Michael A. Nader

Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure

Rhesus monkeys were trained in a discretetrials choice procedure and allowed to choose between food delivery (1–16 pellets; 1 g/pellet) and intravenous injections of cocaine (0.03–0.56 mg/kg/injection;N=4) or procaine (1.0–10 mg/kg/injection;N=4) during daily 3-h sessions. Injections were available as the alternative to food. When the amount of food available as the alternative to drug was held constant and dose of drug was varied, the frequency of drug choice and total drug intake increased in a dose-related fashion for both cocaine and procaine. For both drugs, when the amount of food available as the alternative to drug was increased and the dose of the drug was held constant, the frequency of drug choice and total drug intake decreased. Thus, increases in the magnitude of an alternative non-drug reinforcer decreased cocaine and procaine self-administration. Further, the results suggest that while increasing the magnitude of the alternative reinforcer decreased the potency of cocaine as a positive reinforcer, the reinforcing efficacy of procaine was decreased. Because drug use by humans typically occurs in a context in which other reinforcers are available, the present results are consistent with the hypothesis that drug self-administration by humans can be decreased by increasing the value of alternative positive reinforcers. In addition, these results suggest that the extent to which drug self-administration is sensitive to this manipulation varies across drugs.

Effects of increasing response requirement on choice between cocaine and food in rhesus monkeys.

Rhesus monkeys were trained in a discretetrials choice procedure and allowed to choose between intravenous injections of cocaine (0.01–1.0 mg/kg/injection) and food presentation (1 or 4 pellets; 1 g/pellet) during daily 7-h experimental sessions. When each reinforcer was available under a fixed-ratio (FR) 30 schedule, the frequency of cocaine choice and the total drug intake increased in a dose-related manner for all monkeys. When the FR for cocaine was differentially increased, the frequency of cocaine choice decreased, shifting the cocaine dose-response function to the right and/or downward. When the FR for cocaine was at least 480, cocaine preference could not be recovered up to doses of 1.0 mg/kg/injection. In a second experiment, when the response requirement for food was differentially increased, the frequency of cocaine choice increased. These results demonstrate that altering the response requirement for cocaine or for alternative reinforcers that are available can substantially affect cocaine self-administration.

Behavioral economics and drug choice: effects of unit price on cocaine self-administration by monkeys

The application of microeconomic theory to the experimental analysis of behavior has been termed behavioral economics. There has been an increasing interest in applying the concepts of behavioral economics to the study of drug self-administration. In a previously published experiment (Nader and Woolverton, 1992), rhesus monkeys (N = 3) were trained in a discrete-trials choice procedure and allowed to choose between intravenous injections of cocaine (0.03-1.0 mg/kg/injection) and food presentation (1 or 4 pellets; 1 g/pellet) during daily 7-h experimental sessions. When cocaine or food was available under a fixed-ratio (FR) 30 schedule, cocaine intake increased in a dose-related manner for all monkeys. When the response requirement (FR) for cocaine was differentially increased by doubling or quadrupling, the frequency of cocaine choice decreased, shifting the cocaine dose-response function to the right. The present paper is a reanalysis of data from that experiment. Several mathematical models, differentially incorporating the effects of FR, dose and number of food pellets, were compared. When cocaine consumption was analyzed using a multiple linear regression analysis with FR, dose and number of pellets as separate main effects (model I), the R2 was 0.82. When FR and dose were combined into one factor, unit price (UP, responses/mg/kg), and cocaine consumption was analyzed as a linear function of UP (model IIA), the R2 was 0.54. When cocaine consumption was analyzed as a curvilinear, negatively accelerated function of UP (model IIB), the R2 was 0.53. The difference between models I and IIA was statistically significant while models IIA and IIB were not different.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the discriminative stimulus and reinforcing effects of sertraline in rhesus monkeys

Rhesus monkeys (N = 4) were allowed to self-administer cocaine (0.03 mg/kg/injection) under a fixed-ratio 10 (FR 10) schedule during daily 2-h experimental sessions. When responding was stable, a variety of doses of sertraline, a serotonin reuptake blocker under development as an antidepressant, were made available for self-administration. Baseline conditions were reinstated between doses of sertraline. Cocaine 0.03 mg/kg/injection maintained high rates of injection, while total saline injections decreased to low levels within four to seven sessions. Sertraline (0.05-0.4 mg/kg/injection) did not maintain self-administration above saline levels in three of the four monkeys. In the fourth, responding was marginally above saline levels at two doses but was not systematically related to dose. In a second experiment, rhesus monkeys (N = 6) were trained to discriminate either d-amphetamine (0.56-1.0 mg/kg, IG) or pentobarbital (10 mg/kg, IG) from saline in a discrete-trials shock avoidance/escape paradigm. Sertraline (4.0-32 mg/kg) failed to substitute for either d-amphetamine or pentobarbital as a discriminative stimulus. These results suggest that sertraline is unlikely to have abuse potential in humans and is unlikely to have either d-amphetamine-like or pentobarbital-like subjective effects.

Behavioral and Pharmacological Determinants of Drug Abuse

While there is little doubt that the pharmacological properties of a drug play an important role in the initiation of a multitude of responses, it is also clear that several variables can significantly alter the effects of that drug both on intermediate processes and in its ultimate effects on behavior. This chapter focuses on some of the variables that have been shown to modify the behavioral effects of abused drugs. The emphasis is on describing certain conditions under which the effects of an abused drug are changed, often dramatically, by prior behavioral and/or pharmacological experience. Because these effects have been shown with a wide variety of abused drugs, are stable over lengthy periods of time, and are observed under a broad range of conditions, it would seem that these fictors may have direct relevance for eventually understanding and being able to intercede in altering those conditions that lead to drug abuse. Although several determinants of the behavioral effects of drugs have been described (eg., rate of responding in the absence of the drug, schedule of reinforcement and type of maintaining event), these variables typically are identifiable when assessing

Discriminative and reinforcing effects of brotizolam in rhesus monkeys

The reinforcing and discriminative stimulus effects of brotizolam, a benzodiazepine-hypnotic, were evaluated in rhesus monkeys. In one experiment, separate groups of monkeys (N=3/group) were trained to discriminate pentobarbital (10 mg/kg, IG) ord-amphetamine (0.56–1.0 mg/kg, IG) from saline, in a discrete-trials avoidance/escape paradigm. Pentobarbital (5.6–10 mg/kg), diazepam (1.0–1.7 mg/kg), and brotizolam (0.3–1.7 mg/kg) resulted in 100% drug-lever responding in all three pentobarbital-trained monkeys. Ind-amphetamine-trained monkeys brotizolam administration resulted only in saline-lever responding. In another experiment, monkeys were surgically prepared with indwelling intravenous catheters and lever pressing resulted in an injection of 0.1 mg/kg/injection sodium methohexital under a fixed-ratio 10 (FR 10) schedule. Pentobarbital (0.01–0.3 mg/kg/injection) and diazepam (0.003–0.10 mg/kg/injection) maintained responding above saline control levels when substituted for methohexital. Brotizolam (0.001–0.01 mg/kg/injection) resulted in more injections received compared to saline, but fewer injections compared to pentobarbital or diazepam. Thus, results from the present experiment suggest that brotizolam would have pentobarbital-like subjective effects. However, the abuse liability of brotizolam may be lower than that for diazepam.

Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline

The purpose of the present study was to further investigate the relationship between the DS effects of PB and those of benzodiazepines (BZs) and to begin to collect pharmacological information concerning receptor mechanisms involved in this behavioral effect of BZs. Rhesus monkeys (n=3), trained to discriminate pentobarbital (PB; 10 mg/kg, IG) from saline under a discrete-trials shock avoidance procedure, were given IG diazepam (0.3–10 mg/kg), chlordiazepoxide (1.0–30 mg/kg), or etizolam (0.3–10 mg/kg) alone and in combination with flumazenil (0.01–1.7 mg/kg, IM). Flumazenil was administered 10 min prior to the administration of saline, PB or the BZs. All three BZs fully substituted for PB in all monkeys. Diazepam was the most potent with a mean ED50 of 0.81 mg/kg (SEM=0.04) while chlordiazepoxide was the least potent (mean ED50=5.78 mg/kg, SEM=1.22 mg/kg). The ED50 for etizolam was 1.22 mg/kg (SEM=0.37 mg/kg). Pretreatment with flumazenil (0.01–1.0 mg/kg) resulted in a dose-related parallel shift to the right in the dose-response function for PB-appropriate responding in all monkeys for all three BZs. The mean (n=3) pKB value with 0.1 mg/kg flumazenil was 6.51 (SEM=0.42) for diazepam and 6.57 (SEM=0.17) for chlordiazepoxide. This value could not be calculated for etizolam because only one monkey was tested with 0.1 mg/kg flumazenil. However, the mean pKB for etizolam considering all monkeys and all doses of flumazenil was 6.58 (SEM=0.47). Apparent pA2 values for flumazenil with diazepam were 6.02 for one monkey and 7.11 for another. All three BZs tended to increase average latency to respond. Apparent pKB and pA2 analysis may prove useful for elucidating receptor mechanisms involved in the behavioral effects of BZs.

Behavioral effects of chronic buspirone administration in the pigeon: Comparison to midazolam

The effects of acute and chronic administration of buspirone and midazolam were examined in White Carneau pigeons (N = 5) responding under a fixed-ratio 30 (FR 30) schedule of food presentation. Each drug was studied in all pigeons. For three pigeons, buspirone was studied before midazolam, while the order was reversed for the other two subjects. For each drug, a dose-response curve was determined before (prechronic) and two weeks after (postchronic) discontinuation of chronic administration. Prior to chronic drug administration, buspirone (0.3-5.6 mg/kg) and midazolam (0.1-3.0 mg/kg) decreased response rates in all subjects, in a dose-dependent manner. Midazolam was more potent than buspirone; midazolams ED50 (95% C.I.) was 0.53 (0.41-0.69) mg/kg compared to 2.55 (1.48-4.41) mg/kg for buspirone. For each subject, the lowest dose that decreased responding by at least 50% was administered daily, immediately before the session, for up to 6 weeks. At the lowest daily dose of buspirone, complete recovery of baseline rates was observed in 3 pigeons. However, when the buspirone dose was increased, responding remained below control rates in all but one pigeon. During chronic midazolam administration, tolerance developed to the rate-decreasing effects of midazolam in 4 subjects. When saline was substituted for buspirone or midazolam, suppressed responding returned to predrug rates in all subjects. When the dose-response curves were redetermined, the postchronic ED50 for buspirone was 3.79 (2.10-6.82) mg/kg, which was not significantly different from the prechronic ED50, suggesting that tolerance did not develop to buspirones rate-decreasing effects.(ABSTRACT TRUNCATED AT 250 WORDS)