Human methadone self-administration: effects of diazepam pretreatment

The effect of diazepam on methadone self-administration was examined. Five methadone-maintained patients with a history of benzodiazepine abuse were recruited. Patients were stabilized on 80 mg of methadone per day. After stabilization patients participated in methadone self-administration sessions. During each session, 128 presses (fixed ratio 128) of 1 button delivered 10 ml of 0.054 mg/ml methadone solution. The same number of button presses on a 2nd button delivered 10 ml of vehicle. Forty-five min prior to the self-administration session, 0 (placebo), 5, 10, or 20 mg per 70 kg body weight diazepam was administered. Ratings of drug liking, goodness, strength, and high were collected 5, 30, 60, 90, and 150 min after the end of the self-administration session. Diazepam pretreatment significantly decreased the amount of methadone consumed. The 10- and 20-mg diazepam doses significantly increased reports of good, like, strong, and high.     

Effects of nicotine on methadone self-administration in humans

The effects of nicotine abstinence, ad libitum smoking, and 0, 2, and 4 mg nicotine gum on methadone self-administration were investigated. Five methadone-maintained patients with a history of smoking (18–30 cigarettes/day) were recruited as subjects. Upon arrival expired carbon monoxide levels were measured to confirm self-reported abstinence of 10–12 h. At 30 min prior to the methadone self-administration session, two response options were concurrently available. When a 64-button press requirement (FR64) was completed, 10 ml of 0.054 mg/ml methadone solution, or vehicle, was delivered. Immediately following, and 30, 60, 90, and 120 min after the self-administration session, expired carbon monoxide levels and typical symptoms of nicotine withdrawal were assessed. Relative to abstinence, subjects consumed more methadone following the 4-mg nicotine gum and ad libitum smoking conditions. Ratings of cigarette craving were significantly less following ad libitum smoking or administration of 4-mg nicotine gum, than following abstinence. Implications for understanding opioid and nicotine interactions are discussed.     

Concurrent progressive-ratio schedules to compare reinforcing effectiveness of different phencyclidine (PCP) concentrations in rhesus monkeys

  Rationale: Progressive ratio (PR) schedules have become well accepted for testing the reinforcing effectiveness of drugs. This study extends the methods to concurrent PR schedules with different concentrations of orally delivered phencyclidine (PCP). Objective: The sensitivity of the procedure is tested by presenting different PCP concentrations with independently-operating PR schedules. Method: PCP self-administration was investigated in seven rhesus monkeys. Six different PCP concentrations (0.03–1.0 mg/ml) and water were randomly paired (21 pairings). Liquid delivery (24 ml) was contingent upon lip-contact responses on solenoid-operated drinking spouts; whereby, the response requirement or fixed-ratio (FR) increased (from 8 to 16, 32, 64, 128... to 4096) after each successful completion of a previous FR and subsequent liquid delivery. Monkeys self administered PCP during daily 3-h sessions, and each pair of concentrations was held constant until behavior had stabilized for at least 4 days. Results: The higher of the two PCP concentrations always maintained greater responding, PR break point (BP), or the last ratio completed, and liquid deliveries than did the lower concentration. However, the monkeys did not exclusively respond on the drinking spout that yielded the higher drug concentration. When examined across all drug pairings, the percentage of total available deliveries of the higher concentration was significantly greater than those of the lower concentration. The monkeys maximized the amount (mg) consumed for the response output. Responding, BPs and liquid deliveries maintained by 0.12 and 0.25 mg/ml PCP were significantly greater than other PCP concentrations; however, drug intake (mg) increased directly with PCP concentration. Conclusion: These results indicate that concurrent PR schedules using oral drug self-administration and a concurrent choice paradigm reliably provide an estimation of relative reinforcing strength, and behavior maintained by these schedules is sensitive to small changes in PCP concentration. Received: 18 September 1998 / Final version: 28 December 1998     

Orally delivered methadone as a reinforcer: Effects of the opioid antagonist naloxone.

The effects of the opioid antagonist naloxone were studied with three monkeys under a mutually exclusive fixed-interval 15 s (FI 15 s) schedule of reinforcement. Under this schedule, at the end of each interval, the monkey could obtain one liquid delivery from either the spout that delivered methadone (0.8 mg/ml) or the spout that delivered vehicle (deionized water). Naloxone doses from 0.0125 to 0.2 mg/kg (IM daily 10 min prior to the session) were studied in an ascending then descending order. In the ascending series, low naloxone doses produced increases of methadone deliveries in the first hour of the session for three monkeys and increases over the entire 3-h session for two of the three monkeys. At higher doses naloxone decreased methadone deliveries in all three monkeys. Naloxone's effects were usually greater during the descending dose series than during the ascending series. These findings suggest that a history of naloxone injections is one determinant of response to the drug. Vehicle maintained responding was generally low and not changed by naloxone in a systematic way. The time course of methadone deliveries showed that naloxone's effects were greatest in the first hour of the session and were a direct function of dose. These experiments demonstrate that oral methadone reinforced behavior is sensitive to naloxone pretreatment and that the effects of naloxone are a direct function of dose.     

Oral self-administration of etonitazene in rhesus monkeys: Use of a fading procedure to establish etonitazene as a reinforcer

The establishment of orally delivered etonitazene (a potent opioid) as a reinforcer, was studied in eight rhesus monkeys. Initially, when given concurrent access to 2.5 μg/ml etonitazene and the water vehicle, five of the monkeys rejected the drug, whereas the other three monkeys consumed more drug solution than water. The five monkeys that rejected the drug solution underwent an acquisition phase to establish the drug as a reinforcer. A fading procedure was used to transfer control of responding from a 2% (wt/vol) ethanol solution to a 2.5 μg/ml etonitazene solution. Initially, responding was maintained by contingent deliveries of 2% ethanol. Next, across blocks of six or more sessions, increasing amounts of etonitazene were added in steps to the 2% ethanol solution. Subsequently, the 2% ethanol solution was decreased in steps to zero, leaving only the 2.5 μg/ml etonitazene present. When the fading procedure was completed, dose of etonitazene was varied by increasing the volume delivered, first under fixed ratio (FR 4) and then under an FR 8 reinforcement schedule. The same dose manipulations were made with the three monkeys who did not undergo the fading procedure because they preferred etonitazene over water when first tested. Etonitazene was established as a reinforcer for six of the eight monkeys because drug deliveries exceeded vehicle deliveries across a range of drug doses.     

Orally delivered methadone as a reinforcer in rhesus monkeys

Methadone usually is taken orally for drug abuse treatment in humans but oral methadone self-administration by laboratory animals has not been investigated extensively. The present study examines acquisition and maintenance of oral methadone maintained responding in four adult male rhesus monkeys. Drug solution was available from one liquid delivery system and water from a second system during daily 3-h sessions. Locations of liquids were reversed each session, and liquid (0.65 ml per delivery) was delivered according to a fixed-ratio reinforcement schedule. Initially a test for the reinforcing effects of 0.00625–0.4 mg/ml methadone solutions was carried out but a consistent preference for drug over water was not seen. To establish methadone as a reinforcer, a fading procedure was used in which responding was first maintained by solutions of methadone (0.00625–0.4 mg/ml) combined with ethanol (0.0325–2.0% w/v). Subsequently, the concentration of the ethanol in the combination was gradually reduced to zero. Methadone-maintained responding (0.4 mg/ml) persisted when ethanol was no longer present. To confirm that the drug was serving as a reinforcer, the dose was varied: (a) by changing the volume delivered while the concentration was held constant and (b) by changing the concentration of the methadone while the volume per delivery was held constant. Over a wide range of doses, deliveries of methadone solution usually exceeded deliveries of concurrently available water. Orderly relationships were observed among methadone dose, response rate, and drug intake. The study of oral self-administration of opioid drugs by nonhuman primates may be a useful strategy for the development and evaluation of new drug substitution or replacement therapies.     

Concurrent self-administration of ethanol and an alternative nondrug reinforcer in monkeys: effects of income (session length) on demand for drug

Eight rhesus monkeys (Macaca mulata) were trained to self-administer orally delivered ethanol (8%) and saccharin (0.03 or 0.3% wt/vol) or water under concurrent fixed-ratio (FR) schedules. The FR requirement for saccharin was fixed at 32, while the FR for ethanol was varied (4, 8, 16, 32, 64 and 128) in a nonsystematic order to assess demand for drug. Demand was defined as consumption plotted as a function of price (FR). Income was defined as the duration of access to available resources. Income was varied by allowing access to the concurrently available liquids 20, 60 or 180 min per day. Order of testing was counter-balanced across monkeys. Saccharin deliveries were much higher than ethanol deliveries under the 180-min income condition; however, they were lower than ethanol deliveries when income was reduced to 20 min and the ethanol FR was 4, 8 or 16. Thus, when the price of drug was relatively low, consumption of drug exceeded that of the nondrug reinforcer, and that relationship was reversed as income decreased. Saccharin deliveries sustained a proportionally greater reduction due to decreased income compared to ethanol deliveries. As income decreased from 180 to 20 min, saccharin deliveries were reduced by an average of 79.1% (across ethanol FR conditions) while ethanol deliveries were reduced by an average of 41.2 and 40.8% when concurrent saccharin or water were available, respectively; thus, drug self-administration was more resistant to income changes than saccharin. The demand for ethanol was shifted downward in a parallel fashion as income decreased. As ethanol cost (FR) increased, there were proportionately greater decreases in ethanol intake when saccharin was concurrently available compared to when water was available. There was a 35–50% reduction in ethanol deliveries due to concurrent saccharin (versus water) at FR 4, compared to a 55–75% reduction at FR 128. Cost of ethanol (FR), income level and the availability of a nondrug reinforcer are all variables that modify ethanol-reinforced behavior, and income alters the relative preference for a drug versus nondrug reinforcer.     

Orally delivered pentobarbital as a reinforcer for rhesus monkeys with concurrent access to water: Effects of concentration,fixed-ratio size,and liquid positions

The number of liquid deliveries and pattern of concurrent pentobarbital and water drinking were studied in three food deprived rhesus monkeys during daily 3-hr sessions. During the daily sessions, deliveries of approximately 0.6 ml of each liquid occured under fixed-ratio (FR) schedules of lip contact responses. Between sessions water was freely available. Session drinking was studied as a function of pentobarbital concentration (1.0, 1.41, 2.0, and 4.0 mg/ml) and FR size (4, 8, 16 and 32 lip contacts per delivery). The number of drug deliveries decreased with increases in drug concentration. Drug intake ranged from 21 to 52 mg/kg of body wt./3-hr session. At all concentrations and FR values tested, the number of pentobarbital deliveries substantially exceeded the number of water deliveries. The positive reinforcing effect of the pentobarbital was indicated by a consistent choice of drug over water irrespective of the side position of pentobarbital and by higher rates of drug responding. Pentobarbital drinking occured in a negatively accelerated pattern whereas water drinking did not have any consistent pattern. Marked intoxication followed bouts of drug drinking.     

Progressive ratio performance maintained by buprenorphine, heroin and methadone in Macaque monkeys

The relative reinforcing efficacy of buprenorphine (0.01-0.10 mg/kg/inj.), heroin (0.01-0.10 mg/kg/inj.), methadone (0.03-0.25 mg/kg/inj.) and saline were compared in Macaque male monkeys using progressive ratio procedures. Responding for drugs and food (1 g banana pellet) was maintained on a second order FR 4 (VR 16:S) schedule of reinforcement that required an average of 64 responses for each injection or food pellet. After 40 sessions (10 days) of stable performance, the number of responses for each drug injection was systematically increased until monkeys reached a breakpoint defined by 2 consecutive days of no drug injections. Progressive ratio breakpoints for heroin at intermediate and high doses (0.05 and 0.10 mg/kg/inj.) were two to three times higher than for any other drug (P less than 0.05). Breakpoints for buprenophine (0.01-0.10 mg/kg/inj.) were higher than for a low dose of methadone (0.03 mg/kg/inj.) but were equivalent to an intermediate methadone dose (0.10 mg/kg/inj.). Breakpoints for both low (0.01 mg/kg/inj.) and high (0.10 mg/kg/inj.) buprenorphine doses were greater than for intermediate doses (0.03 and 0.05 mg/kg/inj.) but these differences were not statistically significant. Linear regression and area under the curve analyses were used to quantify the rate at which drug maintained responding decreased by 30% of control levels as response requirements were increased. Extrapolated breakpoints derived from linear regression analyses were significantly correlated (P less than 0.05-0.01) with actual breakpoints for buprenorphine, heroin and methadone. The concordance between 'extrapolated' and traditional breakpoint ranking of these drugs suggests that regression analysis techniques can be used to predict traditional breakpoints.     

Oral self-administration of triazolam,diazepam and ethanol in the baboon: drug reinforcement and benzodiazepine physical dependence

Reinforcing and physical dependence-producing effects of oral diazepam and triazolam (0.01–1.28 mg/ml) were studied in four non-water-deprived baboons in daily 2-3-h sessions. Drinking initially was food-induced, but subsequently it was maintained for>year without the inducing procedures; drug intake>10 mg/kg per session was attained. Triazolam and diazepam reinforcement (compared to vehicle) was concluded for only one baboon for each drug under a single-spout procedure and for two baboons for each drug under a two-spout procedure. However, all baboons showed ethanol reinforcement under a two-spout procedure. When a lever-pressing requirement was imposed for each drink (one-spout procedure), ethanol maintained requirements of 128 or 256 responses/drink, and volume of ethanol consumed was greater than vehicle. Neither benzodiazepine maintained lever pressing better than vehicle at any response requirement and drinking was suppressed by requirements of 1–32. Physical dependence to triazolam and diazepam developed after approximately 1 month of daily ingestion, evidenced by a precipitated withdrawal syndrome after injection of the benzodiazepine antagonist flumazenil. A mild spontaneous withdrawal syndrome occurred after substitution of vehicle for triazolam or diazepam. These data indicate a clear dissociation between the reinforcing and physical dependence-producing effects of triazolam and diazepam.     

Effects of a non-drug reinforcer,saccharin, on oral self-administration of phencyclidine in male and female rhesus monkeys

Rationale Previous research with male subjects has demonstrated that alternative non-drug reinforcers reduce self-administration of drugs of abuse under a wide variety of conditions. Recent findings indicate sex differences in drug self-administration, and females may be more responsive to the suppressive effects of pharmacological treatment strategies than males; however, it is not known whether or not there are similar sex differences in the effect of behavioral interventions, such as non-drug reinforcers, on drug self-administration.Objectives The goal of this research was to determine whether the suppressive effects of non-drug reinforcers vary as a function of sex using behavioral economic measures in rhesus monkeys.Methods During daily 3-h sessions, seven male and seven female adult rhesus monkeys orally self-administered concurrently available phencyclidine (PCP) and water, PCP and saccharin, or saccharin and water, from two separate spouts, under a series of fixed-ratio (FR) values. The FR value was varied from 4 to 8, 16, 32, 64, and 128, and the demand (consumption × FR) for PCP was measured in order to determine the effect of concurrent access to saccharin (versus water).Results The availability of saccharin resulted in reduced PCP self-administration compared with the condition when water was available in both males and females. Consumption of PCP and saccharin was similar between the sexes under the two conditions when water was concurrently available. When saccharin was available with PCP, PCP responses and deliveries were reduced in both sexes at low to intermediate FR values, but the amount of PCP consumed (mg/kg) was reduced significantly more in females than in males only at FR 32.Conclusions Non-drug reinforcers are an effective treatment for drug abuse in females as well as males over a range of PCP FR values. Males show elevated drug-maintained responding compared with females, but when differential body weights are considered (mg/kg) females consume more than males only under limited schedule parameters.     

Cocaine self-administration under conditions of restricted and unrestricted food access

Four rhesus monkeys (Macaca mulatta), maintained at reduced body weight and restricted food availability, had access to a 0.8-mg/ml cocaine solution and vehicle under a concurrent fixed-ratio (FR) 8 schedule. Over days, the cocaine concentration was reduced (0.57, 0.4, 0.2, 0.1, 0.05, 0.025) and then returned, gradually over days, to 0.8 mg/ml. The ratio value was then varied (to 16, 32, 64, 128, and 8). Food access was unrestricted, and the ratio and the concentration manipulations were then repeated. During food restriction cocaine served as a reinforcer for all monkeys, whereas during free feeding cocaine functioned as a reinforcer for 3 of 4 monkeys; with these monkeys, the dose-response curve obtained under free feeding was shifted to the right of that obtained under food restriction. There were no differences in FR response curves obtained during food restriction and unrestricted feeding. These data suggest that food restriction increases cocaine's reinforcing effects and that the higher the cocaine dose, the greater are the reinforcing effects. A demand curve analysis was completed, and data are discussed in terms of microeconomic principles.     

Phencyclidine established as a discriminative stimulus using ethanol as a reinforcer

Long-Evans hooded rats were initially trained to lever press, in standard, operant conditioning chambers, according to a fixed-ratio 1 (FR1) reinforcement schedule using 0.06ml deliveries of 8% w/v ethanol as the reinforcer, during daily Monday-Friday, 1h experimental sessions. Next, experimental sessions were reduced to 0.5h, the FR value was increased to 5, and the rats were trained to discriminate 2.0mg/kg s.c. phencyclidine (PCP) from saline vehicle using standard, drug discrimination training procedures, with 8% ethanol as the reinforcer. Following training, dose-response tests with PCP (0.1-4.0mg/kg), ketamine (0.1-18mg/kg), dexoxadrol (1.0-5.6mg/kg) and morphine (1.0-9.0mg/kg) were conducted. More PCP-lever presses were emitted than saline-lever presses at several doses of PCP, ketamine, and dexoxadrol, indicating generalization from the 2.0mg/kg PCP stimulus. When morphine was tested, more saline-lever than PCP-lever presses were made, and percent PCP-lever pressing never exceeded an average of 12% at any dose tested. This study demonstrates that one drug of abuse, PCP, can serve as a discriminative stimulus when another drug of abuse, ethanol, serves as the reinforcing stimulus, and is the first explicit laboratory demonstration of drug discriminative stimulus control during drug self-administration.     

Relative reinforcing effects of different benzodiazepine doses for rhesus monkeys

The relative reinforcing effects of different doses of benzodiazepines were determined by giving rhesus monkeys concurrent access to different diazepam and midazolam concentrations. For each monkey a dose response function was obtained using three drug concentrations: low (L), intermediate (I), and high (H). The benzodiazepine and the water vehicle were concurrently available under independent fixed-ratio (FR) schedules. After establishing that each concentration was a reinforcer in comparison to vehicle, relative preference for the different concentrations was examined by making pairs of concentrations concurrently available under independent FR schedules. Three pairs were studied (H vs. L, H vs. I, and I vs. L). With both drugs, higher concentrations maintained greater response rates than lower concentrations. Thus, relative reinforcing effects increased with dose. These findings are similar to those obtained with other reinforcing drugs and provide further evidence that benzodiazepines share significant characteristics with other drug reinforcers. Importantly, absolute response rates (responses per session) obtained when only one drug dose was present were not reliably predictive of subsequent preferences for the dose. Both benzodiazepines served as effective reinforcers in that consistent levels of responding were maintained across doses and above vehicle levels under concurrent FR 32 schedules. As with other reinforcing drugs, the reinforcing effects of benzodiazepines increase with increases in dose over a broad range of values.     

Methadone and nicotine self-administration in humans: a behavioral economic analysis

Rationale Prior research has revealed inconsistencies in the behavioral relations between nicotine and opiates among methadone-maintained patients.Objectives The current study examined whether the drug reinforcers cigarette puffs and methadone were economic complements or substitutes.Methods Five methadone-maintained, nicotine-dependent participants were trained to self-administer methadone, cigarette puffs, or concurrently available methadone and puffs. Following training, the fixed ratio (FR) value (price) was increased across sessions (FR 32, 64, 128, 256, and 512), first for methadone and then for puffs. Subsequently, methadone and puffs were concurrently available, and the price of each drug was increased independently, while the price of the alternative (puffs or methadone) remained constant at FR 32.Results Demand for methadone and cigarette puffs decreased as a function of increases in methadone and cigarette puff prices, respectively. When methadone and puffs were concurrently available, an increase in methadones price decreased puff consumption, and demand for methadone was less elastic than when puffs were not concurrently available. An increase in puff price decreased puff and methadone demand, but the elasticity of puff demand was unaffected. The concurrent presence of methadone had no effect on the elasticity of demand for cigarette puffs.Conclusions Methadone and cigarette puffs appear to be asymmetric economic complements.     

The reinforcing properties of diazepam under several conditions in the rhesus monkey

Diazepam self-administration was studied in rhesus monkeys under several conditions of availability. Leverpress responding was maintained in twelve monkeys under a fixed-ratio 10 (FR 10) schedule of IV cocaine or pentobarbital delivery in daily sessions of 1–3 h duration. Each of several doses of diazepam (0.012–0.4 mg/kg/infusion) or vehicle was periodically substituted for 5–14 consecutive sessions. Between each substitution, responding was maintained by the baseline drug (cocaine or pentobarbital). Another procedure was to decrease the response requirement for drug delivery to a fixed-ratio one (FR 1). In three of eleven monkeys studied under conditions of a cocaine baseline and the FR 10 schedule, responding was maintained by diazepam and was inversely related to dose. In each of five monkeys tested in a similar manner but with a pentobarbital baseline, at least one dose of diazepam maintained responding above vehicle levels. Three of these monkeys had previously failed to self-administer diazepam under the cocaine baseline condition. Subsequently when two of these monkeys were returned to the cocaine baseline, diazepam was not self-administered above vehicle levels. Under FR 1 conditions of substitution, vehicle and pentobarbital intake increased in each monkey tested and cocaine intake increased in two of four monkeys. Diazepam self-administration also increased but did not exceed vehicle levels under the FR 1 schedule. However, in two monkeys the number of diazepam infusions was increased compared to the FR 10 substitution condition. These results emphasize the importance of testing drugs under several conditions to determine their relative dependence potential.     

Abuse liability of the anesthetic propofol: self-administration of propofol in rats under fixed-ratio schedules of drug delivery

RATIONALE: Previous reports suggest that propofol (PPF) may have abuse potential in humans. Hence, we hypothesized that PPF could reinforce self-administration behavior in other species. Positive reinforcing effects of PPF could be interpreted as an index of abuse liability. OBJECTIVE: Acquisition and maintenance of i.v. PPF self-administration were examined in 12 rats. METHODS: Six rats were initially given access to methohexital (MHX, 2.0 mg/kg per infusion) under a fixed ratio (FR) 1 schedule, while the other six were initially given access to PPF (1.7 mg/kg per infusion). Once stable responding was established, various doses of PPF (0.56, 1.0, and 1.7 mg/kg per infusion) and vehicle (Intralipid 20%) were made available. RESULTS: The number of PPF infusions per session was an inverse function of dose, with 0.56 mg/kg and 1.0 mg/kg per infusion maintaining significantly more infusions per session than vehicle in most rats under the FR 1 schedule. For some rats, the number of vehicle infusions per session was equal to or greater than the number of PPF infusions. Increasing the response requirement to FR 5 decreased the number of vehicle infusions per session in these rats, while PPF maintained a higher number of infusions than vehicle under this FR value in six of seven rats. CONCLUSION: PPF served as a reinforcer in rats under FR schedules of i.v. drug delivery, adding to the extant evidence that it has abuse potential.     

Reinforcing effects of smoked methamphetamine in rhesus monkeys

Rationale The occurrence of methamphetamine (METH) use by the smoking route is increasing. A nonhuman primate model for examining the reinforcing effects of smoked METH would be valuable for testing potential interventions for treating METH abuse disorders.Objective The purpose of the present study was to examine the reinforcing effects of smoked METH in monkeys.Materials and methods Four rhesus monkeys were trained to smoke cocaine (COC) under a chain fixed-ratio (FR) 64 lever press, FR 5 inhalation schedule of reinforcement. Upon observing stable levels of self-administration, METH was substituted for COC and a dose-response function for METH (0.08–0.8 mg/kg) was determined. Subsequently, the number of deliveries of COC (1 mg/kg), and 0.2 and 0.8 mg/kg METH were examined across increasing response requirements.Results METH was dose-dependently self-administered. Higher doses of METH (0.2, 0.4, and 0.8 mg/kg) produced asymptotic levels of responding that were slightly lower than those obtained with 1 mg/kg COC. Numbers of deliveries of COC and METH decreased as response requirement increased. METH, however, maintained fewer deliveries than 1 mg/kg COC at most response requirements.Conclusions METH is readily self-administered by smoking in rhesus monkeys when substituted for COC. METH may have a lower reinforcing strength than COC, but further research is needed to fully characterize its relative reinforcing strength.An erratum to this article can be found at     

Effects of response requirement upon human sedative self-administration and drug-seeking behavior.

Five male volunteers with histories of sedative drug abuse were given the opportunity to self-administer up to 20 oral doses per day of either diazepam (10 mg per dose) or sodium pentobarbital (30 mg per dose). Each dose was purchased with tokens earned by exercising on a stationary exercise bicycle. Each two minutes of exercise earned one token. In a mixed order across days the number of tokens required to purchase each dose was varied among 1, 3, 5, 8 and 10. Drug intake decreased as a function of increased response requirement for purchasing the drug. Response output for drug tended to be an inverted-U shaped function of the response requirement. Thus, the cost of drug doses act as a powerful environmental influence upon both of these aspects of drug abuse behavior - amount of drug consumed and amount of drug-seeking behavior.     

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

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 mg/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.