Respiratory effects of opioid full and partial agonists in rhesus monkeys.

Respiratory and behavioral effects of the mu selective opioids levorphanol (0.01-3.0 mg/kg), methadone (0.03-5.6 mg/kg) and codeine (0.3-30.0 mg/kg) and the mixed-action opioids buprenorphine (0.003-10.0 mg/kg), butorphanol (0.003-0.3 mg/ kg) and nalbuphine (0.03-30.0 mg/kg) were studied in rhesus monkeys. In respiratory experiments, awake, seated monkeys wore plastic masks through which they breathed air or differing concentrations of CO2 mixed in air. Exposure to CO2 in air stimulated ventilation in a concentration-dependent manner. All opioids produced dose-dependent decreases in ventilation that were more pronounced as the concentration of CO2 increased. The highest doses of levorphanol, methadone, and butorphanol reduced the ventilatory stimulant effects of 5% CO2 in air by 85 to 90%, whereas the highest doses of nalbuphine, buprenorphine and codeine reduced the effects of 5% CO2 in air by only 50 to 75%. After presession butorphanol (0.01-0.1 mg/kg) or nalbuphine (1.0-3.0 mg/kg), levorphanol further reduced the ventilatory stimulant effects of 5% CO2 mixed in air, with some evidence of dose-effect flattening. However, pretreatment with buprenorphine (1.0-10.0 mg/kg) and the highest dose of nalbuphine (10.0 mg/kg) attenuated the effects of 10.0 mg/kg levorphanol, indicative of antagonism. In behavioral experiments, all drugs produced dose-related decreases in responding under a 30-response fixed-ratio schedule. The highest doses of levorphanol, methadone, codeine, and butorphanol nearly abolished responding in all subjects, whereas buprenorphine and nalbuphine most often reduced response rates by no more than 50%. Except for codeine, rank orders of potency were the same in behavioral and respiratory experiments. The lesser effects of nalbuphine and buprenorphine on ventilation, in conjunction with their levorphanol-antagonist effects, suggest their limited mu agonist efficacy at sites mediating the respiratory-depressant effects of opioids.

Activity anorexia: An interplay between basic and applied behavior analysis.

The relationship between basic research with nonhumans and applied behavior analysis is illustrated by our work on activity anorexia. When rats are fed one meal a day and allowed to run on an activity wheel, they run excessively, stop eating, and die of starvation. Convergent evidence, from several different research areas, indicates that the behavior of these animals and humans who self-starve is functionally similar. A biobehavioral theory of activity anorexia is presented that details the cultural contingencies, behavioral processes, and physiology of anorexia. Diagnostic criteria and a three-stage treatment program for activity-based anorexia are outlined. The animal model permits basic research on anorexia that for practical and ethical reasons cannot be conducted with humans. Thus, basic research can have applied importance.

Combination of buspirone and other drugs with beta-CCE in monkeys: effects on respiration and behavior.

The respiratory and behavioral effects of the benzodiazepine receptor (BZR) inverse agonist ethyl-beta-carboline-3-carboxylate (beta-CCE) were determined alone and in combination with buspirone, lorazepam, flumazenil, and SR 95195 in rhesus monkeys. For the respiratory studies, one group of monkeys inhaled either air or 5% CO2 mixed in air according to a fixed alternating schedule; respiratory frequency and minute volume were monitored. For the behavioral studies, another group of monkeys responded under a fixed-ratio (FR 30) schedule of food presentation. The respiratory stimulant effects of beta-CCE in both air and 5% CO2 were enhanced by prior treatment with the 5-hydroxytryptamine1A (5-HT1A) partial agonist buspirone (0.03 and 0.3 mg/kg) and a weak BZR inverse agonist, SR 95195 (10.0 mg/kg). Coadministration of buspirone (0.1 and 0.3 mg/kg) also potentiated the rate-decreasing effects of beta-CCE under the FR schedule. The BZR agonist lorazepam (3.0 mg/kg) and BZR antagonist flumazenil (1.0 mg/kg) attenuated the effects of beta-CCE on respiratory frequency and minute volume particularly under the 5% CO2 condition, and lorazepam (0.1 and 0.3 mg/kg) and flumazenil (0.1 and 0.3 mg/kg) attenuated the effects of beta-CCE on FR responding. These latter results show that the respiratory and behavioral effects of beta-CCE in rhesus monkeys are at least in part due to effects at BZRs. Moreover, the findings suggest either that coactivation of benzodiazepine and 5-HT1A sites lead to a greater than additive effect or that beta-CCE and buspirone share a common mechanism of action that is unrelated to the receptor at which BZR inverse agonists act.

Respiratory effects of benzodiazepine-related drugs in awake rhesus monkeys.

The respiratory effects of several benzodiazepine (BZ) agonists and inverse agonists were compared with those of buspirone and pentobarbital in awake rhesus monkeys. Subjects, fitted with a helmet that served as a pressure displacement plethysmograph, were studied in a ventilated, sound-attenuating chamber; ventilatory frequency, tidal volume (VT) and minute volume (VE) were determined from the plethysmograph signal. During experimental sessions monkeys inhaled either 5% carbon dioxide (CO2) mixed in air or air alone according to a fixed alternating schedule. BZ agonists (alprazolam, 0.01-1.0 mg/kg; lorazepam, 0.3-10.0 mg/kg; quazepam, 1.0-5.6 mg/kg) decreased VT and VE during both 5% CO2 and air inhalation. Pentobarbital (3.0-30.0 mg/kg) also decreased VT and VE and additionally decreased respiratory frequency in monkeys breathing 5% CO2. Two BZ inverse agonists, the beta-carbolines beta-CCE and FG 7142 (0.3-5.6 or 10.00 mg/kg), increased frequency and had no effect on VT, resulting in an increase in VE in monkeys breathing either 5% CO2 or air. The weak BZ inverse agonist CGS 8216 (0.3-5.6 mg/kg) similarly increased ventilation only in monkeys breathing air. Buspirone (0.03-0.3 mg/kg), like the beta-carbolines, increased frequency and VE and, like the BZ agonists, decreased VT. The BZ antagonist Ro15-1788 (0.1-3.0 mg/kg) had little or no effect on ventilation, but Ro15-1788 and also CGS 8216 (both at 1.0 mg/kg) attenuated the respiratory depressant effects of lorazepam or alprazolam. In turn, alprazolam (0.03-0.3 mg/kg) and quazepam (1.0-3.0 mg/kg) attenuated the respiratory stimulant effects of FG 7142.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory effects of xanthines and adenosine analogs in rhesus monkeys.

This study examined the relative contributions of phosphodiesterase inhibition and adenosine receptor blockade in the respiratory-stimulant effects of selected xanthines. The respiratory effects of caffeine, theophylline, 8-phenyltheophylline (8-PT), 8-cyclopentyltheophylline (8-CPT), 3-isobutyl-1-methylxanthine and enprofylline, as well as the nonxanthine phosphodiesterase inhibitor, rolipram, and the adenosine analogs, N6-cyclopentyladenosine (CPA) and 5'-N-ethylcarboxamide adenosine (NECA), were studied in unanesthetized rhesus monkeys. Ventilation was measured continuously by enclosing the monkey's head in a fitted Lexan helmet while a pressure transducer measured differences in pressure produced by inspirations and expirations against a constant flow of air. Drugs were administered (i.m.) using cumulative-dosing procedures while the subjects breathed air or 5% CO2 mixed in air. All xanthines except 8-PT produced dose-related increases in respiratory frequency and less pronounced changes in tidal volume, both in air and in 5% CO2 mixed in air. 8-PT, an adenosine antagonist with little activity as a phosphodiesterase inhibitor, did not have respiratory effects over the range of doses studied. Enprofylline, a phosphodiesterase inhibitor with little activity as an adenosine antagonist, had effects that were comparable to those of caffeine. Rolipram also had effects on respiration that were similar to those of caffeine, and it was approximately 100 times more potent than caffeine. The adenosine A1/A2 agonist, NECA, produced dose-related increases in respiratory frequency, and both CPA (an A1-selective agonist) and NECA produced dose-related decreases in tidal volume; NECA was 30 to 100 times more potent than CPA.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological characterization of supersensitivity to naltrexone in squirrel monkeys.

Effects of naltrexone and of other drugs in decreasing rates of schedule-controlled responding were studied in squirrel monkeys treated weekly with naltrexone while responding under fixed-ratio schedules of either food presentation (FP) or stimulus-shock termination (SST). By the 5th week of treatment, sensitivity to the rate-decreasing effects of naltrexone had increased 32-fold in FP monkeys (supersensitivity) but had not changed in SST monkeys; continued weekly injections of naltrexone did not change the effects of naltrexone further in either group. FP monkeys were more sensitive than SST monkeys to the rate-decreasing effects of other opioid antagonists and mixed agonist-antagonists; however, for some compounds (e.g., MR 2266) differences between groups did not exceed differences reported in nonsensitized monkeys responding under similar schedule conditions. Differences in sensitivity between FP and SST monkeys appeared to be stereospecific; FP monkeys were 28 times more sensitive than SST monkeys to (-)-cyclazocine, but equally sensitive to (+)-cyclazocine. Sensitivity to opioid agonists and to some nonopioids varied by less than 3-fold between groups and doses of lithium that decreased responding in FP monkeys had no effect in SST monkeys. Neither acute nor repeated injections of morphine altered the sensitivity of FP or SST monkeys to naltrexone; however, morphine attenuated the rate-decreasing effects of naltrexone in FP monkeys, and naltrexone reversed the rate-decreasing effects of morphine in all monkeys. Super-sensitivity to opioid antagonists in squirrel monkeys is behaviorally and pharmacologically selective as well as stereospecific. Although other effects of antagonists might contribute to supersensitivity, opioid antagonistic action appears to be one important component of supersensitivity and cross-supersensitivity among opioid antagonists.

Environmental determinants of enhanced sensitivity to the behavioral effects of naltrexone.

Dose-effect curves for naltrexone were determined in three squirrel monkeys studied sequentially under four different schedule conditions: a schedule of shock postponement; a fixed-interval schedule of shock presentation; a fixed-ratio schedule of food presentation; and a fixed-ratio schedule of stimulus-shock termination. In general, responding under the shock-postponement or the fixed-interval schedules was decreased minimally by doses of naltrexone up to 30 mg/kg, and these effects were not altered appreciably after daily injections of naltrexone under the fixed-interval schedule. Under the fixed-ratio schedule of food presentation naltrexone (0.3 to 10 mg/kg) produced dose-related decreases in responding, and after repeated daily injections of naltrexone the dose-effect curve was shifted more than 3-fold to the left. Under the fixed-ratio schedule of stimulus-shock termination, however, this supersensitivity to naltrexone was not apparent: responding was decreased appreciably only after 17.6 mg/kg of naltrexone. When the fixed-ratio schedule of food presentation was reinstated, the supersensitivity to naltrexone observed previously under this schedule was not evident initially, but reappeared quickly in two of the monkeys. The greater rate-decreasing effects of naltrexone under the fixed-ratio schedules compared to the other schedules may reflect a dependency related to the control rate of responding. Supersensitivity to naltrexone occurred only under the fixed-ratio schedule of food presentation and could be reversed temporarily by intervening exposure to the schedule of stimulus-shock termination. These results extend earlier findings that the behavioral effects of drugs can be dependent upon both past and present environmental influences.

Behavioral effects of chronically administered cocaine in squirrel monkeys.

Cocaine (0.1 or 0.3 mg/kg/h) was infused continuously from osmotic minipumps during 14-day periods in three squirrel monkeys trained under a fixed-interval schedule of stimulus-shock termination. Chronic exposure to 0.1 mg/kg/h cocaine increased response rates during control sessions for two subjects, and rates returned to pre-infusion levels after the osmotic minipumps were removed. During chronic administration with 0.3 mg/kg/h cocaine, tolerance developed to the gross behavioral effects observed initially in all subjects and to the rate-suppressing effects observed in one subject. Using a cumulative-dosing procedure, cocaine was administered IV acutely once per week before, during and after each chronic administration with cocaine. The acute effects of cocaine on schedule-controlled responding before chronic administration and during chronic exposure to 0.1 and 0.3 mg/kg/h cocaine were similar, providing no evidence of sensitization or tolerance.

Effects of levorphanol and several kappa-selective opioids on respiration and behavior in rhesus monkeys.

The effects of the mu-selective opioid, levorphanol (0.03-1.0 mg/kg), and the kappa-selective opioids, U-50,488 (0.03-1.0 mg/kg), tifluadom (0.01-0.3 mg/kg), bremazocine (0.0003-0.01 mg/kg) and MR 2034 (0.001-0.03 mg/kg), on ventilation and on schedule-controlled behavior were studied in rhesus monkeys. In seated, unanesthetized monkeys prepared with a head plethysmograph, ventilation during exposure to 5% CO2 mixed in air was measured after cumulative doses of each drug. In other monkeys, effects on behavior were studied by administering cumulative doses preceding sequential periods of fixed-ratio responding. Levorphanol, tifluadom, bremazocine and MR 2034 produced dose-related decreases in minute volume, tidal volume and respiratory frequency. In contrast, U-50,488 had only minimal effects on ventilation over the range of doses studied. All drugs decreased fixed-ratio rates in a dose-related manner. Comparisons between their effects in behavioral and respiratory experiments differentiated levorphanol and MR 2034 from U-50,488, bremazocine and tifluadom. Doses of levorphanol or MR 2034 that decreased minute volume markedly had little effect on behavior. In contrast, bremazocine, tifluadom and U-50,488 had less pronounced effects on minute volume at doses that suppressed behavior markedly. Naltrexone (0.03-1.0 mg/kg) antagonized decreases in minute volume produced by levorphanol, MR 2034, bremazocine and tifluadom, and apparent pA2 values were similar for each naltrexone-agonist pair. When the effects of levorphanol (0.03-0.3 mg/kg) were determined in the presence of U-50,488 (0.3 mg/kg), tifluadom (0.1 mg/kg) or bremazocine (0.003 mg/kg), the levorphanol dose-effect curve was shifted approximately 3-fold to the left, suggesting that the effects of the drugs were additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of quaternary naltrexone and chlordiazepoxide in squirrel monkeys with enhanced sensitivity to the behavioral effects of naltrexone.

Dose-effect curves were determined for the effects of the opioid antagonist, naltrexone, on lever-pressing responses of squirrel monkeys maintained under a 30-response fixed-ratio schedule of food presentation. Cumulative doses of naltrexone up to 3 mg/kg i.m. had little or no effect on fixed-ratio responding, whereas higher doses reduced responding in all monkeys. After initial determinations of the dose-effect curve for naltrexone, repeated daily injections of high doses of naltrexone resulted in enhanced sensitivity to its behavioral effects. The cumulative dose-effect curve for naltrexone determined after termination of daily injections was shifted more than 3-fold to the left. In these same monkeys, the dose-effect curve for naltrexone methobromide, a quaternary derivative of naltrexone with limited access to the central nervous system, was similar to the initial dose-effect curve for naltrexone. Chlordiazepoxide given 1 hr before the experimental session shifted the naltrexone dose-effect curve back toward its initial position before the regimen of daily injections, but had no systematic effect on the dose-effect curve for quaternary naltrexone. Enhanced sensitivity to the behavioral effects of naltrexone in these experiments appears to depend on a central component of action and is attenuated by chlordiazepoxide.

Effects of drugs on schedule-controlled running of mice in a circular runway.

Partially food deprived mice ran in a 1-m circular runway. Every 30 circuits, diluted evaporated milk was delivered. Under control conditions mice averaged 0.18 circuits/s for 1 h. The rate was reduced to 0.11 circuits/s 1 h after gavage of Tylose (cellulose derivative) vehicle. Amphetamine, chlordiazepoxide and pentobarbital increased the rate of responding over some dose range, but chlorpromazine, clozapine, imipramine and morphine caused only decreases in responding at effective dose levels. The results are generally similar to reports of effects of the drugs on responses of much briefer duration occurring at similar rates.

Acute and chronic effects of naltrexone and naloxone on schedule-controlled behavior of squirrel monkeys and pigeons.

Dose-effect curves were obtained for the influence of naltrexone, of naloxone and of morphine on lever-pressing responses of squirrel monkeys and key-pecking responses of pigeons maintained by food presentation during fixed-interval (FI) and fixed-ratio (FR) components of a multiple schedule. Morphine caused dose-related decreases in FI and FR responding, with complete suppression occurring after 3 mg/kg was administered to monkeys and after 10 mg/kg was administered to pigeons. Naltrexone doses as low as 0.03 mg/kg (monkeys) or 0.1 mg/kg (pigeons) and naloxone doses as low as 0.1 mg/kg (monkeys) or 1 mg/kg (pigeons) shifted morphine dose-effect curves by one or more log units to the right. The effects of a 3 mg/kg injection of morphine were blocked completely by naltrexone (0.1-0.3 mg/kg) injected up to 16 hr before morphine, but not by naloxone (0.3-1 mg/kg) injected more than 2 hr before morphine. Thus, naltrexone was 3 to 10 times more potent than naloxone as an antagonist of morphine and was longer acting. Given alone, only high doses of naltrexone or naloxone (10 mg/kg, monkeys; 56 mg/kg, pigeons) had pronounced actions; FR and FI responding were markedly decreased and vomiting often occurred. Repeated daily injections of these high doses of naltrexone or naloxone resulted in little or no tolerance. One to 6 months after termination of chronic treatment, dose-effect curves for naltrexone on FR and FI responding maintained by food presentation were shifted markedly to the left with the monkeys, but not with the pigeons.

Pharmacological studies of behavioral influences on cardiovascular function.

Squirrel monkeys, prepared with chronic arterial and venous catheters, responded (pressed a key) under fixed-ratio schedules of termination of a stimulus associated with electric shock or under fixed-ratio schedules of food presentation. Although there was no necessary correlation between schedule-controlled responding and cardiovascular changes, pronounced elevations in both heart rate and blood pressure occurred during and just after brief periods of fixed-ratio responding. These episodic increases in blood pressure and heart rate were as marked under schedules of food presentation as under schedules of stimulus-shock termination. Thus, these episodic changes appear to be more dependent upon the schedule-controlled behavior than upon the type of event maintaining the behavior. Pharmacological studies indicated that under the conditions of the behavioral experiments the squirrel monkey has a relatively high degree of cardiac sympathetic tone; however, blood pressure elevations produced by administration of 1-norepinephrine were associated with an increased parasympathetic tone and decreased heart rate. The reflex bradycardia induced by 1-norepinephrine was inhibited during periods of schedule-controlled responding, suggesting that environmental and behavioral factors can not only modulate the parameters of physiological variables but also modulate this basic cardiovascular control system.

Behavior maintained under a second-order schedule by intramuscular injection of morphine or cocaine in rhesus monkeys.

Three rhesus monkeys lived in primate cages provided with response keys and enclosed in isolation chambers. During experimental sessions on Monday, Wednesday and Friday, the chamber door was closed and every 10th key-pressing response during a 60-minute interval produced a 2-second red light, but had no other programmed consequences (the 10-response fixed-ratio component of the second-order schedule; FR 10). The first FR 10 component completed after the 60-minute interval had elapsed produced a red light which remained on for 2 minutes while the chamber door was opened; the monkey then extended his arm and was given an intramuscular injection of drug (the 60-minute fixed-interval component of the second-order schedule; FI 60 min). Under this second-order schedule of intramuscular drug injection, repeated sequences of rapid responding were maintained during each session by 0.75 to 3.0 mg/kg injections of either morphine or cocaine. Patterns of responding characteristic of FR schedules were controlled by the 2-second red lights; a pause in responding after each 2-second red light was followed by a sustained high rate of responding until the light was produced again. Pauses in responding became progressively shorter as time elapsed in the 60-minute interval. When saline injections were substituted for drug injections, responding markedly decreased. When responding was maintained by 3.0 mg/kg morphine injections, pretreatment with 0.03 mg/kg of nalorphine increased responding, while pretreatment with 0.1 or 0.3 mg/kg of nalorphine decreased responding.