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 micrograms/kg/inf.) and of buprenorphine (250 micrograms/kg/inf.) generated drug avoidance behavior in the non-dependent rhesus monkey under a continuous avoidance-escape paradigm. Pentazocine (1-100 micrograms/kg/inf.) codeine, (1-100 micrograms/kg/inf. and tilidine (1-250 micrograms/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.

Calcium agonists and antagonists of the dihydropyridine type: antinociceptive effects, interference with opiate-mu-receptor agonists and neuropharmacological actions in rodents.

The calcium antagonist dihydropyridine derivative nimodipine and its enantiomers BAY N 5247, BAY N 5248, as well as BAY R 4407 (calcium antagonist (+)-enantiomer of the calcium agonist dihydropyridine BAY K 8644) do not exert antinociceptive effects in the rat as measured by the vocalization test in doses up to 100 micrograms/kg IV, and in the mouse as measured by the hot plate test in oral doses up to 100 mg/kg. The calcium agonists BAY K 8644 and BAY R 5417 ((-)-enantiomer of BAY K 8644) are also ineffective in the rat vocalization test but BAY K 8644 increases reaction time in the hot plate test (mouse) dose-dependently (1-10 mg/kg PO). mu-receptor agonist (fentanyl) antinociceptive effects are potentiated by simultaneous IV administration of the calcium antagonists, the (-)-enantiomer of nimodipine BAY N 5248 being the most potent. This applies for the rat (vocalization test) and the mouse (hot plate test). The influence on fentanyl antinociception in the rat of the calcium agonist BAY K 8644 and its (-)-enantiomer BAY R 5417 is biphasic: low doses attenuate, high doses potentiate fentanyl antinociception. In the mouse (hot plate test) antinociceptive, effects of BAY K 8644 plus fentanyl are less than additive, indicating that the calcium agonist decreases fentanyl effects. The relative potency of calcium antagonists in potentiation of fentanyl antinociception correlates with their relative potency as calcium antagonists as measured by receptor binding studies, effects on vascular and cardiac muscle, and with their neuropharmacological actions (anticonvulsive effects, inhibition of balance and spontaneous motility as well as tranquilizing effects in the mouse).(ABSTRACT TRUNCATED AT 250 WORDS)

[Potential for dependence of analgesics and psychopharmaceuticals]. / Abhängigkeitspotential von Analgetika und Psychopharmaka.

The dependence liability of analgesic and psychotropic drugs as assessed in animal experiments is described. It is demonstrated that the abuse liability of a given drug does not only depend on its pharmacological or psychopharmacological profile of actions. The abuse liability of a drug is, however, greatly influenced by environmental variables, motivation to self-administration of a drug as well as previous drug exposure. Correlations between dependent behavior of animals and dependent behavior of men are discussed.

Behavioral effects of nimodipine in animals.

Neuro- and psychopharmacological effects of isopropyl-(2-methoxy-ethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (Bay e 9736, nimodipine) are described using a variety of methods measuring behavior under normal conditions, under the influence of psychotropic drugs, as well as under the influence of ischemia or hypoxia. It has been demonstrated that nimodipine -- although not being very potent when measured in mg/kg -- exerts neuro- and psychopharmacological effects characterized by influences on the extrapyramidal system, aggressive defensive behavior, and chemically induced seizures. Electroencephalographical changes become evident whenever the normal equilibrium between cerebral catecholamine and cerebral serotonin levels is disturbed. When measured under the contingencies of a one trial passive avoidance paradigm, nimodipine is able to prevent the occurrence of retrograde amnesia in rodents after amnesiogenic events such as maximal electroconvulsive seizure or hypoxia. The substance prevents behavioral and electroencephalographic disturbances, elicited by a total cerebral ischemia, which is lethal in non-treated cats. It is concluded that nimodipine besides being a cerebrally vasoactive agent has psychopharmacological properties with a profile of actions hitherto unknown.

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 time-out 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.

[The biochemical basis of gerontotherapy (author's transl)]. / Biochemisch-experimentelle Grundlagen der Gerontotherapie.

In animal experiments biochemical changes in the aging brain can be shown to occur in the neurotransmitter systems, in cerebral blood flow and energy metabolism, and as lipofuscin accumulation. Neither the causes nor the functional consequences of these changes are well understood. However, analysis of the data is pointing the way to a rational therapy of geriatric disorders based on new drugs with relevant pharmacological effects.

Endogenous brain angiotensin II disrupts passive avoidance behavior in rats.

The presence of angiotensinogen, the precursor of angiotensin II (ANG II), in brain tissue and in cerebrospinal fluid (CSF) allows stimulation of endogenous brain ANG II by renin. Passive avoidance tests were performed in female Wistar rats. The animals received an electrical shock after entering a black box on the first experimental day. Avoidance was tested every 24 h for 5 consecutive days. Renin in doses of 0.01 and 0.1 units was injected once into the lateral brain ventricles 2 min before the first test. CSF ANG II increased from 40 to 4547 and 5152 fmol per ml (means), respectively. A dose-dependent disruption of avoidance learning was observed, the frequency to enter the black box increasing from 11% (control) to 29% and 46%, and the latency decreasing from 165 (control) to 143 and 116 sec, respectively. These effects were statistically significant (P less than 0.001) for more than 24 h and returned to control levels after 48 to 120 h. Administration of the converting-enzyme inhibitor SQ 14225 i.v.t. prior to renin injections abolished the renin effects. Injections of renin given 22 h after learning were without effect.

The antithrombotic activity of BAY g 6575.

The activity of 1-[2-(beta-naphthyloxy)ethyl]-3-methyl-2-pyrazolin-5-one (= BAY g 6575) was evaluated in models of experimental thrombosis caused by traumatically induced damage of vessel segments. After prophylactic administration of BAY g 6575 (0.3 mg/kg p.o.) to rats the thrombus formation was significantly reduced in the carotid artery as well as in the jugular vein. The thrombus formation in the femoral arteries of rabbits is inhibited at a minimal effective dose of 1 mg/kg p.o. The incidence of occlusive thrombi is not influenced. BAY g 6575 is 10 times more potent than acetylsalicylic acid (ASA). In the arterial system the thrombus formation is frequently completely abolished.

Reinforcing properties of nicocodine in the rhesus monkey.

The present study demonstrates that nicocodine is self-administered by the rhesus monkey in cross self-administration experiments. The minimum reinforcing dose is 10 times higher than that of codeine and 100 times higher than that of heroin. At reinforcing doses the rate of self-administered infusions of nicocodine is comparable with those of codeine. Further experiments are necessary to rank order nicocodine as to its positive reinforcing properties among the opiate-like compounds. On the other hand the present experiments demonstrate that nicocodine is an opium-like reinforcing compound.

[A new method for enteral self administration of psychotropic drugs in the rhesus monkey (author's transl)]. / Eine neue Methode zur enteralen Selbstverabreichung von psychotrop wirksamen Pharmaka beim Rhesusaffen.

This surgical method for the parenteral self administration of psychoactive substances in the Rhesus monkey is a modified gastrostomy. Success is warranted with a catheter-model which can be fixed at the inner wall of the abdomen. The catheter is placed subcutaneously until it leaves between the shoulders. Additionally all monkeys received leather corsets. This method has proved to be very safe in long-time self administration of drugs in the Rhesus monkey.