Physical dependence in baboons chronically treated with low and high doses of diazepam.

Physical dependence on diazepam was evaluated in male baboons chronically treated with either low or high doses of diazepam. Baboons received either a single oral daily administration of a low dose (0.5 mg/kg per day) of diazepam (n=4) or continuous intragastric infusion of a high dose (20 mg/kg per day) of diazepam (n=7). Development of physical dependence during chronic dosing with 0.5 mg/kg per day diazepam was assessed at 2 and 4 weeks and then monthly, during 1-h behavioral observations, following injections of the benzodiazepine competitive antagonist flumazenil. After 3-24 months of diazepam treatment, dosing was discontinued and physical dependence assessed via observation and responding for food pellets. In baboons that received 0.5 mg/kg per day diazepam, flumazenil precipitated a mild- to intermediate-intensity benzodiazepine withdrawal syndrome, which included decreases in the number of food pellets earned per day and increases in withdrawal postures, self-directed behaviors, aggressive behaviors and retching/vomiting. Three of four baboons showed signs of precipitated withdrawal after only 2 weeks of chronic low-dose treatment. Flumazenil continued to precipitate withdrawal signs, but with no systematic increase in severity, throughout the 6-10 months of 0.5 mg/kg diazepam administration. When 0.5 mg/kg per day diazepam dosing was discontinued, the number of food pellets earned per day decreased in two of the four baboons, but no systematic changes in behavioral signs were observed. In contrast, within 7-10 days of termination of 20 mg/kg per day diazepam dosing, withdrawal signs of intermediate intensity and a decrease in the number of food pellets earned per day occurred in all baboons. In the present study, physical dependence developed after 2 weeks of a chronic low dose of diazepam administration but did not increase further over long-term exposure to diazepam.

Oxygen transport dynamics of acellular hemoglobin solutions in an isovolemic hemodilution model in swine.

BACKGROUND: One of the perceived advantages of a hemoglobin-based blood substitute is the provision of oxygen-carrying capacity. Although the hemodynamic response to the infusion of acellular hemoglobin solutions has been extensively studied, less is known about the oxygen transport dynamics of such solutions. We hypothesized that acellular hemoglobin solutions are useful oxygen carriers in anemic states and that higher P50 solutions transport O2 more efficiently than low P50 solutions. We sought to quantify O2 transport dynamics of hemoglobin solutions in an isovolemic hemodilution model in swine. METHODS: Eighteen swine were anesthetized, ventilated, and instrumented for hemodynamic measurements and for withdrawal of arterial and mixed venous blood. The swine were randomized into three groups and progressively bled from an initial hematocrit (Hct) of 30% to Hcts of 19%, 13%, and 8% using isovolemic exchange with pyridoxalated hemoglobin polyoxyethylene conjugate (PHP, n = 6); an identical hemoglobin solution without the pyridoxalation, resulting in a low P50 solution (POE-Hb, n = 6); or an osmotically similar control solution of pentastarch (PS, n = 6). Hemodynamic measurements, arterial and mixed venous O2 content, and O2 extraction ratio (ER), were determined in whole blood (WB), the red blood cell (RBC) phase, and the plasma phase utilizing a compartmentalized approach. RESULTS: Mean pulmonary arterial pressure was higher with hemodilution in the PHP and POE-Hb groups than in the PS group (p < 0.05). Cardiac index increased with hemodilution in all groups, but was significantly less than the cardiac index in the PS group at Hcts = 19% and 13%. Oxygen delivery and consumption were maintained at all hematocrits at baseline levels in the PHP and POE-Hb groups, but O2 delivery was significantly decreased in the PS group at Hct = 8% (p < 0.05 for PS vs. baseline and p < 0.05 for PHP and POE-Hb vs. PS). Oxygen extraction ratio increased with progressive hemodilution in both the RBC hemoglobin and plasma phases to a maximum of 39% for PHP and 36% for POE-Hb at Hct = 8%. The percent contribution from the plasma phase to total oxygen delivery and consumption likewise increased with hemodilution to maximum values of 52.7% (PHP) and 68.2% (POE-Hb) for delivery and 40.9% (PHP) and 39.3% (POE-Hb) for consumption. CONCLUSION: Acellular hemoglobin solutions provide a significant contribution to O2 delivery and consumption, particularly in severe anemia, in this model of isovolemic exchange. The differences in the P50 of the two hemoglobin solutions do not appear to significantly influence oxygen dynamics over the range of hematocrits studied.

Behavioral and pharmacological variables affecting risky choice in rats.

The effects of manipulations of response requirement, intertrial interval (ITI), and psychoactive drugs (ethanol, phencyclidine, and d-amphetamine) on lever choice under concurrent fixed-ratio schedules were investigated in rats. Responding on the "certain'' lever produced three 45-mg pellets, whereas responding on the "risky" lever produced either 15 pellets (p = .33) or no pellets (p .67). Rats earned all food during the session, which ended after 12 forced trials and 93 choice trials or 90 min, whichever occurred first. When the response requirement was increased from 1 to 16 and the ITI was 20 s, percentage of risky choice was inversely related to fixed-ratio value. When only a single response was required but the ITI was manipulated between 20 and 120 s (with maximum session duration held constant), percentage of risky choice was directly related to length of the ITI. The effects of the drugs were investigated first at an ITI of 20 s, when risky choice was low for most rats, and then at an ITI of 80 s, when risky choice was higher for most rats. Ethanol usually decreased risky choice. Phencyclidine did not usually affect risky choice when the ITI was 20 s but decreased it in half the rats when the ITI was 80 s. For d-amphetamine, the effects appeared to he related to baseline probability of risky choice; that is, low probabilities were increased and high probabilities were decreased. Although increase in risky choice as a function of the ITI is at variance with previous ITI data, it is consistent with foraging data showing that risk aversion decreases as food availability decreases. The pharmacological manipulations showed that drug effects on risky choice may be influenced by the baseline probability of risky choice, just as drug effects can be a function of baseline response rate.

Zaleplon and triazolam physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons.

The ability of the GABA(A)-receptor-subtype-selective hypnotic zaleplon to produce physical dependence was compared to the nonselective benzodiazepine triazolam. Progressively increasing doses of zaleplon and triazolam were given to baboons by intragastric infusion once each day, with doses increasing every 17 days. Next, the highest dose was given for 10-34 additional days by continuous infusion. Both drugs produced increases in food-maintained lever pressing, ataxia, and time to complete a fine motor task. Plasma levels increased dose-dependently; drug was detectable 24 h after higher doses. Flumazenil produced a mild or intermediate precipitated-withdrawal syndrome on day 14 of all dosing conditions. When drug delivery ended after 85-100 days, a benzodiazepine-type withdrawal syndrome occurred. Physical dependence potential of zaleplon and triazolam appear similar.

Stable low-rate midazolam self-injection with concurrent physical dependence under conditions of long-term continuous availability in baboons.

The current research was undertaken to characterize intravenous midazolam self-injection and the concurrent development of physical dependence under conditions of continuous drug availability. Baboons (n=6) i.v. self-injected midazolam under conditions of continuous availability under a fixed-ratio 30 schedule of lever-pull responses with a 5-min time-out after each injection. Midazolam (1.0 mg/kg) maintained an orderly spaced within-day pattern of injections and low, but stable, daily rates of self-injection over 30 or more days (e.g. <20 injections/day). Sequential substitution of saline and then midazolam produced rapid extinction and then reinstatement of responding at the same stable rate. In subsequent manipulations, a range of lower doses of midazolam (0.0156-0.25 mg/kg) were also shown to reinstate self-injection responding after extinction on saline; however, both chronic and acute dose manipulations indicated that dose-regulation was poor. Chronic self-injection of the high dose (1.0 mg/kg) but not lower doses produced a suppression in responding maintained by food pellet delivery. Chronic self-injection of 1.0 and 0.25 mg/kg midazolam produced physical dependence as reflected in classic benzodiazepine spontaneous and flumazenil-precipitated withdrawal syndromes, including tremor, vomiting and, in one instance, seizure. The stable, low-rate self-injection of midazolam, with concurrent development of physical dependence, demonstrated in the present study may provide a useful model system for investigating factors which contribute to long-term inappropriate use of benzodiazepines by physically dependent patients.

Intravenous self-injection of four novel phenethylamines in baboons.

The present study evaluated the intravenous self-administration of four substituted phenethylamines, using a substitution procedure in baboons. Baboons were trained to self-inject 0.32mg/kg/injection cocaine under a fixed-ration (FR) schedule, with a 3h timeout following each injection. Doses of (+/-)-N-ethyl-3, 4-methylenedioxyamphetamine HCI (MDE), (+/-)-N-hydroxy-3, 4-methylendioxyamphetamine HCI (N-OH-MDA), (+)-N-N-dimethylamphetamine HCI (NNDMA), and 4-bromo-2,5-dimethyoxy-beta-phenethylamine (BDMPEA) and their vehicles were substituted for cocaine for 15 or more successive days. High doses of MDE and N-OH-MDA maintained self-injection; however, NNDMA and BDMPEA self-injection was less consistent. NNDMA did not reliably maintain self-injection, whereas one or more doses of BDMPEA maintained self-injection in each of three baboons. Intermediate to high doses of all four compounds decreased food pellet intake maintained under a FR schedule of reinforcement on a different lever. In some baboons, high doses of N-OH-MDA, NNDMA and BDMPEA produced signs of behavioral toxicity (e.g. cyclic pattern of self-injection, behavioral agitation, stereotypical movements) that were similar to those previously observed after administration of high doses of classic psychomotor stimulants such as d-amphetamine; however, the severity and profile of this behavioral toxicity differed between compounds. Thus, the present study documents both similarities and differences in the behavioral profiles of these four phenethylamines.

Absorption rate of methylxanthines following capsules, cola and chocolate.

OBJECTIVE: To compare caffeine and theobromine absorption after oral administration of capsules, cola beverage and chocolate candy. METHODS: Three males and four females who abstained from methylxanthines received five methylxanthine-containing treatments: caffeine in capsules (72 mg), administered twice; theobromine in capsules (370 mg); cola beverage (72 mg caffeine) and chocolate candy (72 mg caffeine and 370 mg theobromine). Plasma methylxanthine levels were assayed from samples collected before and 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, and 3.0 h after caffeine capsule and cola treatments and, additionally, at 4.0 and 6.0 h after theobromine capsule and chocolate treatments. RESULTS: Caffeine plasma concentrations increased rapidly and peaked at approximately 30 min following both capsule treatments 1 (Cmax: 1.93 micrograms.ml-1); and 2 (Cmax: 2.05 micrograms.ml-1). Relative to capsules, caffeine absorption from cola and chocolate was delayed and produced lower maximum caffeine plasma concentrations which peaked 1.5-2.0 h after treatment (For cola, Cmax: 1.57 micrograms.ml-1); and for chocolate, Cmax: 1.50 micrograms.ml-1. Theobromine plasma concentrations peaked approximately 3 h after capsule administration (Cmax: 6.72 micrograms.ml-1). Relative to capsules, theobromine absorption from chocolate was more rapid and produced higher maximum theobromine plasma concentrations which peaked approximately 2 h after treatment (Cmax: 8.05 micrograms.ml-1). CONCLUSIONS: The results suggest that a usual dietary portion of the cola or chocolate used in this study would produce behaviorally discriminable plasma levels of caffeine in most subjects and of theobromine in at least one subject.

Discriminative stimulus and subjective effects of theobromine and caffeine in humans.

Theobromine versus placebo discrimination and caffeine versus placebo discrimination were studied in two consecutive experiments in seven volunteers who abstained from methylxanthines. Daily sessions involved PO double-blind ingestion of two sets of capsules sequentially, one of which contained drug and the other placebo. Subjects attempted to identify, and were later informed, which set of capsules contained the drug. In each experiment subjects were exposed to progressively lower doses. Five subjects acquired the theobromine discrimination; the lowest dose discriminated ranged from 100 to 560 mg. All seven subjects acquired the caffeine discrimination; the lowest dose discriminated ranged from 1.8 to 178 mg. A final experiment evaluated subjective effect ratings following 560 mg theobromine, 178 mg caffeine and placebo, which were administered double-blind in capsules once daily, five times each in mixed sequence. Caffeine produced changes in both group and individual ratings (e.g. increased well-being, energy, social disposition and alert). Theobromine did not produce changes in group ratings but changed ratings in some subjects. Across subjects, sensitivity to caffeine discriminative effects in the discrimination experiment correlated significantly with the number and magnitude of caffeine subjective effects in the final experiment. This study documents modest discriminative effects of theobromine in humans, but the basis of the discrimination is unclear. This study suggests that commonly consumed cocoa products contain behaviorally active doses of caffeine and possibly theobromine.

Intravenous self-injection of methcathinone in the baboon.

Methcathinone is a phenylisopropylamine that has been produced by clandestine laboratories and identified in illicit drug traffic. The present study evaluated the intravenous self-administration of methcathinone in three baboons using a cocaine substitution procedure. Intravenous self-injections were available 24 h/day according to a fixed-ratio (FR) schedule with a 3-h timeout following each injection. Doses of racemic methcathinone HCl (0.01-1.0 mg/kg/injection) and its vehicle were substituted for cocaine for 15 or more days. A concurrent FR schedule of food pellet delivery allowed evaluation of any changes in food intake. Self-injection of methcathinone was dose dependent. The lower doses of methcathinone, 0.01 and 0.032, maintained low and intermediate rates of self-injection, respectively, while the higher doses, 0.1, 0.32, and 1.0, maintained rates above vehicle control and comparable to those maintained by cocaine. Acute administration of 3.2 mg/kg to two baboons produced signs of psychomotor stimulant toxicity. Systematic changes in food intake were not observed. The present data indicate that methcathinone functions as a positive reinforcer in baboons and suggests that methcathinone may have abuse potential.

Conditioned reinforcement of human observing behavior by descriptive and arbitrary verbal stimuli.

College students earned monetary reinforcers by pressing a key according to a compound schedule with variable-interval and extinction components. Pressing additional keys occasionally produced displays of either of two verbal stimuli; one was uncorrelated with the schedule components, and the other was correlated with the extinction component. In Experiments 1 and 2, the display area of the apparatus was blank unless an observing key was pressed, whereupon a descriptive message appeared. Most students preferred an uncorrelated stimulus stating that "Some of this time scores are TWICE AS LIKELY as normal, and some of this time NO SCORES can be earned" over a stimulus stating that "At this time NO SCORES can be earned." In Experiment 3, the display area indicated that "The Current Status of the Program is: NOT SHOWN." Presses on the observing keys replaced this message with stimuli that provided arbitrary labels for the schedule conditions. All of the students preferred a stimulus stating that "The Current Status of the Program is: B" over an uncorrelated stimulus stating that "The Current Status of the Program is: either A or B." Thus, under some circumstances, observing was maintained by a stimulus correlated with extinction-a finding that poses a challenge for Pavolvian accounts of conditioned reinforcement. Differences in the maintenance of observing by the descriptive and arbitrary stimuli may be attributed to differences in either the strength or nature of the instructional control exerted by the verbal stimuli.

General activity in baboons measured with a computerized, lightweight piezoelectric motion sensor: effects of drugs.

A small, 1-oz activity-monitoring device is described for measuring motor activity continuously for periods of up to 42 days. The monitor employs a piezoelectric sensor that detects extremely small accelerations induced by movements. The monitor can be placed on collars or harnesses (e.g., for rabbits, cats, dogs, nonhuman primates, etc.). The use of the monitor is described within numerous laboratories studying the behavioral pharmacology of drugs in individually caged laboratory baboons. Patterns of daily activity were reliably recorded over periods of several months, and reflected the normal activity patterns of animals. The activity monitor recorded reliable, drug-induced changes in general activity that paralleled the known effects of the same drugs on learned behaviors. Low doses of the stimulants cocaine and d-amphetamine both increased general activity. Marked reductions in general activity were observed following both the administration of delta-9-tetrahydrocannabinol and an antihypertensive drug combination of diuretic and verapamil.

Stimulus control of Pavlovian facilitation.

Two experiments were conducted using an autoshaping procedure with pigeons to examine whether dimensional stimulus control by a Pavlovian facilitator parallels the control established following operant discrimination training. Facilitation training consisted of the presentation of a black vertical line on a white background as the B stimulus in a feature-positive discrimination in which the A stimulus (white keylight) was followed by grain presentation only if preceded by B. In this way, B facilitates or sets the occasion for pecking at A. Subsequent testing for generalization along the line-orientation dimension produced decremental gradients when the facilitation paradigm incorporated an explicit feature-negative stimulus (B-). These results parallel the decremental control obtained following operant discrimination training and suggest that Pavlovian facilitators and instrumental discriminative stimuli are functionally equivalent.