Mark G. LeSage

Fundamentals of behavior analytic research

Science and Analysis of Behavior. Designing Experiments. Conducting and Socially Validating Experiments. Data Collection. Withinsubject Experimental Designs. Betweensubjects Designs and Nonexperimental Methods. Graphic Analysis of Data. Statistics. Disseminating Research Findings. Index.

Continuous nicotine infusion reduces nicotine self-administration in rats with 23-h/day access to nicotine

The effects of continuous nicotine infusion on nicotine self-administration (NSA) were studied in rats as a model of nicotine replacement therapy (NRT) in humans. A NSA model in which rats had 23-h/day access to nicotine was used to approximate nicotine access conditions in cigarette smokers. In order to estimate serum nicotine concentrations associated with NSA, arterial and venous serum nicotine concentrations were measured during a simulation of NSA. Nicotine was noncontingently administered as 30 doses/12 h of 0.03 mg/kg/i.n.f. or 60 doses/12 h of 0.01 mg/kg/i.n.f. daily. Venous serum nicotine concentrations were measured after the first nicotine dose of the day, and arterial and venous concentrations were measured after doses in the middle of the day. The range of mean concentrations measured was similar to those reported in cigarette smokers (venous concentrations 6-59 ng/ml, arterial concentrations 42-96 ng/ml). The effects of continuous nicotine infusion on NSA were studied by noncontingently administering nicotine at various rates via osmotic pump to animals self-administering nicotine (0.01 or 0.03 mg/kg/i.n.f.) during 23-h/day sessions. Continuous nicotine infusion at all infusion rates substantially suppressed NSA, but suppression was rate-related only for the 0.01-mg/kg/inf NSA unit dose. Nicotine infusion rates producing venous serum nicotine concentrations equaling or exceeding the peak venous levels associated with simulated NSA were more effective than lower infusion rates only at the lower NSA unit dose. The highest nicotine infusion rate had no sustained effect on food-maintained responding, demonstrating its specificity for suppression of NSA. These data provide a model for studying NRT in the rat.

Differential Effects of Passive Immunization with Nicotine-Specific Antibodies on the Acute and Chronic Distribution of Nicotine to Brain in Rats

Vaccination against nicotine blocks or attenuates nicotine-related behaviors relevant to addiction in rats. Passive immunization with nicotine-specific antibodies is an alternative to vaccination with the potential advantages of allowing control of antibody dose and affinity. In the current study, the effects of two antibodies on the distribution of nicotine to brain were evaluated during chronic nicotine administration in rats; the monoclonal antibody Nic311 (Kd = 60 nM) and nicotine-specific antiserum (Kd = 1.6 nM). Nicotine was administered via repeated i.v. bolus doses over 2 days and antibody was administered during the first day. Neither antibody appreciably reduced the chronic accumulation of nicotine in brain, despite high protein binding of nicotine in serum (98.9%) and a 73% reduction in the unbound serum nicotine concentration with the highest Nic311 dose. However, both antibodies substantially reduced the early distribution of nicotine to brain 5 min after a dose. The higher affinity antibody was no more effective than Nic311. The highest Nic311 dose produced serum antibody levels 10 times higher than those reported with vaccination. The efficacy of Nic311 was dose-related, with the highest dose producing a 76% decrease in the early distribution of nicotine to brain. These findings, along with previous data, suggest that the primary effect of passive immunization is to slow, rather than prevent, the distribution of nicotine to brain. In the setting of chronic nicotine dosing, antibodies with a moderate affinity for nicotine produced substantial effects on the early distribution of nicotine to brain and were as effective as higher affinity antibodies.

MDMA and memory: the acute and chronic effects of MDMA in pigeons performing under a delayed-matching-to-sample procedure.

The purpose of the present study was to examine the acute and chronic effects of (±)3,4-methylenedioxymethamphetamine (MDMA) in pigeons responding under a delayed-matching-to-sample procedure with 0-, 3-, and 6-s delays. In the absence of drug, accuracy (percent correct responses) was inversely related to delay length. When administered pre-chronically, MDMA (0.32–5.6 mg/kg) generally decreased accuracy and response rates at doses of 3.2 mg/kg and above. Although humans report a distinct “hangover” when exposure to MDMA ends, performance of pigeons in the present study did not deteriorate when the chronic regimen ended, indicating an absence of behavioral dependence on the drug. Tolerance developed following chronic exposure to 3.2 mg/kg. In general, greater tolerance occurred at the 0-s delay than at longer delays. Although MDMA is reported to have neurotoxic effects, it does not inevitably produce long-lasting or cumulative behavioral impairment.

Effects of cocaine in pigeons responding under a progressive-ratio schedule of food delivery

Although the progressive-ratio schedule has been used frequently to quantify the reinforcing effectiveness of self-administered drugs, it has seldom been used to examine the effects of drugs on food-maintained behavior and has never been used to evaluate the effects of cocaine on such behavior. In the present study, the effects of acute administrations of cocaine were evaluated in pigeons responding under a progressive-ratio 5 schedule of food delivery that continued for 1 h or until responding ceased for 5 consecutive min, whichever occurred first. The largest ratio completed each session (breaking point) was the primary dependent variable. In general, acute administrations of cocaine at 0.56 to 3.2 mg/kg increased breaking points, whereas doses above 5.6 mg/kg decreased breaking points. Although cocaine reduces food intake and subjective hunger for food, the present data indicate that the drug reduces the reinforcing effectiveness of food only at high doses.

Effects of Chlorpromazine on Rats’ Acquisition of Lever-Press Responding with Immediate and Delayed Reinforcement

The effects of chlorpromazine (0, 2, 6, and 10 mg/kg) on the acquisition of lever-press responding by rats were examined under conditions where reinforcement (water delivery) was immediate or delayed. Under the immediate reinforcement condition, water-deprived rats were exposed during 8-h sessions to a fixed-ratio 1 (FR 1) schedule of water delivery without prior autoshaping or hand shaping. Under the delayed reinforcement condition, similar rats were exposed to a tandem FR 1 fixed-time 8-s schedule of water delivery. A different squad of eight rats was exposed to each delay condition and drug dose. For all subjects, responses on one lever produced water and responses on a second lever had no programmed consequences. Regardless of whether reinforcement was immediate or delayed, chlorpromazine reduced in dose-dependent fashion the mean number of operative-lever responses emitted, which suggests that the drug interfered with learning. At all chlorpromazine doses except 10 mg/kg, substantially more operative-lever than inoperative-lever responding occurred, indicating that the operant response was acquired. Chlorpromazine at 2 and 6 mg/kg disrupted the acquisition of stimulus control by the operative lever when reinforcement was delayed, but not when it was immediate. At 10 mg/kg, most subjects did not acquire lever-pressing regardless of whether they were exposed to the immediate or delayed reinforcement procedure. Procedures similar to those used in the present study appear to provide a reasonable assay for examining how drugs affect the initial behavioral effects of immediate and delayed reinforcement, and may merit further investigation.

Effects of Cocaine and Morphine Under Mixed-Ratio Schedules of Food Delivery: Support for a Behavioral Momentum Analysis

Previous studies have shown that ratio size influenced the development of tolerance under simple and multiple schedules, but not under progressive-ratio (PR) schedules. PR schedules share certain features with mixed-ratio (MR) schedules, and pilot data suggested that ratio size fails to modulate tolerance to cocaine or morphine under MR schedules. The present study examined more comprehensively the pre- and postchronic effects of cocaine and (in separate birds) morphine under MR schedules with fixed-ratio (FR) 5 and FR 95, FR 25 and FR 75, and FR 50 and FR 50 components. Acute doses of cocaine and morphine initially were given in an ascending series (beginning with 0.56 mg/kg) until responding was reduced to near-zero levels. Chronic (daily) dosing with a dose that reduced, but did not eliminate, responding then occurred until response rates stabilized. Finally, postchronic dose-response determinations were conducted. Both cocaine and morphine reduced response rates at all FR values. Tolerance was consistently observed to the effects of morphine, but not to those of cocaine. With both drugs the degree of tolerance observed did not vary as a function of FR value. These findings, like those obtained under PR schedules, indicate that ratio size does not always modulate drug tolerance. A behavioral momentum analysis of drug action appears to account for whether or not ratio size modulates tolerance, and such an analysis is provided.

Acute and chronic effects of morphine in pigeons responding under a progressive-ratio schedule of food delivery

Although progressive-ratio schedules have often been used by behavioral pharmacologists to index the relative reinforcing effects of drugs of abuse, they have been ignored in the study of tolerance to opioids. The present study examined tolerance to morphine in pigeons responding under a progressive-ratio 5 schedule of food delivery. Acute administrations of morphine produced general dose-dependent reductions in response rates and breaking points. Dose-response curves for both measures shifted rightward substantially (roughly fivefold) following chronic (daily) exposure to morphine, indicating that tolerance developed to the drugs effects.

Pharmacokinetic Correlates of the Effects of a Heroin Vaccine on Heroin Self-Administration in Rats

The purpose of this study was to evaluate the effects of a morphine-conjugate vaccine (M-KLH) on the acquisition, maintenance, and reinstatement of heroin self-administration (HSA) in rats, and on heroin and metabolite distribution during heroin administration that approximated the self-administered dosing rate. Vaccination with M-KLH blocked heroin-primed reinstatement of heroin responding. Vaccination also decreased HSA at low heroin unit doses but produced a compensatory increase in heroin self-administration at high unit doses. Vaccination shifted the heroin dose-response curve to the right, indicating reduced heroin potency, and behavioral economic demand curve analysis further confirmed this effect. In a separate experiment heroin was administered at rates simulating heroin exposure during HSA. Heroin and its active metabolites, 6-acetylmorphine (6-AM) and morphine, were retained in plasma and metabolite concentrations were reduced in brain in vaccinated rats compared to controls. Reductions in 6-AM concentrations in brain after vaccination were consistent with the changes in HSA rates accompanying vaccination. These data provide evidence that 6-AM is the principal mediator of heroin reinforcement, and the principal target of the M-KLH vaccine, in this model. While heroin vaccines may have potential as therapies for heroin addiction, high antibody to drug ratios appear to be important for obtaining maximal efficacy.

Acute and chronic effects of morphine under a progressive-ratio 25 schedule of food delivery.

The present study examined the effects of morphine in pigeons responding under a progressive-ratio 25 schedule of food delivery. Morphine initially reduced response rates and breaking points. With chronic exposure, tolerance developed to these effects. The magnitude of the observed tolerance was not obviously different from that previously reported under a PR 5 schedule of food delivery. In addition, when drug effects were compared under the fixed-ratio 25 and fixed-ratio 100 components comprised by the progressive-ratio schedule, comparable tolerance was observed. Although prior studies using other procedures have shown that ratio size modulates the development of tolerance to morphine and other drugs, the present data suggest that this relation is constrained, and is not easily observed under progressive-ratio schedules.