester, J.B., Rudzik, A.D. and Kamdar, B.V. (1971) 6-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines which have central nervous system depressant activity. J. Med. Chem. 14, 1078- 1081. Hughes J.R., Higgins S.T., Bickel W.K., Hunt W.K., Fenwick J.W., Gulliver S.B. and Mireault G.C. (1991) Caffeine self-administration, withdrawal and adverse effects among coffee drinkers. Arch. Gen. Psychiatry 48, 611-617. Jasinski, D.R. (1977) Assessment of the abuse potential of morphine-like drugs (methods used in man). In: Drug Addiction I (Martin, W.R., ed.), pp. 197-258, SpringerVerlag, New York. Johanson, C.-E. (1991a) The discriminative stimulus effects of diazepam in humans. J. Pharmacol. Exp. Ther. 257, 634-643. Johanson, C.-E. (1991b) Further studies on the discriminative stimulus effects of diazepam in humans. Behav. Pharmacol. 2, 357 - 368. Martin, W.R., Sloan, J.W., Sapiro, J.D. and Jasinski, D.R. (1971) Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine and methylphenidate in man. Clin. Pharmacol. Ther. 12, 245 -258. Mathers, D.A. and Yoshida, H. (1987) The benzodiazepine

triazolam: Direct and GABA depressant effects on cultured mouse spinal cord neurons. Eur. J. Pharmacol. 139, 53 - 60. McLeod, D.R., Griffiths, R.R., Bigelow, G.E. and Yingling, J. (1982) An automated version of the digit symbol substitution test (DSST). Behav. Res. Methods Instrum. 14, 463- 466. Mumford, G.K. and Holtzman, S.G. (1991) Qualitative differences in the discriminative stimulus effects of low and high doses of caffeine in the rat. J. Pharmacol. Exp. Ther. in press. Oliveto, A.H., Bickel, W.K., Hughes, J.R., Shea, P.J., Higgins, S.T. and Fenwick, J.W. (1992) Caffeine drug discrimination in humans: acquisition, specificity and correlation with self-reports. J. Pharmacol. Exp. Ther., in press. Pakes, G.E., Brogden, R.N., Heel, R.C., Speight, T.M. and Avery, G.S. (1981) Triazolam: A review of its pharmacological properties and therapeutic efficacy in patients with insomnia. Drugs 22, 81- 110. Physicians Desk Reference (1991) Medical Economics Co., Inc., New Jersey. Preston, K.L., Bigelow, G.E., Bickel, W.K. and Liebson, I.A. (1987) Three-choice drug discrimination in opioiddependent humans: Hydromorphone, naloxone and saline. J. Pharmacol. Exp. Ther. 243, 1002- 1009. Preston, K.L., Bigelow, G.E., Bickel, W.K. and Liebson, I.A. (1989) Drug discrimination in human post-addicts: Agonist-Antagonist opioids. J. Pharmacol. Exp. Ther. 250, 184 - 196. Preston, K.L., Bigelow, G.E. and Liebson, I.A. (1990) Discrimination of butorphanol and nalbuphine in opioiddependent humans. Pharmacol. Biochem. Behav. 37, 511- 522. Roache, J.D. and Griffiths, R.R. (1985) Comparison of triazolam and pentobarbital: Performance impairment, subjective effects and abuse liability. J. Pharmacol. Exp. Ther. 234, 120-133. Roache, J.D. and Griffiths, R.R. (1986) Repeated administration of diazepam and triazolam to subjects with histories of drug abuse. Drug Alcohol Depend. 17,15- 19. Rudzik, A.D., Hester, J.B., Tang, A.H., Straw, R.N. and Friis, W. (1973) Triazolobenzodiazepines, a new class of central nervous system-depressant compounds. In: The Benzodiazepines, pp. 285 - 297, Raven Press, New York. Schuster, C.R. and Johanson, C.-E. (1988) Relationship between discriminative stimulus properties and subjective effects of drugs. In: Transduction Mechanisms of Drug Stimuli, Psychopharmacology Supplemental Series (Colpaert, F.C. and Balster, R.L., eds.), pp. 161-175. Shannon, H.E. and Holtzman, S.G. (1979) Morphine training dose: A determinant of stimulus generalization to narcotic antagonists in the rat. Psychopharmacology 61,239-244. Woods, J.H., Katz, J.L. and Winger, G. (1988) Use and abuse of benzodiazepines: Issues relevant to prescribing. J. Am. Med. Assoc. 260. 3476-3480.