The intravenous self-administration of antihistamines by rhesus monkeys

117

Drug and Alcohol Depen&nce, 30 (1992) 11’7 - 126 Elsevier Scientific Publishers Ireland Ltd.

The intravenous

self-administration of antihistamines rhesus monkeys

by

Patrick M. Beardsley* and Robert L. Balster Department of Pharmacology

and Toxicology, Medical College of Virginia, Virginia Station, Richmond, VA 23298 (U.S.A.)

(Accepted

Commonwealth

University, Box 613 MCV

December 6th, 1991)

Rhesus monkeys were trained to lever press for infusions of cocaine during daily, l-h experimental sessions. Following stabilization of the cocaine-maintained baselines, various antihistamines were substituted for cocaine to determine whether they would be self-administered. The results indicated that all monkeys tested self-administered tripelennamine and chlorpheniramine. One monkey out of the four self-administered pyrilamine, but only at a single (300 pglkg) high dose. Phenyltoloxamine, cimetidine and hydroxyzine were not self-administered. These results further illuminate differences amongst Hi antagonists in their potential for self-administration and, when examined in context with other reports, suggest that stimulantlike properties may help mediate their reinforcing effects when present. Key words: antihistamine; self-administration;

rhesus monkey; cocaine

Introduction

The H1 histaminergic antagonists (H, antagonists) express a wide range of effects and are used clinically for a variety of indications. For example, tripelennamine, chlorpheniramine, phenyltoloxamine and pyrilamine are used for treating allergic rhinitis, nasal congestion due to the common cold, allergic conjunctivitis and skin reactions. Other Hi antagonists, such as hydroxyzine, have been used as anxiolytics, antiemetics and as preanesthetic sedatives (Dowd, 1990). When not desired in and of itself, the effect of the H1 antagonists which causes the highest incidence of complaint is sedation, Correspondence to: R.L. Balster, Department of Pharmacology and Toxicology, Box 613, MCV Station, Richmond, VA 232930613, U.S.A. Abbreviation-s: FR, fixed-ratio. ‘Present address: G.D. Searle and Company, CNS Diseases Research, K229, 4901 Searle Parkway, Skokie, IL 60077, U.S.A.

although hallucinations, convulsions and excitation have also been reported (Douglas, 1985). In addition to their therapeutic applications, the Hi antagonists have also been used for illegal, non-prescribed purposes. One of the earliest reports of H1 antagonist abuse involved the intravenous self-administration of tripelennamine by a heroin addict (O’Driscoli and Lindley, 1957). More common than singular use has been the abuse of Hi antagonists in polydrug combinations. During the 196Os, for example, intravenous abuse of combinations of tripelennamine with paregoric, heroin or morphine (‘blue velvet’) became popular (Burton et al., 1965). During the 1970s and 198Os, reports of illicit usage of pentazocine and tripelennamine combinations, known on the street as T’s and blues, were described reaching epidemic levels (Butch, et al., 1979; Lahmeyer and Steingold, 1980; Poklis and Whyatt, 1980; Showalter, 1980). Although the number of experimental reports

0376~8716/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

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regarding the behavioral pharmacology of the HI antagonists has increased in recent years, they have not completely illuminated which Hi antagonists would be self-administered under typical laboratory conditions nor why the Hi antagonists are abused in combination with other drugs. Bergman and Spealman (1986) have demonstrated that squirrel monkeys with cocaine self-administration histories would also self-administer tripelennamine and diphenhydramine. In their study the Hi antagonists were delivered under second-order 50-min schedules in which only a maximum of two drug deliveries occurred during each session. Diphenhydramine and pyrilamine have also been reported to be self-administered by rhesus monkeys (Johanson and Balster, 1978). Additionally, in an abstract, other researchers reported the self-administration of tripelennamine by rhesus monkeys (Krohn et al., 1982). The purpose of the present study was to evaluate several H1 antagonists to determine whether they would be self-administered by rhesus monkeys under conditions in which most known drugs of abuse have been shown to be self-administered (Johanson and Balster, 1978). The drugs hydroxyzine, phenyltoloxamine, pyrilamine and tripelennamine, and chlorpheniramine representing piperazine, ethanamine, ethylenediamine and alkylamine H1 antagonists, respectively, were tested in rhesus with cocaine monkeys self-administration histories to determine whether they also would be self-administered. In addition, the Hz antagonist, cimetidine, was also tested as a negative control. Methods Self-administration

Eight

procedure

adult male rhesus monkeys (Macaca mulatta) weighing between 6.7 and 10.5 kg were used. The monkeys had previous i.v. drug selfadministration experience. They were housed for the duration of the experiment inside their experimental cubicles (1.0 m3) where water was continuously available. The animals were fed Purina Monkey Chow (at least 20 g/kg body wt.)

and a chewable multiple vitamin tablet each day following the experimental session. Two response levers were mounted 30 cm above the floor on the transparent door at the front of each experimental cubicle. Three 2.8-W jewelled stimulus lights (a red light between two white lights) were located above each lever. Peristaltic infusion pumps (MasterFlex, ColeParmer Co., Chicago, IL) delivered lo-s, l.O-ml infusions through i.v. catheters. The catheters travelled from the pumps through the back of the cubicles and into protective spring arms which were attached at one end to the rear of the cubicle and at the other end to a stainless steel restraint harness fitted to the monkey (Deneau et al., 1969). Swivel joints allowed the monkeys nearly complete mobility within the cubicles. The activation of stimulus lights and infusion pumps and the recording of response lever depressions were accomplished by computer-based equipment located in an adjacent room. The monkeys were surgically prepared with silicone i.v. catheters (0.08 cm i.d.; Ronsil Rubber Products, Belle Mead, NJ) under PCP (1.0 mg/kg, i.m.)/pentobarbital (10 - 20 mg/kg, i.v.) anesthesia. The internal and external jugular veins and the femoral veins could be catheterized. Catheters were routed subcutaneously from the catheterized vein and exited in the midscapular area. If a catheter became defective during the experiment, it was removed and a new one was inserted into another vein after a minimum 14-day recovery period. The protocol was then resumed. The monkeys were tested during daily, l-h experimental sessions. The white stimulus lights were lit above the left lever at the beginning of each session. During the 10-s infusions, the white lights were turned off and the red stimulus light was illuminated. Animals obtained infusions by pressing the left lever according to a fixed-ratio (FR)-10 schedule; that is, infusions occurred for every 10 left-lever presses. Responses during infusions were recorded but did not count toward completion of the FR requirement. Responses on the right lever did not have scheduled contingencies, but were recorded.

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Initially, all monkeys were trained to respond for 33 pg/kg per infusion cocaine until three consecutive sessions occurred in which there were no increasing or decreasing trends in the number of cocaine infusions. Next, the monkeys entered substitution tests. Each substitution test lasted four consecutive sessions and was followed and preceded by a cocaine baseline condition. Each baseline condition lasted until three consecutive sessions occurred during which there were no increasing or decreasing trends in the number of infusions; this insured that substitutions were all made from stable baselines. The H1 antagonists hydroxyzine, phenyltoloxamine, pyrilamine, tripelennamine and chlorpheniramine and the Hz antagonist, cimetidine, were evaluated during substitution tests. Doses of 3, 10, 30, 100 and 300 pg/kg per infusion were tested of each drug in a random order. Two to four monkeys were tested with each compound. The number of monkeys used to evaluate each compound was, in part, determined by subject availability and by the number of animals perceived to be needed to come to conclusions about an individual drug’s effect. Substitution tests with saline vehicle, each lasting four consecutive sessions, were included with evaluations of each drug. Data analysis

The number of infusions over the last three sessions of each antihistamine and saline associated substitution condition were used in the data analysis. The data from the last three sessions of all cocaine and saline baseline conditions within tests with a particular antihistamine were used in summarized data. A test dose of an antihistamine was considered to be a positive reinforcer if the mean number of infusions exceeded the mean number of saline infusions obtained during tests with a particular drug and their ranges did not overlap. Drugs

Chlorpheniramine maleate, pyrilamine maleate, hydroxyzine dihydrochloride and phenyltoloxamine citrate were all obtained from the Sigma Chemical Co. (St. Louis, MO). Tripelennamine HCl was obtained from N.I.A.D.D.K.

(Bethesda, MD). Cimetidine HCl was obtained through the Committee on Problems of Drug Dependence which received it as a gift from the Smith Kline & French Laboratories (Philadelphia, PA). Cocaine HCl was obtained from N.I.D.A. (Rockville, MD). All drugs were solubilized in 0.9% sterile saline and doses are expressed in terms of the salts. Results The Hi antagonists, tripelennamine and chlorpheniramine, maintained self-administration by all monkeys tested. Two of the H1 antagonists, hydroxyzine and phenyltoloxamine, and the Hz antagonist, cimetidine, were not self-administered at any dose by the monkeys. One monkey self-administered one dose of pyrilamine; the other three monkeys tested with pyrilamine failed to self-administer any dose. Tripelennamine was self-administered above vehicle control rates in all three monkeys tested (Fig. 1). At least three doses, spanning a lo-fold range, maintained high infusion rates in all subjects. At some tripelennamine doses for monkeys M840 and M319 mean infusions obtained exceeded those of the baseline drug, cocaine. Generally, for all monkeys, numbers of tripelennamine infusions first increased and then decreased with dose. Never was there a progressive decrease in the number of infusions obtained across the 4 days of substitution at any dose that was self-administered of tripelennamine (data not shown). Additionally, in seven of 12 instances in which a tripelennamine dose was self-administered, more infusions occurred on the last day than on the first day of substitution. These latter results suggest that when a dose of tripelennamine was self-administered, there was no evidence that responding was extinguishing across the 4 days of substitution. Tripelennamine intake (mg/kg per h), on the other hand, generally increased with increases in dose with maximal intakes ranging from 3.1 (M840) to 4.5 (M432) mg/kg per h (Fig. 1). At the highest doses, when the greatest intake of tripelennamine occurred, overt behavioral effects were observed in some monkeys which included ocular-motor hyperactivity, various

cs 3 1030100300 TRIPELENNAMINE

3 IO30100300 ( pg/kg/inf)

Fig. 1. Left panel: The mean number of cocaine (C), saline (S), and tripelennamine infusions obtained during the last three sessions of each condition for each monkey tested. Cocaine data points represent the mean of the last three sessions of all cocaine baseline conditions. Saline data points represent the mean of the last three sessions of the first (0) and second (0) saline substitution condition. Vertical lines through the saline and tripelennamine data points represent the range. Vertical lines through the cocaine data points represent the S.D. Right panel: Mean total intake (mgkg) of tripelennamine obtained per l-h session during the last three sessions of each substitution condition for each monkey. Vertical lines through the data points represent the range.

stereotypes and a general agitated demeanor. These effects were not unlike those seen following the self-administration of psychomotor stimulants such as amphetamine observed in other studies in the laboratory. At least one dose of chlorpheniramine was self-administered above vehicle control rates in each monkey tested, and in two of the four subjects ehlorpheniramine maintained rates comparable to, or exceeding those maintained by cocaine (Fig. 2). Never was there a progressive decrease in infusions across the 4 days of

+ : J-L

cs 3 1030 100 300 CHLORPHENIRAMINE

3 IO 30

100

300

(pg/kg/inf)

Fig.2. Left panel: The mean number of cocaine (C), saline (S), and chlorpheniramine infusions obtained during the last three sessions of each condition for each monkey tested. Cocaine data points represent the mean of the last three sessions of all cocaine baseline conditions. Saline data points represent the mean of the last three sessions of the first (0) and second (0) saline substitution condition. Vertical lines through the saline and chlorpheniramine data points represent the range. Vertical lines through the cocaine data points represent the S.D. Right panel: Mean total intake (mg/kg) of chlorpheniramine obtained per l-h session during the last three sessions of each substitution condition for each monkey. Vertical lines through the data points represent the range.

substitution at any dose of chlorpheniramine tested, further suggesting responding was being maintained and not extinguishing at doses selfadministered (data not shown). Chlorpheniramine intake generally increased with increases in dose (Fig. 2). Monkey M319 self-infused the greatest intake of chlorpheniramine of the

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monkeys and at 300 pg/kg he was obtaining on average 9.7 mglkg per h. At none of the doses of phenyltoloxamine, nor of the Hz antagonist, cimetidine, did the number of obtained infusions for any monkey exceed the range of saline infusions (Figs. 3 and 4). These results suggest that these drugs failed to serve as a positive reinforcer for the monkeys under current testing conditions. None of the doses of hydroxyzine were selfadministered above saline control rates by monkeys M840 and M432 (Fig. 5). Monkey M314, however, did obtain more infusions of hy-

I ii L w I

cs

, 3 1030100300 CIMETIDINE

3 IO 30 100 300

( pg/kg

/inf)

Fig. 4.

Left panel: The mean number of cocaine (C), saline (S), and cimetidine infusions obtained during the last three sessions of each condition for each monkey tested. Cocaine data points represent the mean of the last three sessions of all cocaine baseline conditions. Saline data points represent the mean of the last three sessions of the first (0) and second (0) saline substitution condition. Vertical lines through the saline and cimetidine data points represent the range. Vertical lines through the cocaine data points represent the standard deviation. Right panel: Mean total intake (mg/kg) of cimetidine obtained per l-h session during the last three sessions of each substitution condition for each monkey. Vertical lines through the data points represent the range.

cs

3

1030100300

PHENYLTOLOXAMINE

Fig. 3.

3

IO 30

100 300

(pg/kg/inf)

Left panel: The mean number of cocaine (C), saline (S), and phenyltoloxamine infusions obtained during the last three sessions of each condition for each monkey tested. Cocaine data points represent the mean of the last three sessions of all cocaine baseline conditions. Saline data points represent the mean of the last three sessions of the first (0) and second (0) saline substitution condition. Vertical lines through the saline and phenyltoloxamine data points represent the range. Vertical lines through the cocaine data points represent the SD. Right panel: Mean total intake (mg/kg) of phenyltoloxamine obtained per l-h session during the last three sessions of each substitution condition for each monkey. Vertical lines through the data points represent the range.

droxyzine at 3 pg/kg than saline. Mean hydroxyzine intake, however, was very low at this dose (0.72 mg/kg per h) and was lower than what M314 had obtained at 30, 100 and 300 pg (Fig. 5). The lack of self-administration of hydroxyzine by M314 at doses greater than 3 pglkg was not due to response-rate suppressing effects from preventing infusion number to exceed those of saline. For example, M314 was capable of infusing rates of hydroxyzine as high as 1.3 mglkg per h, which he had obtained at the 300 pglkg dose. If M314 would have obtained this level of intake at lower doses of hydroxyzine, the number of infusions resulting in this intake would have exceeded those of saline. Consequently, it is unlikely that response-rate suppressing effects of hydroxyzine, if present at all, prevented demonstration of positive

cs

3 1030100300 HYDROXYZINE

3 IO 30 100 300 (pg/kg/infl

Fig. 5. Left panel: The mean number of cocaine (C), saline (S), and hydroxyzine infusions obtained during the last three sessions of each condition for each monkey tested. Cocaine data points represent the mean of the last three sessions of all cocaine baseline conditions. Saline data points represent the mean of the last three sessions of the first (0) and second (0) saline substitution condition. Vertical lines through the saline and hydroxyzine data points represent the range. Vertical lines through the cocaine data points represent the standard deviation. Right panel: Mean total intake (mglkg) of hydroxyzine obtained per l-h session during the last three sessions of each substitution condition for each monkey. Vertical lines through the data points represent the range.

reinforcing effects at doses between 3 and 300 fig/kg. Overall, these data suggest that hydroxyzine did not serve as a positive reinforcer for M314 or for the other monkeys. Pyrilamine did not serve as a reinforcer ror three of the four monkeys tested (Fig. 6). Numbers of pyrilamine infusions never exceeded the range of saline control infusions for monkeys M306, M315, and M420 at any dose tested. Monkey M431, however, self-administered more infusions of pyrilamine at 300 pglkg

cs

3

1030100300 PYRILAMINE

3 IO 30 100 300 (pg/kg/mf)

Fig. 6. Left panel: The mean number of cocaine (C), saline (S), and pyrilamine infusions obtained during the last three sessions of each condition for each monkey tested. Cocaine data points represent the mean of the last three sessions of all cocaine baseline conditions. Saline data points represent the mean of the last three sessions of the first (0) and second (0) saline substitution condition. Vertical lines through the saline and pyrilamine data points represent the range. Vertical lines through the cocaine data points represent the standard deviation. Right panel: Mean total intake (mg/kg) of pyrilamine obtained per l-h session during the last three sessions of each substitution condition for each monkey. Vertical lines through the data points represent the range.

than saline control, but did so only at this dose. At this dose, M431’s intake of pyrilamine was greatest and averaged 4.7 mg/kg per h. Overall, in only one instance (i.e. M431 at 300 pg/kg) out of 20 tests (five doses x four monkeys tested) did pyrilamine infusions exceed those of saline.

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Discussion The Hi antagonists, tripelennamine and chlorpheniramine, were self-administered by all monkeys, however, hydroxyzine, phenyltoloxamine and pyrilamine and the Hz antagonist, cimetidine, were not. The demonstration of the self-administration of tripelennamine in the present study confirms other reports of its selfadministration by laboratory animals when tested under other conditions (Bergman and Spealman, 1986; Krohn et al., 1982) and is consistent with its occasional reported abuse by humans (O’Driscoli and Lindley, 1957). The lack of self-administration of cimetidine by the rhesus monkeys in the present study is also consistent with its lack of self-administration reported in squirrel monkeys (Bergman and Spealman, 1986). Pyrilamine was self-administered above saline control rates at only one dose (300 pglkg) by only one of the four monkeys tested (M431). The lack of self-administration of pyrilamine in the other three monkeys tested suggests that this drug was not a robust positive reinforcer across subjects. It was reported that rhesus monkeys self-administered pyrilamine during tests conducted by Johanson and Kotzin (reported in Johanson and Balster, 1978). This report, however, was contained in a general review of self-administration studies, and details of the conditions of the Johanson and Kotzin study, including doses tested, were unpublished, making it difficult to compare the results of the present study to theirs. Only at one dose (3 pg/kg) for only one (M314) of the three monkeys tested did the number of hydroxyzine infusions exceed those of saline control. Because the overall intake of hydroxyzine at this dose was so low, often lower than that occurring at the other doses tested, it is doubtful that hydroxyzine was serving as an effective positive reinforcer at this dose for monkey M314. In light of the observation that neither of the other two monkeys tested with hydroxyzine self-administered the drug above saline-control rates at any dose tested, it can be concluded that hydroxyzine was not a positive

reinforcer for the monkeys under these experimental conditions. The CNS effects of tripelennamine and chlorpheniramine that support their self-administration are not completely understood; however, they clearly are not common to all Hi antagonists. Presumably the Hi antagonists hydroxyzine, phenyltoloxamine and pyrilamine, and the Hz antagonist, cimetidine, which were not consistently self-administered, were either devoid of these intrinsic properties, possessed the properties to a lesser extent, or had other effects which prevented their self-administration. Although sedation is often an effect attributed to the Hi antagonists, stimulation is also occasionally reported (Douglas, 1985). Studies in laboratory animals have shown that some Hi antagonists, including tripelennamine and chlorpheniramine but not generally cimetidine, can increase rates of schedule-maintained behavior not unlike the effects of psychomotor stimulants (Bergman, 1990; Bergman and Spealman, 1986; Bergman and Spealman, 1988; McKearney, 1982; McKearney, 1985; Rastogi and McMillan, 1984). Increasing rates of schedule-maintained behavior, however, is not a specific effect of psychomotor stimulants. Drugs from other classes can also increase schedule-maintained performance which can depend upon ongoing baseline rates (Kelleher and Morse, 1968). A procedure which generates data more specifically pertaining to stimulant-like subjective effects, and, hence, to their abuse liability, is the drug discrimination procedure. The discriminative stimulus properties of drugs have been considered an animal model of their subjective effects in humans (Schuster et al., 1981) and the subjective effects of a drug are a predictor of their abuse liability (Jasinski, 1977). Previous reports suggest that the discriminative stimulus effects of those Hi antagonists self-administered in the present study are similar to each other, and also to psychomotor stimulants, but are different from those Hi antagonists which were not self-administered. In pigeons trained to discriminate 2.0 mg/kg d-amphetamine from vehicle several antihistamines were evaluated

124

for their ability to produce d-amphetamine-like effects (Evans and Johanson, 1987; Evans and Johanson, 1989). Hydroxyzine and cimetidine failed to substitute for the d-amphetamine stimulus. Tripelennamine and chlorpheniramine, however, produced d-amphetamine-like stimulus properties in all pigeons tested. Pyrilamine generated intermediate results in that two of three pigeons tested responded on the d-amphetamine lever at least 80% of the time at least at one dose. Evans and Johanson (1989) also evaluated several Hi antagonists in rhesus monkeys trained to discriminate administrations of d-amphetamine from saline. Similar to their pigeon studies, tripelennamine, but not hydroxyzine, completely generalized from the amphetamine stimulus (Evans and Johanson, 1989). Unlike the results obtained with pigeons, however, chlorpheniramine did not produce d-amphetamine-like discriminative stimulus effects up to 30 mg/kg. Pyrilamine also failed to substitute for d-amphetamine in these amphetamine-trained monkeys. Other studies have examined the relationship of the discriminative stimulus properties of Hi antagonists with those of the psychomotor stimulants. Both tripelennamine and chlorpheniramine have been shown to substitute for cocaine in cocaine-trained rats (Slifer, 1988; Winters and Slifer, 1988) and cocaine-trained pigeons (Zacny, 1990), and d-amphetamine was shown to substitute for tripelennamine in tripelennamine-trained rats @lifer, 1988). Different results were obtained by Karas and colleagues where d-amphetamine failed to substitute in tripelennamine-trained pigeons (Karas et al., 1985). Studies with other training drugs have shown that tripelennamine and chlorpheniramine do not substitute for the discriminative stimulus effects of morphine (Oliveto et al., 1988; Shannon and Su, 1982; Shook et al., 1984) or pentobarbital (Evans and Johanson, 1989), nor does tripelennamine substitute for midazolam (Evans and Johanson, 1989; Spealman, 1985) or phencyclidine (Gore and Slifer, 1988). Overall, the results obtained from drug discrimination studies generally suggest a positive correlation exists between those

Hi antagonists substituting for the discriminative stimulus effects of psychomotor stimulants, such as cocaine and d-amphetamine, and those which are self-administered in the present study. The observation of this correlation between the discriminative stimulus and the reinforcing effects of these Hi antagonists is consistent with the hypothesis by Bergman and colleagues who have argued that the biochemical events mediating the stimulant-like activity of the Hi antagonists are not likely due to Hi receptor blockade, but more likely mediated through the inhibition of dopamine uptake, as, in part, are the classical psychomotor stimulants such as cocaine (e.g. Bergman, 1990; Bergman and Spealman, 1988). The evidence that tripelennamine and chlorpheniramine can serve as positive reinforcers and produce d-amphetamine-like and cocainelike discriminative stimulus effects in laboratory animals might suggest that these drugs would have psychomotor stimulant-like potential for abuse. These properties, as evidenced in animal studies, might help explain the occasional episodes of abuse of these drugs. Nonetheless, there is little evidence that antihistamines produce stimulant-like effects in humans, beyond the occasional reports of idiosyncratic stimulation (Douglas, 1985). In a direct study of the reinforcing and subjective effects of tripelennamine in normal human subjects, Stern and colleagues did not find evidence for stimulant-like abuse liability (Stern et al., 1989). Subjects were given the opportunity to choose color-coded capsules containing tripelennamine or placebo. The low dose of tripelennamine (25 mg) was chosen no more than placebo and the high dose (50 mg) less than placebo. Thus, under procedures where d-amphetamine and other sympathomimetic stimulants exhibit reinforcing effects (Chait et al., 1987; Johanson and Uhlenhuth, 1980), tripelennamine failed to function as a reinforcer at the two, orally-delivered doses tested. Stern and colleagues (Stern et al., 1989) also measured the subjective changes in mood produced by tripelennamine in their normal subjects, and found primarily sedative-like effects. In a study of the subjective effects of tripelennamine in

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opiate abusers, Lange and Jasinski (1986) found little effect at 50 mg, but reported subjective effects similar to those produced by the mixed agonist-antagonist opioid, pentazocine, at 100 mg. These researchers also found that their subjects sometimes identified tripelennamine as ‘dope’ (Lange and Jasinski, 1986). Thus, there are differences in the conclusions to be drawn from animal studies, where tripelennamine, and perhaps chlorpheniramine as well, have reinforcing effects which may be stimulant like, and from human studies, where reinforcing effects are less clear and would not appear to be stimulant-like. A more systematic comparison of the behavioral pharmacology of a number of HI antagonists in both animal and human species will be needed to fully determine the basis for these possibly discrepant results. Acknowledgements

This research was supported by National Institute on Drug Abuse Grant DA-00490 and contract No. 271-85-8101. The technical assistance of Robert D. Groseclose is greatly acknowledged. References Bergman, J. (1990) Psychomotor stimulant effects of the stereoisomers of chlorpheniramine. Psychopharmacology 100, 132- 134. Bergman, J. and Spealman, R.D. (1986) Some behavioral effects of histamine H, antagonists in squirrel monkeys. J. Pharmacol. Exp. Ther. 239, 104- 110. Bergman, J. and Spealman, R.D. (1988) Behavioral effects of histamine Hi antagonists: Comparison with other drugs and modification by haloperidol. J. Pharmacol. Exp. Ther. 245, 471-478. Burton, J.F., Zawadzki, E.S., Wetherell, R. and Moy, T.W. (1965) Mainliners and blue velvet. J. Forensic Sci. 10, 466 - 472. Butch, A.J., Yokel, R.A., Sigell, L.T., Hanenson, I.B. and Nelson, E.D. (1979) Abuse and pulmonary complications of injecting pentazocine and tripelennamine tablets. Clin. Toxicol. 14, 301-306. Chait, L.D., Uhlenhuth, E.H. and Johanson, C.E. (1987) Reinforcing and subjective effects of several anorectics in normal human volunteers. J. Pharm. Exp. Ther. 242, 777 - 783. Deneau, G., Yanagita, T. and Seevers, M.H. (1969) Self-

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