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Biomedical subjects

C A Sannerud

Publications and source records attributed to C A Sannerud.

At least 19 recordsLinked to original sources
PubMed2003

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.

Animals↗
PubMed1998

The stimulus properties of two common over-the-counter drug mixtures: dextromethorphan + ephedrine and dextromethorphan + diphenhydramine.

Two groups of rats were trained in a two-choice drug discrimination procedure under a fixed-ratio 10 schedule of food reinforcement. One group of rats (n=12) was trained to discriminate the presence and absence of a drug mixture containing 10 mg/kg dextromethorphan + 10 mg/kg diphenhydramine. The other group of rats (n=12) was trained to discriminate the presence and absence of another drug mixture containing 10 mg/kg dextromethorphan + 10 mg/kg ephedrine. Cross-generalization tests conducted with each of the stimulus elements demonstrated that (1) the drug mixtures were not perceived as new entities distinct from their component elements and (2) the stimulus element saliency may be a factor determining the nature of discriminative control by drug mixtures. Cross-generalization tests conducted with the psychomotor stimulants, cocaine and amphetamine, engendered complete generalization to the training cues in both groups, whereas, pentobarbital engendered predominantly saline- or default-lever responding. These data suggest a potential abuse liability for both of these common over-the-counter drug mixtures and cautions against the use of such combinations in pediatric patients.

Adrenergic Agents↗
PubMed1996

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.

Absorption↗
PubMed1995

Drug discrimination analysis of midazolam under a three-lever procedure. II: Differential effects of benzodiazepine receptor agonists.

Twelve rats were trained to discriminate 0.32 and 3.2 mg/kg s.c. midazolam from no drug under a three-lever, multiple trials drug discrimination procedure. In cumulative dose-response tests, midazolam s.c. (0.032-10 mg/kg) and i.p. (0.1-10 mg/kg) occasioned dose-dependent increases first in 0.32 mg/kg (low-dose) lever responding and then in 3.2 mg/kg (high-dose) lever responding. The benzodiazepines diazepam (0.032-18 mg/kg) and triazolam (0.0032-3.2 mg/kg) produced patterns of generalization similar to that of midazolam; however, chlordiazepoxide (0.1-32 mg/kg), lorazepam (0.032-10 mg/kg), flurazepam (0.01-10 mg/kg), bretazenil (0.01-32 mg/kg) and the imidazopyridazine zolpidem (0.032-3.2 mg/kg) dose-dependently occasioned > 80% responding on the low- but not the high-dose midazolam lever. Clonazepam (0.1-10 mg/kg) occasioned 0% responding on the high-dose lever, but also failed to occasion full generalization to the low-dose midazolam lever in 40% of the rats. Bretazenil has been well-characterized as a partial benzodiazepine agonist and zolpidem as benzodiazepine-receptor-subtype selective; the present results are consistent with their partial or selective agonist effects in those other paradigms. The differential effects of the classic 1,4 benzodiazepine agonists tested suggest that the discriminative stimulus effects of these other compounds may be more differentiable than previous drug discrimination studies have suggested. This three-choice drug discrimination procedure appears to be a useful model for studying relative intrinsic efficacies of this class of compounds.

Animals↗
PubMed1995

Drug discrimination analysis of midazolam under a three-lever procedure: I. Dose-dependent differences in generalization and antagonism.

Twelve rats were trained to discriminate two doses of midazolam, 0.32 and 3.2 mg/kg, from no drug under a three-lever, multiple-trials procedure (15-min time-out, 5-min fixed-ratio-10 schedule of food reinforcement). In tests, midazolam (0.0032-10 mg/kg), administered cumulatively within a session or acutely across sessions, produced dose-dependent increases in responding on the low-dose lever after 0.1 to 1.0 mg/kg and on the high-dose lever at higher doses in all rats. Flumazenil dose-dependently antagonized the discriminative stimulus effect of 3.2 mg/kg of midazolam in all rats but antagonism of the lower midazolam training dose was not obtained in all rats. Pentobarbital dose-dependently produced responding on the levers associated with the no-drug and 0.32-mg/kg midazolam conditions but not on the lever associated with 3.2 mg/kg of midazolam. These results differed from those that would have been predicted from studies in midazolam-trained rats in two-lever procedures. The muscle relaxant methocarbamol and nonsedative/anxiolytic drugs (morphine, caffeine and d-amphetamine) did not produce responding on the lever associated with either the low or high midazolam training dose. However, cocaine produced partial responding on the lever associated with the low midazolam dose. Thus, the discriminative stimulus effects of 3.2 mg/kg of midazolam were benzodiazepine-like and not a function of general sedative or muscle-relaxant effects. The 0.32-mg/kg midazolam training dose, in this context, appeared less specific than 3.2 mg/kg of midazolam. Taken together, the results suggest that not all differences among the training stimuli in this three-lever context reflect simple differences in dose.

Animals↗
PubMed1994

The effects of sertraline on nicotine self-administration and food-maintained responding in squirrel monkeys.

Recent reports suggested the involvement of serotonergic mechanisms in nicotine self-administration. The present study assessed the effects of sertraline, a selective serotonergic uptake inhibitor, on the reinforcing effects of i.v. nicotine (30 microgram/kg per injection) in squirrel monkeys responding under a fixed-ratio schedule. Nicotine (10-100 micrograms/kg per injection) produced a significant inverted U-shaped distribution on FR rate. Vehicle or sertraline (3, 6, 12, 24 mg/kg, p.o.) produced no changes in the response rates maintained by 30 micrograms/kg per injection i.v. nicotine, but sertraline produced non-significant increases response rates maintained by 10 micrograms/kg per injection nicotine and vehicle. In a separate group of monkeys, sertraline given in combination with i.m. doses of nicotine produced a significant dose-dependent decrease in responding maintained by food-pellet delivery. Thus, sertraline produced differential effects on response rates that may be related to (1) route of nicotine administration and (2) whether the behavior was maintained by nicotine or food. In addition, the results of the self-administration study suggest that sertraline would not disrupt well-maintained responding for nicotine.

1-Naphthylamine↗
PubMed1994

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.

Adult↗
PubMed1993

Behavioral pharmacology of tandospirone in baboons: chronic administration and withdrawal, self-injection and drug discrimination.

The behavioral pharmacology of tandospirone (SM 3997), a novel anxiolytic/antidepressant pyrimidinylpiperazine compound with selective pharmacological effects at the 5-HT1A binding site, was investigated in baboons. Animals administered 50 mg/kg/day i.g. tandospirone, showed few behavioral changes (lip droop, ataxia), which decreased over 2 weeks. Substitution of vehicle for tandospirone after 7 weeks produced time-limited suppression of food intake, suggesting a mild withdrawal syndrome. Under an i.v. self-injection procedure, tandospirone (1.0-32 mg/kg/injection) did not maintain responding greater than vehicle, although cocaine and triazolam did. Under a drug discrimination procedure, tandospirone (1-3.2 mg/kg p.o.; 0.1-32 mg/kg, i.m.) did not occasion drug-appropriate responding in baboons trained to discriminate lorazepam or pentobarbital and buspirone (1-18 mg/kg, p.o.; 0.1-1.0 mg/kg, i.m.) did not occasion drug-appropriate responding in the pentobarbital-training group. Tandospirone's profile of effects differs from those for barbiturates and benzodiazepines and suggests low abuse liability.

Animals↗
PubMed1993

Tolerance to the behavioral effects of chlordiazepoxide: pharmacological and biochemical selectivity.

There is a dynamic interaction between a drug's pharmacological effects and the behavioral context in which it is administered. The present study evaluated the influence of behavioral processes on the development of tolerance and cross-tolerance to the rate-decreasing effects of chlordiazepoxide in rats. Sprague-Dawley rats responded under a fixed-ratio 30 schedule of food delivery. Different groups of rats received 18 mg/kg/day of chlordiazepoxide either before (PRE, n = 8) or after (POST, n = 10) daily experimental sessions for 8 weeks. Cumulative dose-response curves for chlordiazepoxide were obtained before and during chronic chlordiazepoxide administration and during chronic saline administration. Cumulative dose-response curves for midazolam, FG 7142 (N-methyl-beta-carboline-3-carboxamide) flumazenil, pentobarbital, caffeine, morphine and d-amphetamine were determined before, during and 4.5 to 5 months after chronic chlordiazepoxide administration. Group PRE developed tolerance to chlordiazepoxide, whereas group POST did not develop tolerance. Although cross-tolerance developed to midazolam in both groups, it was greater in group PRE. Both groups showed comparable sensitization to FG7142 and neither group showed a significant change in sensitivity to any of the other drugs. Biochemical studies of gamma-aminobutyric acid (GABA)-related functioning in groups of rats that received chronic chlordiazepoxide administration either before (BIO-PRE, n = 6) or after (BIO-POST, n = 6) daily sessions found that GABA-stimulated 36Cl-uptake increased in both cortical and cerebellar preparations. However, GABA sensitivity in cerebellar tissue was significantly lower in group BIO-PRE compared with group BIO-POST. Thus, behavioral tolerance to chlordiazepoxide was associated with both pharmacological and biochemical effects, which suggests a relationship between behavioral tolerance to benzodiazepines and changes in the functional state of the GABA-benzodiazepine receptor complex.

Amphetamine↗
PubMed1992

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.

Animals↗
PubMed1992

Zolpidem behavioral pharmacology in baboons: self-injection, discrimination, tolerance and withdrawal.

This study examined in baboons various behavioral effects of zolpidem, a short-acting imidazopyridine hypnotic which has selectivity for subtypes of the benzodiazepine receptor. Intravenous drug self-injection was studied under a fixed-ratio 80- or 160-response schedule with a 3-hr timeout after each injection. Maximal rates of self-injection maintained by zolpidem (0.01-1 mg/kg) were consistently higher than those maintained by vehicle and the benzodiazepine hypnotic triazolam. Substitution of vehicle after about 2 weeks of zolpidem self-injection (7-8 mg/kg/day) resulted in a time-limited suppression of food pellet intake, indicating a drug withdrawal effect. In a drug discrimination study, baboons were trained to discriminate either lorazepam (1.8 mg/kg p.o.) or pentobarbital (10 mg/kg p.o.) from the no-drug condition. Zolpidem (0.1-18 mg/kg p.o.) occasioned both lorazepam- and pentobarbital-appropriate responding (greater than 80%) in a dose-dependent manner. In a final experiment, zolpidem (3.2 or 5.6 mg/kg i.m.) produced ataxia and sedation that progressively decreased over 7 consecutive days of administration. The withdrawal, discriminative stimulus effects and tolerance shown with zolpidem were similar to those shown previously with benzodiazepines under similar conditions. The rates of self-injection of zolpidem were similar to those maintained by intermediate duration barbiturates (e.g., pentobarbital) and higher than those maintained by 11 benzodiazepines studied previously under similar conditions. Further research on the reinforcing effects of zolpidem may provide useful insights into mechanisms underlying the maintenance of behavior by compounds acting through the benzodiazepine receptor.

Animals↗
PubMed1991

Behavioral effects of benzodiazepine ligands in non-dependent, diazepam-dependent and diazepam-withdrawn baboons.

Acute i.m. injections of benzodiazepine receptor ligands were administered to baboons before 1-h observational sessions. The agonist midazolam produced sedative effects, the antagonist flumazenil produced no behavioral effects, the inverse agonist FG7142 produced tremor and the inverse agonist 3-carboethoxy-beta-carboline hydrochloride (beta CCE) produced tremor, vomiting, jerks and seizures. Co-administration of these drugs (midazolam + beta CCE, midazolam + flumazenil or flumazenil + beta CCE) produced a mutual antagonism of these effects. Compared to the non-dependent condition, in the diazepam-dependent condition (baboons maintained on 20 mg/kg per day diazepam) and withdrawn condition (dependent baboons tested during withdrawal), midazolam produced decreased sedative effects, flumazenil produced increased effects (i.e., tremor, vomiting and jerks), and beta CCE produced increased frequency of seizures. Taken together, these data suggest that (1) benzodiazepine receptor ligands lie on a continuum of behavioral activity, and (2) chronic diazepam administration alters the behavioral effects of these benzodiazepine ligands, producing a shift in the direction of the inverse agonist.

Animals↗
PubMed1991

Self-injection of barbiturates, benzodiazepines and other sedative-anxiolytics in baboons.

Self-injection of 12 sedative-anxiolytics was examined in baboons. Intravenous injections and initiation of a 3-h time-out were dependent upon completion of a fixed-ratio schedule requirement, permitting eight injections per day. Before testing each dose of drug, self-injection performance was established with cocaine. Subsequently, a test dose was substituted for cocaine. At some doses, all five of the benzodiazepines examined (alprazolam, bromazepam, chlordiazepoxide, lorazepam, triazolam) maintained rates (number of injections per day) of drug self-injection above vehicle control in each of the baboons tested. Maximum rates of benzodiazepine self-injection were generally submaximal. Of the benzodiazepines examined, triazolam maintained the highest rates of self-injection. Among the three barbiturates tested, methohexital generally maintained high rates of self-injection in contrast to hexobarbital and phenobarbital, which only maintained low rates. Of the four non-benzodiazepine non-barbiturate sedatives examined, both chloral hydrate and methyprylon occasionally maintained high rates of self-injection. Although there were differences within and across animals, baclofen maintained intermediate rates of self-injection. The novel anxiolytic buspirone maintained only low rates of self-injection that were not different from vehicle. This study further validates the self-injection methodology for assessing sedative-anxiolytic abuse liability and provides new information about drug elimination rate as a determinant of drug self-administration.

Animals↗
PubMed1991

Comparison of the discriminative stimulus effects of midazolam after intracranial and peripheral administration in the rat.

Rats were trained in a two-lever drug discrimination paradigm to discriminate midazolam (0.32 mg/kg, i.p. or 1.0 mg/kg, i.p.) from the no-drug condition. After completion of i.p. and s.c. midazolam generalization gradients (0.032-1.0 mg/kg), rats were surgically implanted with unilateral cannulae into the lateral ventricles. Intracerebroventricular (i.c.v.) doses of 1.1-44.2 micrograms midazolam were delivered to unrestrained rats. Midazolam produced dose-dependent increases in drug-appropriate responding by all three routes of administration, but was 2.4- to 4.3-fold more potent when given i.c.v. than when given s.c. or i.p. Midazolam, over the dose range tested, did not produce substantial decreases in response rate by any route of administration. The discriminative-stimulus effect of i.c.v. midazolam was blocked by peripherally administered flumazenil, and such antagonism was surmounted by a 2- to 5-fold increase in the i.c.v. midazolam dose. Taken together, these data suggest that the discriminative-stimulus effects of midazolam are mediated via central benzodiazepine (BZ) receptors.

Animals↗
PubMed1990

Tolerance to morphine stimulus control: role of morphine maintenance dose.

Experiments assessed the development of tolerance to morphine stimulus control during treatment with selected maintenance doses of morphine. Separate groups of rats were trained to discriminate saline and either 3.2 mg/kg or 5.6 mg/kg morphine under fixed-ratio schedules of food delivery. Dose-response functions for generalization of morphine stimulus control were determined before, during, and after repeated treatment with selected doses of morphine. Similar experiments were performed with repeated pentobarbital treatment in order to assess the pharmacological selectivity of tolerance. Repeated treatment with saline, 3.2 mg/kg morphine, or twice daily injections of 17.8 mg/kg pentobarbital produced no tolerance to morphine stimulus control. In contrast, treatment with daily injections of 10 mg/kg or twice daily injections of 10 or 17.8 mg/kg morphine produced a dose-dependent increase in the dose of morphine required for stimulus control. The magnitude of tolerance to morphine stimulus control varied directly with the maintenance dose of morphine and was slightly greater for a lower than a higher morphine training dose. Termination of repeated treatment was followed by a return to initial sensitivity, without additional training. Tolerance to morphine stimulus control was not necessarily accompanied by tolerance to its rate-suppressing effects.

Animals↗
PubMed1990

Intravenous self-administration of 4-methylaminorex in primates.

The reinforcing effects of (+/-)-cis-2-Amino-4-methyl-5-phenyl-2-oxazoline (4-methylaminorex) were determined in two models of intravenous drug self-administration in primates. In baboons, lever pressing was maintained under a fixed-ratio (FR) 80- or 160-schedule of intravenous cocaine delivery (0.32 mg/kg per injection). Each drug injection was followed by a 3-h time-out allowing a maximum of 8 injections per day. Vehicle or 4-methylaminorex doses were substituted for cocaine for a period of 15 or more days. One of the two 4-methylaminorex doses evaluated (0.32 mg/kg per injection) maintained self-administration behavior above vehicle control levels in all four animals. This dose of 4-methylaminorex maintained cyclic patterns of self-injection behavior across days and produced signs of psychomotor stimulant toxicity. In rhesus monkeys, 4-methylaminorex (0.0003-0.1 mg/kg per injection) was made available to animals trained to self-administer cocaine (0.01 or 0.033 mg/kg per injection) under an FR 10 schedule of reinforcement during daily 1-h sessions. Each of the three monkeys self-administered at least two doses of 4-methylaminorex at rates exceeding those maintained by vehicle injections. Taken together with reports of recreational abuse of 4-methylaminorex, the present results indicate that this drug has a potential for abuse similar to that of other psychomotor stimulants.

Animals↗