Friedrich Hoffmeister

Reinforcing properties of some opiates and opioids in rhesus monkeys with histories of cocaine and codeine self-administration.

Rhesus monkeys were conditioned to press a key to selfadminister intravenous injections of either cocaine (8 monkeys) or codeine (7 monkeys). Every tenth lever press resulted in an injection of 50 mcg/kg/inj. cocaine or codeine during daily 3 h sessions. Equal doses of cocaine and codeine generated regular comparable rates of self-administration responding. After responding stabilized, different narcotic and non-narcotic analgesics (morphine, codeine, detropropoxyphene, propiramfumarate, pentazocine and nalorphine) were substituted for cocaine or codeine. At appropriate doses all drugs except for nalorphine, maintained self-administration responding. Monkeys with a codeine self-administration history self-administered higher numbers of injections and showed less intraindividual variability than monkeys with a cocaine self-administration history.

Progressive-ratio performance in the rhesus monkey maintained by opiate infusions.

Heroin, codeine, dextropropoxyphene, and pentazocine were compared using a drug-maintained progressive-ratio procedure in the rhesus monkey.Infusions of the drugs were contingent on completion of increasing fixed ratio (FR) response requirements with variable time-out periods following each infusion. Prior to drug experiments, stabile self-infusion performance was established with 1000 mcg/kg codeine infusions contingent on completion of a FR 100. Doses of study drugs were substituted for this standard dose of codeine. FR requirements were doubled daily until the number of self-administered infusions per day decreased to less than two infusions (maximal possible: eight infusions/day). This decrease in the number of infusions is referred to as the breaking point. The dose ranges tested were 1–500 mcg/kg of heroin, 10–16,000 mcg/kg of codeine, 50–10,000 mcg/kg of dextropropoxyphene, and 50–10,000 mcg/kg of pentazocine. Heroin increased breaking points dose dependently up to a FR requirement of 12,800. This applies to codeine also, the maximum breaking point occurring at FR 6400. The breaking-point dose curves of dextropropoxyphene and pentazocine plateaued at an infusion dose of 5000 mcg/kg. At this dose the breaking point was a FR 6400. Further increase of infusion doses of these two drugs decreased breaking points to the saline level. These drug-specific dose breaking-point functions supplement information on reinforcing properties achieved in other animal experiments and correspond with the clinical pharmacologic information about the abuse liability of the studied drugs.

Negative reinforcing properties of morphine-antagonists in naive rhesus monkeys

Rhesus monkeys were trained to press a lever to extinguish a light associated with a drug infusion scheduled to occur 30 sec after the onset of the light. Each response during the light period terminated the light for a 1-min time-out period (avoidance); a response during the infusion terminated the infusion (escape). Under these conditions the monkeys tolerated a high number of saline infusions. Saline was replaced by different unit doses of nalorphine, cyclazocine, naloxone, cocaine, codeine, pentazocine and propiramfumarate each for six successive daily 2-h sessions.Infusions of nalorphine (unit doses from 500 to 10 mcg/kg/infusion) and cyclazocine (10 to 2.5 mcg/kg/infusion) generated and maintained avoidance/escape behavior, while infusions of naloxone (100 to 5 mcg/kg/infusion), cocaine, codeine, pentazocine and propiramfumarate (all 50 mcg/kg/infusion) were tolerated by the subjects.The results show that in rhesus monkeys with no drug experience prior to the experiment the morphine-antagonists nalorphine and cyclazocine but not naloxone have negative reinforcing properties.

A comparison of the stimulus effects of codeine in rhesus monkeys under the contingencies of a two lever discrimination task and a cross self-administration paradigm: tests of generalization to pentazocine, buprenorphine, tilidine, and different doses of codeine

The stimulus effects of codeine were assessed in three monkeys trained to perform first under the contingencies of a cross self-administration paradigm and then under a two lever discrimination task. Codeine-trained monkeys generalized to pentazocine, buprenorphine, and codeine under both procedures in doses different from the training dose. Codeine-trained monkeys did not generalize to tilidine. These results indicate that monkeys do not behave in a qualitatively different way when presented with the study drugs under both contingencies. However, there were marked quantitative differences between the generalization effects of doses of pentazocine, buprenorphine, and codeine to doses other than that used in training between the two paradigms. Much higher doses of codeine and pentazocine, but not of buprenorphine, were necessary for inducing generalization effects in the two lever task than in the cross self-administration procedure. The possible reasons for these quantitative differences are discussed. It is concluded that the cross self-administration procedure is more sensitive for the assessment of opioid-like stimulus properties of drugs than the two lever discrimination task.

Negative reinforcing properties of naloxone in the non-dependent rhesus monkey: influence on reinforcing properties of codeine, tilidine, buprenorphine, and pentazocine

Scheduled infusions of naloxone (1–100 μg/kg/inf.) and of buprenorphine (250 μg/kg/inf.) generated drug avoidance behavior in the non-dependent rhesus monkey under a continuous avoidance-escape paradigm. Pentazocine (1–100 μg/kg/inf.) codeine, (1–100 μg/kg/inf.) and tilidine (1–250μg/kg/inf.) were ineffective. Addition of varying doses of naloxone to scheduled infusions of codeine, tilidine, and pentazocine generated avoidance behavior not present with scheduled infusions of these opioids alone. The naloxone doses necessary for generation of avoidance behavior were low with the agonists codeine and tilidine, higher with the weak antagonist pentazocine, and highest with the strong antagonist buprenorphine. When monkeys were presented with the fixed tilidine-naloxone combination (100+8 parts) and pentazocine-naloxone combination (100+1 part) and the buprenorphine-naloxone combination (100+66 parts) presently in clinical use only the tilidine-naloxone combination generated drug avoidance behavior to an appreciable extent.

Influence of intravenous self-administered psychomotor stimulants on performance of rhesus monkeys in a multiple schedule paradigm.

Rhesus monkeys were trained to complete three multiple schedules. The schedules consisted of three components: a fixed interval (component 1), a variable interval (component 2), and a fixed ratio (component 3). During components 1 and 2, pressing lever 1 was always reinforced by food delivery. During component 3, pressing lever 2 resulted in either food delivery or intravenous infusions of saline solution, solutions of cocaine, of d-amphetamine, of phenmetrazine, or fenetylline. In schedule I, animals were presented with all three components independent of key-pressing behavior during components 1 and 2. In schedule II the availability of component 2 was dependent on completion of component 1. Component 3 was made available only on completion of component 2. Noncompletion of components 1 or 2 resulted in timeoutperiods of 15 and 10 min, respectively. Schedule III was identical with schedule II, except that in schedule III the completion of components was indicated only by a change in the lever lights. The influence of self-administered drugs on behavior in all three components was evaluated. Self-administration of psychomotor stimulants impaired the performance of animals and delayed completion of components 1 and 2 of schedules I, II, and III. The effects on behavior were similar with low drug intake in schedule III, moderate intake in schedule II, and high drug intake in schedule I. These effects were strong with self-administration of phenmetrazine, moderate with self-administration of cocaine and d-amphetamine, and weak with self-administration of fenetylline.

Vergleichende elektrencephalographische Untersuchungen einiger Phenothiazin-Derivate an wachen Katzen und Kaninchen

ZusammenfassungPromazin-Derivate (Chlorpromazin und 3-Propionyl-Promazin), die Perazin-Derivate 3-Propionyl-Perazin, 3-Butyryl-Perazin, 3-Chlor-Perazin und Perphenazin, weiterhin Promethazin und 3-Propionyl-Morazin wurden vergleichend in 3 elektrencephalographischen Versuchs-Anordnungen untersucht.1.Das Spontan-EEG von wachen Katzen wurde durch Chlorpromazin (4,5 mg/kg intravenös) und 3-Propionyl-Promazin (5 mg/kg intravenös) im Sinne einer Amplitudenzunahme und Frequenzverminderung verändert, während unter 3-Propionyl-Perazin (5 mg/kg intravenös) keine gröberen EEG-Veränderungen beobachtet wurden.2.Die Amplitude der Reizantwort im Cortex auf niederfrequenten elektrischen Reiz in der Formatio reticularis mesencephalica von wachen Katzen und Kaninchen wurde durch die Stoffe der Promazin-Gruppe (5–10 mg/kg intravenös) stark verkleinert, während unter Perazin-Gabe (1–10 mg/kg intravenös) ein solcher Effekt nicht nachweisbar war. Bei Kaninchen wurde die Amplitude dieser Reizantwort unter Promethazin (5 mg/kg intravenös) und 3-Propionyl-Morazin ebenfalls stark verkleinert. Die Amplitude von Recruiting-Potentialen im Cortex von Katzen und Kaninchen wurde durch die Stoffe der Promazin-Gruppe erhöht, alle anderen geprüften Stoffe waren hier ohne Wirkung.3.Die elektrische Reizschwelle der corticalen und Hippocampus-Arousal von wachen Kaninchen wurde durch Promethazin (5 mg/kg intravenös) stark, durch die Stoffe der Promazin-Gruppe (0,1–10 mg je kg intravenös) und das Morazin-Derivat (5 mg/kg intravenös) mittelstark, durch die Verbindungen der Perazin-Gruppe (5 mg/kg intravenös) praktisch nicht erhöht. Diese Ergebnisse werden besonders unter dem Gesichtspunkt der allgemein-pharmakologischen sowie der klinischen Wirkung der untersuchten Stoffe diskutiert.

Self-administration of codeine plus acetylsalicylic acid in rhesus monkeys with unlimited access to the drugs.

The reinforcing effects of codeine (5.0 mcg/kg/infusion), acetylsalicylic acid (ASA) (2500 mcg/kg/infusion) and those of combinations of codeine (50 mcg/kg/infusion) plus (2500 or 10,000 mcg/kg/infusion) were studied in four groups of drug naive rhesus monkeys. Responding was engendered and maintained by infusions of 50 mcg/kg of codeine; maximal number of daily infusions being 500 to 1000. Infusions of 2500 mcg/kg of ASA plus 50 mcg/kg of codeine per infusion initiated responding from the 9th to the 10th day of the drug period on. The number of self-administered infusions did not exceed 200 daily. Monkeys self administered codeine without signs of intoxication. All three monkeys self-administering the combination of 50 mcg/kg of codeine plus 2500 mcg/kg of ASA died during the experiment. They exhibited signs of severe intoxication. A combination of 50 mcg/kg of codeine and 10,000 mcg/kg of ASA was not self-administered until the 12th day of the drug period. Two out of three monkeys initiated responding for the combination during the drug period. The number of self-administered infusions did not exceed 50 per day. A third monkey did not initiate self-administration during the 14 day drug period. Both monkeys which engendered self-administration died on the 14th day of the experiment as a result of general intoxication. These experiments suggest that even toxic doses of ASA will not prevent monkeys from self-administration when offered together with a positive reinforcing drug such as codeine under a schedule of continuous self-administration.

Drug Abuse: Control Through National and International Regulatory Practice

Pain as a medical and anthropological challenge has, in our time and age, again become—and I would like to say surprisingly become—one of the most urgent problems of mankind because its medical treatment is far from being satisfactory. One may even say that progress in the management and therapy of pain during the past 15 years have been slower and less distinct and successful than in other disciplines such as therapy of infectious diseases or even in the not very advanced therapy of psychoses.

Neue estergruppenhaltige Phenoxy- essigsäureamide mit narkodischer Wirksamkeit

Unter den Abkommlingen des substituierten Brenzkatechins, zu denen auch bekannte Naturstoffe wie Eugenol, Isoeugenol, Chavi- betol, Vanillin und Kaffeesaure gehoren, finden sich pharmakodynamisch interessante Stoffe von sehr unterschiedlicher Wirkungsqualitat. So gehorte der in den Elberfelder Laboratorien der ehemaligen I. G. Farbenindustrie AG synthetisierte, oxytocisch wirksame Di- athylaminoathylather des 6-Allylguajacols [1] (I) als Gravitol® lange Jahre dem Arzneischatz an. Die Wiederaufnahme alterer Arbeiten in Elberfeld fuhrte 1955 zu zentral dampfend wirkenden y-Dimethyl- aminopropylathern des Propenylguathols [2], von denen die Verbindung II langere Zeit klinisch gepruft wurde. Entsprechende Aminoalkyl-brenzkatechin-ather mit sekundarer Aminogruppe [3], wie z. B. III, besasen dagegen vorwiegend blutdrucksenkende Eigenschaften. Ahnliche, sympathikolytisch und sedativ wirksame basisch substituierte Alkylather des Guajakols [4, 5] sind kurzlich auch an anderer Stelle aufgefunden worden.