Download - Effects of concurrent saccharin availability and buprenorphine pretreatment on demand for smoked cocaine base in rhesus monkeys

Psychopharmacotogy (1994) 115:15-23 Psychopharmacology © Springer-Verlag 1994

Effects of concurrent saccharin availability and buprenorphine pretreatment on demand for smoked cocaine base in rhesus monkeys Sandra D. Comer, Vincent R. Hunt, Marilyn E. Carroll Department of Psychiatry, University of Minnesota, Medical School, Box 392 UMHC, Minneapolis, MN 55455, USA

Received: 31 July 1993 / Final version: 15 December 1993

Abstract. The effects of saccharin and the opioid partial agonist buprenorphine on cocaine base smoking were evaluated in five male rhesus monkeys. Monkeys completed a sequence of responding consisting of lever-press responses maintained under a fixed-ratio (FR) schedule followed by inhalation responses (FR5) on a smoking spout to gain access to a single delivery of volatilized cocaine base (1.0 mg/kg per delivery). Monkeys could receive a maximum of ten smoke deliveries per session. In the first experiment, either saccharin (0.03% wt/vol) or water was concurrently available under an FR1 schedule through a lip-operated drinking device. As lever FR values increased from 128 to 256, 512, 1024 and 2048, the number of cocaine smoke deliveries decreased. Cocaine intake was not statistically different when water versus saccharin was concurrently available. However, as cocaine consumption decreased, saccharin intake increased demonstrating that under these conditions, saccharin was substituting for cocaine as a reinforcer. On the first day that lidocaine replaced cocaine, all of the monkeys received the maximum number of smoke deliveries (ten) and saccharin intake increased. Lever-press responding gradually extinguished over days when lidocaine (1.0 rag/ kg per delivery) was available with concurrent saccharin. In the second experiment, water was concurrently available with cocaine and buprenorphine (0.01 or 0.1 mg/kg) was administered intramuscularly (IM) 30 min before the start of the session. Although pretreatment with the lower dose of buprenorphine (0.01 mg/kg) had little effect on cocaine intake overall, individual differences in cocaine intake occurred. The higher dose of buprenorphine (0.1 mg/kg) decreased the amount of cocaine consumed at all lever FR values tested.

Key words: Behavioral economics - Buprenorphine - Co- caine base -~ Crack - Demand Drug self-administration - Elasticity Lidocaine - Rhesus monkeys - Saccharin - Smoking - Unit price

Correspondence to: S. D. Comer

Drugs that are readily self-administered by laboratory" animals are also abused by humans, suggesting that the drug self-administration paradigm in laboratory animals is useful for investigating variables that may be important in human drug-taking behaviors (Brady et al. 1987; Katz 1990). Several methods, both behavioral and phar- macological, have been effective in reducing the self-administration of drugs in the laboratory setting (Carroll 1985; Bergman et al. 1990; Carroll et al. 1992; Winger et al. 1992). However, in contrast to traditional self-administration paradigms in laboratory animals, drug self-administration in humans is typically controlled by the complex interaction of a number of variables such as changes in the cost and supply of drugs, and the presence of alternative, competing nondrug reinforcers.

Recently, a model has been proposed that attempts to evaluate drug-taking behaviors from an economic point of view (Hursh 1980, 1991; Hursh and Bauman 1987; Bickel et al. 1990, 1991). A reanalysis of ten animal drug self-administration studies (Bickel et al. 1990) showed that the consumption of a wide variety of drugs in a number of different species is subject to an interaction between two functionally equivalent variables: response requirement and amount of drug per administration. Unit price (responses/rag), defined as response requirement divided by reinforcer magnitude, is used to analyze the amount of drug consumed. As unit price increases, consumption of drug decreases according to a positively decelerating function, using traditional drug self-administration procedures (Bickel et al. 1990). When consumption is plotted as a function of unit price, a demand curve is generated.

Elasticity of demand describes the interaction between price and consumption. It is a measure of the rate of change in consumption with changes in unit price and is quantitatively indicated by the slope of the demand curve measured in log-log coordinates. Over a given range of unit prices, a demand curve with a slope between - 1 and 0 is considered to be inelastic, while a demand curve with a slope less than - 1 is elastic. Demand for a commodity that is in some way very important to the organism, such

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as food, is typically inelastic or relatively resistant to change (e,g. Hursh and Bauman 1987; Foltin 1991). On the other hand, demand for a commodi ty that is a luxury, such as entertainment, is typically elastic.

Another important concept in behavioral economics is substitution (Green and Freed 1993). Under some conditions, when the unit price for one reinforcer increases, and consumption decreases for that reinforcer, consumption of a second, fixed-price alternative reinforcer may increase. In contrast to substitution is complementari ty: when unit price for one commodi ty increases, and consumption decreases for that commodity, consumption of a second commodi ty may also decrease. Finally, the interaction between reinforcers may be independent, where unit price affects the consumption of one commodi ty but not the fixed-price alternative. These concepts of reinforcer interactions are relevant for drug-taking behaviors because in designing methods to decrease drug intake, the availability of nondrug alternative reinforcers that function as substitutes may be critical for sustained absti- nence.

Studies designed to evaluate the effects of nondrug, alternative reinforcers on drug-taking behavior in laboratory animals demonstrated that the consumption of drug decreased in the presence of an alternative reinforcer (Carroll t985; Carroll et al. 1991; Carroll and Lac 1993; Carroll and Rodefer 1993). For example, in rhesus monkeys, oral consumption of PCP decreased when a saccharin solution was concurrently available (Carroll 1985; Carroll et al. 1991). In addition, acquisition of intravenous cocaine self-administration was delayed when a glucose and saccharin solution was concurrently available (Carroll and Lac 1993). Labora to ry animals also typically consumed less drug when they were food satiat- ed, relative to consumption of drug in animals that were food deprived (Carroll et al. 1981; Carroll and Boe 1982, t984; Carroll and Meisch 1984). Thus, the presence of alternative nondrug reinforcers clearly affects drug-taking behaviors.

Several investigators also showed that pretreatment with various compounds reduced drug self-administration in laboratory animals. In particular, the low-efficacy, ~ t -op io id agonist buprenorphine (Cowan et at. 1977a, b) was effective in reducing both opioid and cocaine self-administration in laboratory animals (Mello et al. 1983, 1989, 1990, 1993; Carroll and Lac 1992; Carroll et al. 1992; Winger et al. 1992) and is currently being assessed as an alternative form of therapy in opioid and cocaine dependent humans (Kosten et al. 1989a, b, 1992; Mendel- son et al. 1991; Gastfriend et al. 1992). Buprenorphine (0.1 3.2 mg/kg IV or 0.003~0.8 mg/kg IM) suppressed IV cocaine self-administration in rats (Carroll and Lac 1992) and smoked (Carroll et al. 1992) and IV (Mello et al. 1989, 1990, 1991; Winger et al. ]992) cocaine self-administration in rhesus monkeys, at doses that produced little or no effect on food-maintained responding. The effects of intermittent buprenorphine administration on IV cocaine self-administration was also evaluated in rhesus monkeys (Mello et al. 1993). While both intermittent and continuous administration of buprenorphine suppressed cocaine self-administration, continuous treatment with

buprenorphine was more effective than intermittent treatment. Thus, under a range of doses and treatment conditions, in a number of species, buprenorphine suppressed cocaine self-administration. However, the magnitude and duration of buprenorphine 's suppression of cocaine self-administration varied widely across studies. One variable that may account for differences in buprenorphine 's effect is response requirement or cost of drug. The purposes of these experiments were to (1) evaluate the effects of an alternative non-drug reinforcer (a saccharin solution) on the demand for cocaine base smoking in rhesus monkeys and (2) determine whether pretreatment with the partial g - opioid agonist buprenorphine will modify demand for cocaine base smoking when lever F R values are progressively increased.

Materials and methods

Subjects

Five adult male rhesus monkeys (Macaca mulatta) weighing between 9.4 and 15.0 kg were studied in daily experimental sessions. Two of the monkeys (M-S and M-L) self-administered cocaine intravenously in another laboratory. Two monkeys (M-O and M-L) self-administered orally-delivered phencyclidine in another experiment in this laboratory. The two remaining monkeys (M-LR and M-W) were drug naive. Subjects M-L, M-O and M-S had been previously tested with 0.003-0.8 mg/kg buprenorphine IM (Carroll et al. 1992). At the beginning of data collection, subjects M-O, M-S, M-L, M-LR and M-W had been self-administering smoked cocaine base for 57, 44, 43, 4 and 4 months, respectively.

Monkeys were individually housed in their experimental chambers in a humidity- and temperature-controlled (23,3 °C) room (lights on at 6:00 a.m. and off at 6:00 p.m.). They were given free access to water between 12:30 p.m. and 7:30 a.m. every day and either saccharin (0,03% wt/vol) or water was available from a lip- operated drinking device under an FR1 schedule during the experimental session between 8:30 a.m. and 12:30 p.m. No water was available between 7:30 and 8:30 a.m., during which time data from the previous day were collected, water consumption from the previous day was measured, and either water or saccharin was prepared for the experimental session. Between 175 and 250 g Purina high protein monkey chow was given at 12:40 p.m. each day, at the end of the experimental session. Fresh fruit was given later in the after- noon every day. Monkeys were weighed every 2 weeks and, if neces- sary, their daily food allotment was increased or decreased in order to maintain their body weights at approximately 85% of free-feeding weights. This level of food deprivation was used because the potential for excessive weight gain and related health problems that can occur in free-feeding caged animals are minimized and the experimental data that are obtained are more stable when body weight is controlled. The experimental protocol was approved by the University of Minnesota Institutional Animal Care and Use Committee under protocol number 9302017,

Apparatus

Monkeys were housed in custom made stainless-steel chambers (Lab Products, Maywood, N.J.) consisting of a wire mesh floor and a work panel located on one side of the chamber (for a detailed description of the apparatus see Carroll et al. 1990). Vertical bars on the front of each chamber allowed free visual access to the other monkeys. Each panel was equipped with a smoking and a drinking spout mounted on clear Plexiglas plates located 31 cm apart, 48 cm

above the chamber floor. The smoking spout extended 2.5 cm into the experimental chamber and the drinking spout extended 1.75 cm into the chamber. A response lever was located equidistant between the spouts, 37.5 cm above the chamber floor. The drinking spout delivered approximately 0.55 ml of liquid, contingent upon a single lip contact with the spout. The smoking spout delivered cocaine base smoke, contingent upon a predefined sequence of responding on the lever and inhalations on the smoking spout.

Three jeweled stimulus lights were located on each work panel; one light was located directly above the response lever and the other two were located above the drinking and smoking spouts. A solid green light was constantly illuminated above the drinking spout. With each lip contact on the drinking spout, two white lights located behind the Plexiglas plate surrounding the spout were briefly illuminated, and a fixed amount of liquid was delivered. A flashing red light over the response lever signaled the lever-pressing contingency. When the predetermined number of lever presses was completed, the flashing red light turned off and a flashing green light above the smoking spout was illuminated, signaling the inhalation contingency. Monkeys were required to make five inhalations on the smoking spout to gain access to volatilized cocaine base. With each inhalation, measured by a vacuum sensor (Coventry Specialty Corp., Westfield, Mass., model 505-3), two white lights located behind the Plexiglas plate surrounding the spout were briefly illuminated. During the fifth inhalation, a cocaine or lidocaine base-coat- ed nichrome wire coil inserted partway into the smoking spout was heated, the cocaine was volatilized and the green flashing light was turned off.

Drugs

Cocaine or lidocaine base was dissolved in 95% ethanol (100.0 mg/ ml) and stored in an airtight flask. A precise amount of drug was dripped onto the wire coils which were allowed to air dry for at least 24 h before use. Coils were weighed both before and after drug was placed on them to ensure that the correct dose was placed on the wire. Saccharin was dissolved in tap water and stored in covered 2000 ml flasks. Every 3 or 4 days, a new solution was made and the old saccharin solution was discarded. Buprenorphine HC1 was dissolved in sterile water. Cocaine base and buprenorphine HC1 were provided by the National Institute on Drug Abuse (Research Trian- gle Institute, Research Triangle Park, N.C.). Lidocaine and reagent grade saccharin were purchased from Sigma (St Louis, Mo.). Ethanol (95%) was purchased from the University of Minnesota Chemical Storehouse.

Procedure

Monkeys were initially trained to make one inhalation on the smoking spout to receive 1.0 mg/kg per delivery cocaine base. When monkeys were reliably taking ten deliveries per experimental session, the number of inhalations required to receive each delivery of cocaine was gradually increased to five (fixed-ratio (FR) 5). The monkeys were then required to make responses on the lever to gain access to the smoking component of the schedule. A previous study showed that responding for cocaine base is rapidly established using this procedure and that blood levels of cocaine are similar to those obtained by humans smoking cocaine base (Carroll et al. 1990). Lidocaine, a local anesthetic with little or no reinforcing effects (Carroll et al. 1992), was substituted for cocaine to establish that cocaine was serving as a reinforcer and to evaluate the interaction between drug and saccharin intake.

Under training conditions, the lever response requirement was gradually increased by doubling the FR value from FR1 to 2, 4, 8, 16, 32, etc. Once monkeys were reliably responding under these procedures, a baseline demand curve was generated in which a range of FR values was tested. The range of FR values that allowed for determination of a complete demand curve was different for

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each monkey: FR16-128 was used for monkey M-L, FR64-512 was used for monkey M-S, FR64-1024 was used for monkeys M-LR and M-W, and FR64-2048 was used for monkey M-O. At the low end of the range of lever FR values, at least two FR values were used that maintained the maximum number of smoke deliveries (ten). A range of FR values allows for the calculation of unit price (responses/rag) which is used in the demand function. Demand is defined as consumption of drug (rag) as a function of unit price. When responses are plotted as a function of unit price, it is possible to determine the unit price at which maximum responding occurs (Pmax) according to an equation by Hursh (1991). This point is analogous to break point on a progressive-ratio schedule and is an indicator of the reinforcing efficacy of the self-administered sub- stance.

After each smoke delivery a 15-min time-out period was im- posed during which responding on either the lever or the smoking spout had no programmed consequences. Monkeys could still re- spond on the drinking spout to receive deliveries of either water or saccharin. At the end of the time-out period, the next trim was signaled by the flashing red light over the response lever. A maximum of ten smoke deliveries could be obtained during each experimental session, If a monkey failed to make the required number of lever and inhalation responses within 30 min during a trial, the lights were turned off and a second trial was begun immediately. If the monkey failed to make the required responses for two consecutive trials, the amount of water or saccharin consumed up to that time was measured and the experimental session ended. If a monkey received all ten smoke deliveries, the amount of water or saccharin consumed was measured after the tenth delivery.

Effects of saccharin on demand for smoked cocaine base. The number of cocaine smoke deliveries at each FR was measured for each monkey. The lever FR values for cocaine access in the presence of water were increased in an ascending manner. :Responding was maintained at each lever FR value until at least 5 consecutive days of stable smoke deliveries were obtained. The FR value was then increased and 5 days of stable smoke deliveries were again obtained. The FR values were increased until the mean of 5 days of smoke deliveries was less than 1. After the range of FR values was tested, a low FR value (one that resulted in the maximum number of smoke deliveries obtained per session) was repeated until 5 consecutive days of stable smoke deliveries were obtained. After the range of FR values was tested in the presence of water, saccharin (0.03% w/v) was made available and lever FR values were again increased as described previously. Stability was defined as no increasing or decreasing trend in the number of smoke deliveries over the 5-day period and no increasing or decreasing trend in the amount of water or saccharin consumed per session over the 5-day period.

When the range of FR values was tested in the presence of saccharin, lidocaine (1.0 mg/kg per delivery) was placed on the wire coils instead of cocaine and both saccharin consumption and the number of smoke deliveries was measured. Lidocaine was used instead of cocaine until responding extinguished. Different FR values were used for each monkey: M-S responded under an FR32 schedule, M-LR and M-W responded under an FR64 schedule, and M-O initially responded under an FR128 schedule. These FR values were chosen because they reliably maintained responding for the maximum number (ten) of cocaine smoke deliveries in the presence of saccharin. After 22 days, subject M-O was still responding for lidocaine so his FR value was increased from 128 to 256.

Effects of buprenorphine on demand for smoked cocaine base. After the experiment with saccharin and lidocaine was completed, water and cocaine base were again made available and the lever FR was decreased until monkeys were again reliably self-administering the maximum number (ten) of cocaine smoke deliveries per day. After 3 days of stable behavior were obtained at FR16 for M-L and FR64 for M-LR, M-S, M-O and M-W, buprenorphine (0.01 or 0.1 mg/kg) was administered IM 30 min prior to the start of the experimental session for 3 consecutive days. After buprenorphine treatment, when behavior again stabilized, the FR value was increased and 3

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days of stable behavior were again obtained. As before, buprenorphine was administered for 3 consecutive days. Thus, lever FR values were increased in an ascending manner and the number of smoke deliveries was measured both in the presence and absence of buprenorphine at each lever FR value.

Data analysis

The mean number of smoke deliveries and liquid consumption was based on data from either 3 or 5 consecutive days within each monkey and then averaged across monkeys. Cocaine intake (in rag) was calculated by multiplying the number of smoke deliveries obtained per day (1.0 mg/kg per smoke delivery) for each monkey by the average body weight across monkeys (11.5 kg). Unit price was determined by dividing each lever FR value by cocaine dose (1.0 mg/kg per smoke delivery) multiplied by the average body weight across monkeys (1t.5 kg). The slope of each demand curve was obtained by plotting consumption as a function of unit price on log-log coordinates. The slope between adjacent points (e.g. between FR128 and 256, 256 and 512, 512 and 1024, etc.) on each demand curve was calculated and then the mean of the individual slopes was obtained. The point to point method of calculating slopes was used because the demand curves contained mixed elas- ticities. A simple regression analysis produced similar slope values. Pmax, the unit price at which maximum responding occurred, was calculated with the use of Superanova (Version 1.11D for Macin- tosh) according to methods described by Hursh (1991). The slopes of the curves for saccharin and water were calculated by plotting fluid intake as a function of cocaine unit price on log-log coordinates and obtaining a simple regression coefficient• Slope values that are positive indicate substitution, whereas slopes that are neg- ative or close to zero indicate that the two commodities are comple- mentary or independent, respectively•

A repeated measures analysis of variance was used to evaluate the effects of treatment (saccharin versus water, buprenorphine pretreatment versus no pretreatment) and the mean number of smoke deliveries for different lever FR values• One-tailed, paired t-tests were used to determine whether the number of smoke deliveries differed in individual monkeys and for group means when saccharin versus water was concurrently available and when buprenorphine (0.01 or 0.1 mg/kg) was administered as a pretreatment compared to no pretreatment.

Results

Effects of saccharin on demand for smoked cocaine base

Figure 1 shows that when lever F R value was increased f rom FR128 to 1024, the number of cocaine smoke deliveries that was self-administered significantly decreased when either water or saccharin was concurrent ly available (F = 47.12, P < 0.05). Paired t-tests showed that the mean number of cocaine smoke deliveries at FR512 and 1024 were significantly different f rom FR128 when water was concurrent ly available (P < 0.05). The mean number of cocaine smoke deliveries at FR1024 was significantly different f rom F R I 2 8 when saccharin was concurrent ly available (P < 0.05). An analysis of g roup means showed that the number of smoke deliveries was not significantly different when saccharin as opposed to water was concurrent ly available. However, an analysis of da ta for individual monkeys showed that the number of smoke deliveries for two of the four monkeys tested was significantly reduced in the presence of saccharin at F R t 0 2 4 (P < 0.05, da ta no t shown).

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Fig. l. Mean number of cocaine smoke deliveries (_+_ SE) and water or saccharin intake ( ± SE) are presented as a function of lever FR value. The upper panel shows the mean number of cocaine smoke deliveries (closed circles) when water (open circles) was concurrently available. The lower panel shows the mean number of cocaine smoke deliveries (closed triangles) when saccharin (open triangles) was concurrently available. Each point represents the mean of 5 consecutive days of stable behavior for four monkeys (M-LR, M-W, M-O and M-S). Standard error bars were calculated for 5 consecutive days in individual monkeys and then averaged across monkeys. Crosses above data points indicate statistically significant differences from data points at FR128 (P < 0.05)

Water intake ranged f rom 68.95 (__ 10.64) to 99.15 (__ 19.14) ml and saccharin intake ranged from 231.25 (_+ 41.32) to 335.7 ( _ 37.36) ml dur ing the session (Fig. 1). As lever F R values increased and cocaine intake decreased, saccharin intake significantly (P < 0.05) increased at FR1024, compared to saccharin intake at FR128 (Fig. 1, lower panel). The slopes of the curves for water and saccharin intake plot ted as a function of cocaine unit price (data not shown) were 0.11 and 1.42, respectively. W h e n the lever F R value was decreased f rom 1024 to 32 (M-S), 64 ( M - L R and M-W) or 128 (M- O), the m a x i m u m number (ten) of cocaine smoke deliveries was again obta ined by each m o n k e y and saccharin intake decreased to a mean of 204.t (_+ 29.3), (data no t shown). In contras t to saccharin, water intake did not change in an orderly manner as lever F R value increased.

Figure 2 (upper panel) shows the da ta plot ted as cocaine intake (mg/day) as a funct ion of unit price (responses/mg). The slopes of the demand curves for cocaine in the presence of water ( - 0 . 7 2 ) or saccharin ( - 0 . 9 4 ) were not statistically different (see Table 1). The number of lever responses emit ted per day were also plot ted as a function of unit price (Fig. 2, b o t t o m panel). As unit price increased, responding first increased then decreased. The Pmax values (the unit price at which the m a x i m u m num-

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Fig. 2. Cocaine intake (mg/day, upper panel, circles) and lever press responses (lower panel, triangles) are plotted as a function of unit price (responses/mg) when either water (closed symbols) or saccharin (open symbols) was concurrently available. Vertical lines indicate Pmax values, the unit price at which the peak of responding occurs, when either water (solid lines) or saccharin (dashed lines) was concurrently available. Each point represents the mean of 5 consecutive days of stable behavior for four monkeys (M-LR, M-W, M-O and M-S). Standard error bars were calculated for 5 consecutive days in individual monkeys and then averaged across monkeys

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Fig. 3. Number of cocaine (filled circles) or lidocaine (open circles) smoke deliveries are plotted over days in individual monkeys when saccharin (filled triangles) was concurrently available. Monkey M-S responded under an FR32 schedule, M-LR and M-W responded under an FR64 schedule, and M-O responded under an FR128 schedule

ber of responses occurred) in the presence of saccharin or water are indicated by the dashed and solid vertical lines, respectively. The Pmax value for cocaine in the presence of water was 57.7 and for cocaine in the presence of saccharin was 48.2 (see Table 1). Thus, when saccharin was concurrently available, cocaine-maintained responding peaked at a lower unit price than when water was concurrently available. Cocaine intake was not significantly different in the presence of water versus saccharin.

Figure 3 shows the number of smoke deliveries consumed over days in individual monkeys when either cocaine (first 5 days) or lidocaine (remaining days) was available. Fixed ratio values for each monkey were chosen that maintained the maximum number of cocaine smoke deliveries. When lidocaine (1.0 mg/kg) was placed on the coils instead of cocaine, the number of smoke deliveries decreased over days for monkeys M-S, M-LR and M-W (see Fig. 3). One monkey, M-O, never com- pletely stopped responding at FR128 (Fig. 3), even after 22 days. When his lever FR value was increased to 256, he stopped responding for lidocaine within 1 week (data not shown). In subject M-O, FR256 reliably maintained responding for the maximum number of cocaine smoke deliveries. Saccharin intake increased an average of 217.3 (_+ 32.4)% on the first 5 days that lidocaine became available, relative to the last 5 days that cocaine was available (data not shown).

Effects of buprenorphine on demand for smoked cocaine base

The number of cocaine smoke deliveries as a function of lever FR value in the presence and absence of 0.01 mg/kg buprenorphine are shown for individual monkeys and as a mean for four monkeys (M-O, M-LR, M-W and M-S) in Fig. 4. Data from subject M-L were not included in the mean because his range of lever FR values did not over- lap the other monkeys' lever FR values. A pretreatment dose of 0.0t mg/kg buprenorphine significantly decreased the number of cocaine smoke deliveries for subject M-L at FR16, 32 and 128 (P < 0.05). Buprenorphine significantly reduced the number of cocaine smoke deliveries at FR512 for subjects M-O and M-LR and at FR256 for subject M-S (P < 0.05). In monkey M-W, buprenorphine pretreatment significantly increased the number of cocaine smoke deliveries self-administered at FR512 (P < 0.05). The effect of 0.01 mg/kg buprenorphine on cocaine base smoking at FR512 was replicated in monkey M-W to confirm that the results were not due to a nonspecific change in baseline over time. Thus 0.01 mg/kg buprenorphine had very different effects on cocaine self-administration in individual monkeys. How- ever, when the number of smoke deliveries was averaged across monkeys that were tested at similar FR values (M-LR, M-S, M-O and M-W), buprenorphine had no

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Fig. 4. Number of cocaine smoke deliveries (± SE) in either the presence (open circles) or absence (closed circles) of a pretreatment (30 min) dose of 0.01 mg/kg buprenorphine are presented as a function of lever FR value in individual monkeys• Symbols in the bottom right panel represent the mean of 3 consecutive days of stable behavior for three monkeys (M-LR, M-W, M-O and M-S). Standard error bars were calculated for 3 consecutive days in individual monkeys and then averaged across monkeys. In all other panels, each symbol represents the mean number of cocaine smoke deliveries (+_ SEM) for individual monkeys. *Above data points indicate a statistically significant decrease relative to cocaine alone at that point while **indicates a statistically significant increase relative to cocaine alone at that point (P < 0.05). Crosses adjacent to data points indicate statistically significant differences from data points at FR128 (P < 0.05)

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Fig. 5. Number of cocaine smoke deliveries (__ SE) in either the presence (open circles) or absence (closed circles) of a pretreatment (30 rain) dose of 0.1 mg/kg buprenorphine are presented as a function of lever FR value in individual monkeys. Symbols in the bottom right panel represent the mean of 3 consecutive days of stable behavior for three monkeys (M-LR, M-W and M-S). Standard error bars were calculated for 3 consecutive days in individual monkeys and then averaged across monkeys. In all other panels, each symbol represents the mean number of cocaine smoke deliveries (_+ SEM) for individual monkeys. *Above data points indicate a statisticMly significant decrease relative to cocaine alone at that point while **indicates a statistically significant increase relative to cocaine alone at that point (P < 0.05). Crosses adjacent to data points indicate statistically significant differences from data points at FR128 (P < 0.05)

statistically significant effects on cocaine self-administration. A significant decrease in cocaine smoke deliveries due to F R value did occur: the mean number of smoke deliveries at FR1024 was significantly different from FR64 in either the presence or absence of buprenorphine (P < O.05).

Figure 5 shows the number of smoke deliveries as a function of lever F R value in individual monkeys in both the presence and absence of the higher dose of buprenorphine (0.1 mg/kg IM). Subjects M - L R and M-S self-administered significantly fewer cocaine smoke deliveries at FR1024 and FR128 and 256 (P < 0.05), respectively, when they were pretreated with buprenorphine. The number of cocaine smoke deliveries self-administered by subject M-W was not suppressed by a pretreatment dose of 0.1 mg/kg buprenorphine. In fact, at FR512, the number of cocaine deliveries was increased significantly (P < 0.05) in subject M-W when buprenorphine was administered as a pretreatment. The mean number of cocaine smoke deliveries across the three monkeys was lower when 0.1 mg/kg buprenorphine was administered as a pretreatment. However, al though there were significant changes due to buprenorphine in individual monkeys, the mean did not achieve statistical significance (Fig. 5, lower right panel). A significant decrease in cocaine

smoke deliveries due to F R value did occur: the mean number of smoke deliveries FR1024 was significantly different from FR64 in either the presence or absence of buprenorphine (P < 0.05). The higher dose of buprenorphine was not tested in monkey M-L because the number of cocaine smoke deliveries self-administered by this monkey was already substantially suppressed by the lower pretreatment dose of buprenorphine. Subject M-O de- veloped an allergic reaction to the higher dose of buprenorphine, consisting of facial edema, body rash and pruritis starting 2-3 min after injection. This condition was reversed by an IM injection of dexamethasone (7 rag). Testing could not be completed using the higher buprenorphine dose in this monkey.

Figure 6 shows demand curves (upper panels) and responses per day (lower panels) as a function of unit price. The slopes of the demand curves for cocaine in the presence (----0.99) and absence ( -0 .94) of 0 .01mg/kg buprenorphine were not statistically different (see Table 1). The Pmax values for cocaine in the presence and absence of 0.01 mg/kg buprenorphine were 75.8 and 96.4, respectively (see Table 1). The slopes of the demand curves for cocaine in the presence ( -1 .06) and absence ( -0 .95) of 0.1 mg/kg buprenorphine were not statistically different (see Table 1). The Pmax values for cocaine in

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I I I I

. . . . . . . . i . . . . . . . . . . . . . . . . =

10 O0 1000

Unit Price (responses/mg)

I t I I

,, i I

i m

t I i

I

i i I

1

10

Unit Price

. . . . . . J ' , l

O0 1000

(responses/rng)

21

Fig. 6. Cocaine intake (mg/day, upper panels, circles) and lever-press responses (lower panels, triangles) are plotted as a function of unit price (responses/rag) in either the absence (closed symbols) or presence (open symbols) of a pretreatment dose of 0.01 (left panels) or 0.1 (right panels) mg/kg buprenorphine. Vertical lines indicate Pmax values in either the absence (solid lines) or presence (dashed lines) of buprenorphine. Each point represents the mean of 3 consecutive days of stable behavior for either three (right panels; M-LR, M-W and M-S) or four (left panels; M-LR, M-W, M-O and M-S) monkeys. Standard error bars were calculated for 3 consecutive days in individual monkeys and then averaged across monkeys.

Table 1. Slopes and Pmax values for demand curves

Condition Slope _ S.E. Pmax

w/Water 0.72 0.21 57.7 w/saccharin 0.94 0.28 48.2 Baseline -0.94 0.32 96.4 w/0.01 Bup -0.99 0.32 75.8 Baseline 0.95 0.40 75.0 w/0.1 Bup ...... 1.06 0.58 49.0

the presence and absence of 0.1 mg/kg buprenorphine were 49.0 and 75.0, respectively (see Table 1).

Discussion

Effects o f saccharin on demand .for smoked cocaine base

Both saccharin and cocaine functioned as reinforcers in this experiment since consumption of these substances was higher than consumption of either water or lidocaine, respectively. When saccharin was concurrently available, cocaine intake showed a small, but statistically insignificant decrease at high lever F R values, relative to cocaine intake when water was concurrently available (Fig. 2). Previous studies that showed that when saccharin was concurrently available, IV cocaine self-administration in rats (Carroll et al. 1989) and oral PCP consumption in rhesus monkeys was reduced (Carroll 1985; Carroll et al. 1991; Carroll and Rodefer 1993). In these earlier studies, saccharin had a much more robust effect on drug self-administration. In the present study, saccharin substituted for smoked cocaine as a reinforcer as indicated by the fact that saccharin consumption increased as cocaine consumption decreased with increases in lever F R value (Fig. 1, lower panel). While the positive slope

for saccharin intake plotted as a function of cocaine unit price indicated that saccharin and cocaine were substi- tutable reinforcers, the near-zero slope for water indicated that water and cocaine were independent commodities under these conditions. That saccharin consumption increased when lidocaine replaced cocaine was also consistent with the notion that saccharin was substituting for cocaine as a reinforcer (Fig. 3).

The fact that the slope of the demand curve for cocaine was between - 1 and 0 under most conditions indicated that the demand for smoked cocaine base was inelastic or one that was resistant to change (Hursh and Bauman 1987) Although saccharin substituted for cocaine as a reinforcer, it had little effect on Pmax and no effect on elasticity of demand. In contrast to these results, previous studies showed that when saccharin (0.03 % wt/ vol) was concurrently available, the elasticity of demand for oral PCP increased (Carroll et al. 1991; Carroll and Rodefer t993). The ability of saccharin to alter the demand for oral PCP may have been due to the fact that the demand for PCP alone was elastic (slope < - 1) under those conditions; whereas, in the current experiment the demand for smoked cocaine base was inelastic. Thus, although 0.03 % saccharin clearly increased the elasticity of demand for orally delivered PCP, it had no effect on the elasticity of demand for smoked cocaine base. Thus, although the presence of an alternative reinforcer may be a useful adjunct in treating dependence on substances such as PCP or on cocaine administered intravenously, it may have a much smaller effect on dependence on smoked cocaine base.

Effects o f buprenorphine on demand for smoked cocaine base

The lower pretreatment dose of buprenorphine (0.01 mg/ kg) produced significant decreases in cocaine base smok-

22

ing in the majority of monkeys (four of five tested, Fig.4). In one monkey, cocaine self-administration was increased in the presence of 0.01 g/kg buprenorphine. When the data were averaged across monkeys, this dose of buprenorphine did not alter either the demand or the number of responses for smoked cocaine base (Fig.6, left panels). A higher dose of buprenorphine (0.1 mg/kg) reduced cocaine intake at various FR values in two of three monkeys tested and, in contrast to the results with the lower dose of buprenorphine, 0.1 mg/kg buprenorphine produced a consistent decrease in both the demand for cocaine and the number of responses emitted per day at all of the unit prices tested. However, the elasticity of demand for cocaine was not changed by either dose of buprenorphine. One monkey again showed an increase in cocaine base smoking in the presence of the higher dose of buprenorphine. Furthermore, the higher dose of buprenorphine produced a pronounced allergic reaction in one monkey (subject M-O). These results emphasize the individual variability in the effects of buprenorphine on cocaine self-administration.

Although the results reported here with buprenorphine were generally consistent with other studies show- ing that buprenorphine decreases cocaine self-administration in laboratory animals (Mello et al. 1991 ; Carroll et al. 1992; Winger et al. 1992), the consistent increase in cocaine self-administration produced by a pretreatment dose of buprenorphine in one monkey should be noted. An increase in both drug and saccharin self-administration in individual subjects due to pretreatment with higher buprenorphine doses has been reported previously in this laboratory (Carroll et al. 1992). Similarly, in a previous study evaluating the interaction of buprenorphine and cocaine in a conditioned place preference paradigm in rats, buprenorphine enhanced the conditioned place preference produced by cocaine (Brown et al. 1991). Buprenorphine (0.0-0.9 mg/kg) itself also elicited conditioned place preference in an inverted U-shaped function. In addition, in the same study, extracellular dopamine concentrations in the nucleus accumbens of rats were increased more by the combination of cocaine and buprenorphine than by either drug alone (Brown et al. 1991).

A subsequent study showed that conditioned place preference was not elicited by buprenorphine and that buprenorphine decreased the conditioned place preference produced by cocaine (Kosten et al. 1991). However, the Kosten et al. (1991) study differed from the Brown et al. (1991) study in at least two important ways. First, only single doses of buprenorphine (0.5 mg/kg) and cocaine (15.0 mg/kg) were tested by Kosten et al. (1991). This dose of buprenorphine (0.5 mg/kg) also did not elicit conditioned place preference in the Brown et al. (1991) study since it was on the high-dose end of the inverted U- shaped dose-effect curve. Second, buprenorphine was administered chronically (15 days) by Kosten et al. (1991) and acutely by Brown et al. (1991). Thus, the effects of buprenorphine may be with different after acute treatment than after chronic treatment. Other investigators have also shown that in rhesus monkeys trained to self- administer cocaine intravenously, acute, intermittent treatment with buprenorphine was less effective than

chronic treatment in suppressing cocaine self-administration (Mello et al. 1993). Furthermore, a recent study of human cocaine abusers showed that buprenorphine was more effective in reducing cocaine use with higher buprenorphine doses and with longer time on buprenorphine (Schottenfeld et al. 1993). In the study described here, buprenorphine was administered for 3 consecutive days. Perhaps buprenorphine would have been more effective in suppressing cocaine base smoking if it had been administered for a longer period of time or if a higher pretreatment dose had been administered. Nevertheless, it is important to note that under some conditions, buprenorphine may actually increase the self-administration of smoked cocaine base.

The results with buprenorphine are an important ex- tension of previous work because they demonstrated that although buprenorphine produced a decrease in the overall intake of smoked cocaine base, it had little effect on the elasticity of demand for cocaine, indicating that the reinforcing efficacy of smoked cocaine was not changed by buprenorphine. Consistent with these results was the finding that buprenorphine did not increase rat- ings of cocaine-induced euphoria in humans dependent on both opioids and cocaine, although it was also effective in reducing cocaine use in that study (Schottenfeld et al. 1993). Thus, while these studies are consistent with the notion that buprenorphine does not decrease cocaine use by increasing the potency of cocaine's reinforcing effects, the exact mechanism by which buprenorphine does affect cocaine self-administration is not clear. Finally, the data reported here also indicated that, compared to orally-delivered PCP, the demand for smoked cocaine base was in general more resistant to both behavioral and pharmaco- logical treatment. The reduced effectiveness of both saccharin and buprenorphine on cocaine base smoking, relative to either IV cocaine (MeUo et al. 1990, 1991, 1993; Carroll and Lac 1992) or oral PCP (Carroll et al. 1992) self-administration, may be related to the fact that the demand for smoked cocaine base was inelastic and was therefore resistant to change under these conditions.

Acknowledgements. The authors would like to thank Dona Turner and Shelly Thompson for technical assistance with the experiments. This research was supported by National Institute on Drug Abuse Grants R01 DA07716 (Dr. Marilyn Carroll, Principal Investigator), P01 DA08131 (Dr. Horace Loh, Principal Investigator), and T32 DA07097 (Dr. Sheldon Sparber, Principal Investigator).

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