Barbara J. Kaminski

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.

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 μg ⋅ ml−1); and 2 (Cmax: 2.05 μg ⋅ 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 μg ⋅ ml−1); and for chocolate, Cmax: 1.50 μg ⋅ ml−1. Theobromine plasma concentrations peaked approximately 3 h after capsule administration (Cmax: 6.72 μg ⋅ 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 μg ⋅ 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.

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.

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.

A modified adjusting delay task to assess impulsive choice between isocaloric reinforcers in non-deprived male rats: effects of 5-HT2A/C and 5-HT1A receptor agonists

RationaleExisting animal models of impulsivity frequently use food restriction to increase subjects’ motivation. In addition, behavioral tasks that assess impulsive choice typically involve the use of reinforcers with dissimilar caloric content. These factors represent energy-homeostasis limitations, which may confound the interpretation of results and limit the applicability of these models.ObjectivesThis study was aimed at validating face and convergent validities of a modified adjusting delay task, which assesses impulsive choice between isocaloric reinforcers in ad libitum fed rats.MethodsMale Wistar rats (n = 18) were used to assess the preferredness and reinforcing efficacy of a “supersaccharin” solution (1.5% glucose/0.4% saccharin) over a 1.5% glucose solution. A separate group of rats (n = 24) was trained in a modified adjusting delay task, which involved repeated choice between the glucose solution delivered immediately and the supersaccharin solution delivered after a variable delay. To pharmacologically validate the task, the effects of the 5-HT2A/C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)-DOI] and the 5-HT1A receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide [(±)-8-OH-DPAT] on impulsive choice were then evaluated.ResultsSupersaccharin was highly reinforcing and uniformly preferred over the glucose solution by all subjects. Rats quickly learned the task, and impulsivity was a very stable and consistent trait. DOI and 8-OH-DPAT significantly and dose dependently increased impulsive choice in this modified adjusting delay task.ConclusionsWe validated a rodent task of impulsive choice, which eliminates typical energy-homeostasis limitations and, therefore, opens new avenues in the study of impulsivity in preclinical feeding and obesity research.

Baclofen effects on alcohol seeking, self-administration and extinction of seeking responses in a within-session design in baboons.

Baclofen, a gamma‐aminobutyric acidB receptor agonist, is currently under investigation as a potential treatment to prevent relapse to drinking in alcohol‐dependent persons. In the current study, two groups of baboons were trained under a chained schedule of reinforcement (CSR), with three linked components, which were each correlated with different response requirements and cues. Fulfilling the requirement in the second link initiated the third link where either alcohol (n = 4) or a preferred non‐alcoholic beverage (Tang, n = 5) was available for self‐administration; failure to complete the response requirement in Link 2 ended the session (no access to alcohol or Tang). Seeking responses in Link 2 were used as indices of the motivational processes thought to be involved in relapse. The effects of baclofen (0.1–2.4 mg/kg) were examined under conditions with alcohol or Tang access and under extinction. Under the CSR, baclofen (1.8 and 2.4 mg/kg) significantly decreased (P < 0.05) alcohol self‐administration responses and total g/kg alcohol intake. In contrast, only the highest dose of baclofen (2.4 mg/kg) reduced Tang self‐administration and consumption. Under within‐session extinction conditions, baclofen (1.8 and 2.4 mg/kg) facilitated extinction of responding for both alcohol and Tang, particularly during the first 10 minutes of extinction. Baclofen may be effective in reducing craving and alcohol drinking, although the facilitation of extinction and suppression of both alcohol and Tang self‐administration by baclofen suggests these effects may be related to a more general suppression of consummatory and conditioned behaviors.

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

&NA; 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 intermediateintensity 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. ‐ Behavioural Pharmacology 14:331‐342

Intravenous self-administration of gamma-hydroxybutyrate (GHB) in baboons

BACKGROUND Abuse of gamma-hydroxybutyrate (GHB) poses a public health concern. In previous studies, intravenous (IV) self-administration of GHB doses up to 10 mg/kg was not maintained in non-human primates under limited-access conditions, which was inconsistent with the usual good correspondence between drugs abused by humans and those self-injected by laboratory animals. METHODS Self-administration of GHB was studied in 10 baboons using procedures standard for our laboratory to assess drug abuse liability. Each self-injection depended on completion of 120 or 160 lever responses. Sessions ran continuously; a 3-h timeout limited the number of injections per 24h to 8. Self-injection was established at 6-8 injections/day with cocaine (0.32 mg/kg/injection) prior to substitution of each GHB dose (3.2-178 mg/kg/injection) or vehicle for 15 days. Food pellets were available 24h/day. RESULTS GHB maintained significantly greater numbers of injections when compared to vehicle in 6 of the 9 baboons that completed GHB evaluations that included 32 mg/kg/injection or higher. The baboons that self-administered GHB at high rates were ones for which GHB was the first drug each had tested under the 24-h/day cocaine baseline procedure. Self-injection of the highest doses of GHB decreased food-maintained responding. CONCLUSIONS High-dose GHB can function as a reinforcer in non-human primates under 24-h access, but self-administration history may be important. The findings are consistent with the demonstrated abuse liability of GHB in humans, and remove GHB as an exception to the typical good correspondence between those drugs abused by humans and those self-administered by nonhuman primates.

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.

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 0.32 mg/kg/injection cocaine under a fixed-ratio (FR) schedule, with a 3 h timeout following each injection. Doses of (±)-N-ethyl-3,4-methylenedioxyamphetamine HCI (MDE), (±)-N-hydroxy-3,4-methylenedioxyamphetamine HCI (N-OH-MDA), (+)-N-N-dimethylamphetamine HCI (NNDMA), and 4-bromo-2,5-dimethyoxy-β-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.