Which smokers report most relief from craving when using nicotine chewing gum?

Seventy-seven smoker clinic clients who managed at least 2 weeks of smoking abstinence while chewing 2 mg nicotine gum reported the degree to which the gum reduced their craving for cigarettes, their daily gum consumption and the extent of urges to smoke despite the gum. Greatest relief from craving by the gum was reported by smokers with higher pre-abstinence expired-air carbon monoxide (CO) concentrations and higher stimulant and dependent scores on a smoking motivation questionaire but not greater usual daily cigarette consumption. Gum consumption correlated positively with expired-air CO, usual daily cigarette consumption, and stimulant and dependent smoking scores. Despite the gum, urges to smoke and difficulty not smoking were reported and the severity of these was associated with indulgent, stimulant and dependent smoking scores but not CO or usual daily cigarette consumption. The results are discussed in terms of the possible role of pharmacological and non-pharmacological factors in craving.     

Modification of Δ9-THC-actions by cannabinol and cannabidiol in the rat

Cannabinol (CBN) and Cannabidiol (CBD) were tested in several test procedures known to be altered by ⁹-tetrahydrocannabinol (THC) or crude cannabis preparations. They were inactive in doses up to 80 mg/kg in tests on animal motility, food and water intake, body temperature and catalepsy. In contrast, CBD enhanced the hexobarbitone sleeping time more pronounced than ⁹-THC whereas CBN increased the sleeping time only slightly. When administered in combination CBD prolonged all actions of THC, whereas CBN selectively blocked the effect of THC on hexobarbitone sleeping time. The enhancement by CBD is best explained by an inhibition of THC-metabolism.This paper was in part presented at the C.I.N.P., Copenhagen, 1972.Supported in part by a research grant of the Bundesminister für Jugend, Familie und Gesundheit.     

Cannabis and alcohol: Effects on estimation of time and distance

The effect of cannabis and alcohol on estimation of time and distance during simulated car driving was studied. Cannabis resin containing 4% 1-tetrahydrocannabinol (THC) was administered orally in 3 doses equivalent to 8, 12, and 16 mg THC. Alcohol was given orally in one dose of 70 g. The subjects were 8 men, 21 to 29 years old. Cannabis showed much stronger effect than alcohol on the estimation of time and distance. The effect of cannabis was more marked on the subjective than on the objective estimation. A dose-response type of effect was seen on cannabis.     

Über den Mechanismus der Wirkung des Reserpins auf den Glykogengehalt der Organe

Zusammenfassung Untersuchungen an Mäusen über die durch Reserpin verursachte Zunahme des Glykogengehaltes der Organe und den zugrunde liegenden Mechanismus haben zu folgenden Ergebnissen geführt:1. Nach der subcutanen Injektion von 5 mg/kg Reserpin kommt es zu einem Anstieg des Organglykogens, der in Skeletmuskulatur, Herz und Leber nach 12 Std mit 100 bzw. 174 bzw. 300% sein Maximum erreicht und im Gehirn nach 18 Std 100% beträgt. Von dieser Zunahme des Glykogengehaltes ist nur die Fraktion des freien, mit Trichloressigsäure extrahierbaren Glykogens betroffen.2. Versuche mit ¹⁴C-Alanin ergaben, daß der in Gehirn und Leber nach Reserpin erfolgende Anstieg des Glykogengehaltes mit einer vermehrten Gluconeogenese verbunden ist, d. h. mit einer erhöhten Inkorporierung von ¹⁴C in das Organglykogen. Hiervon war auch die Fraktion des gebundenen Glykogens betroffen, obwohl ihr absoluter Glykogengehalt nach Reserpin unverändert blieb.3. Die Fraktion des gebundenen Glykogens stellt wahrscheinlich den Anteil des Gewebsglykogens dar, in dem zuerst der enzymatische Auf- und Abbau stattfindet. In ihr ist nach Injektion von ¹⁴C-Alanin die spezifische Aktivität primär (1–3 Std p.i.) höher als in der Fraktion des freien Glykogens, nimmt aber unter Reserpin auch schneller ab: bereits nach 6 Std, bei den Kontrolltieren erst nach 9 Std (vgl. Abb. 7). Der mit einer vermehrten Gluconeogenese verbundene Glykogen anstieg nach Reserpin in Gehirn und Leber geht daher offensichtlich auch mit einem erhöhten Glykogen umsatz einher.4. Die nach Reserpin gesteigerte Gluconeogenese ist in der Leber mit einem erhöhten Einstrom von Aminosäuren verbunden, im Gehirn jedoch mit einem verminderten exogenen Aminosäureangebot, wie Versuche mit ¹⁴C--Aminoisobuttersäure (AIB) als Modellsubstanz für körpereigene, einem aktiven Transport unterliegende Aminosäuren ergaben. Iproniazid wirkte umgekehrt wie Reserpin, indem es die ¹⁴C-AIB-Konzentration im Gehirn erhöhte.5. Die Frage einer Mitbeteiligung von Nebennierenrindenhormonen am Zustandekommen der beschriebenen Reserpinwirkungen wird diskutiert.

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Summary Experiments in mice were carried out to elucidate the mechanism by which reserpine increases the glycogen content in several organs.1. 12 hours after the injection of reserpine (5 mg/kg) the glycogen content of the sceletal muscle, heart muscle and liver reached maximum values (100, 174 and 300% resp. above the controls). The glycogen content of the brain was increased by 100% (18 hours after reserpine injection). This accumulation was found only in the fraction of free glycogen (TCA extractable fraction).2. Following a single injection of ¹⁴C-alanine reserpine increased the incorporation of radioactivity into the glycogen of brain and liver, indicating that the accumulation of glycogen in these organs is due to an enhanced gluconeogenesis. Increased specific activity was found in the fraction of free glycogen as well as in the fraction of bound glycogen, although the amount of bound glycogen was not increased by reserpine.3. Changes in specific activity following the injection of ¹⁴C-alanine first occured in the fraction of bound glycogen, indicating, that this fraction of glycogen is metabolized predominantly: at first (1–3 hours) the specific activity is higher in the bound than in the free fraction, while lateron (6 hours) the distribution is reversed (higher specific activity in the free than in the bound fraction). After pretreatment with reserpine this reversal in the distribution of specific activity takes place earlier (after 3 hours) which is due to an accelerated decrease of specific activity in the fraction of bound glycogen.Thus, the reserpine induced increase of glycogen in brain and liver is due to gluconeogenesis and probably associated with an increased metabolic turnover of glycogen.4. Experiments with ¹⁴C--aminoisobutyric acid — a model substance for endogenous amino acids subject to an active transport through cell membranes—have shown, that the reserpine induced gluconeogenesis is accompanied by a rapid influx of amino acids into the liver, while the influx into the brain is significantly lowered. Iproniazid, in contrast to reserpine, enhanced the AIB transfer into the brain.5. The significance of the data presented is discussed regarding a possible involvement of adrenocortical hormones in these actions of reserpine.

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Mit 7 Textabbildungen

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Herrn Professor Dr. P. Holtz zum 60. Geburtstag gewidmet.

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Ausgeführt mit Unterstützung der Deutschen Forschungsgemeinschaft.     

Decrease in bradycardic effect of AQ-A 39 and alinidine in guinea-pig sinoatrial node depolarized by high external K+-concentration

Summary The effects of the two specific bradycardic agents AQ-A 39 and alinidine on the spontaneous electrical discharge rate of intact guinea-pig sinus node preparations were investigated. At high external K⁺-concentrations (10.8 and 16.2 mmol/l) the bradycardic effect of the two drugs was diminished or abolished. In contrast, the negative chronotropic effect of the reference compound verapamil (Ca²⁺-antagonist) was enhanced. These results show that the bradycardic effects of AQ-A 39 and alinidine are diminished in depolarized preparations, which makes it unlikely that in intact sinus node preparations the mechanism of action is the same as that of Ca²⁺-antagonists.     

Mild analgesics evaluated with the “Submaximum Effort Tourniquet Technique”

In a first study with the Submaximum Effort Tourniquet Technique mild analgesics were better discriminated from placebo by subjects, demonstrating a calm behavior in the test-situation than by individuals with prominent arousal reactions.In the present study a tranquilizer-benzoctadiene-was given in order to induce relaxation, with the aim to enhance the subjects ability to discriminate analgesics from placebo.The homogeneity of the variances (Bartlett-test) were between P 0.1 and 0.05. Therefore an analysis of variance and additionally a non-parametric test (Mann-Whitney U test) were done.Pain tolerance times in the six groups (placebo, C-44328-Ba, paracetamol, alone, or in combination with benzoctadiene) on the four pain-levels slight, moderate, severe and unbearable were not significantly different when compared by means of analysis of variance.The comparison of the groups by means of the Mann-Whitney U test showed a) that the combination of the analgesics with benzoctadiene was more effective than either analgesic given alone on three, resp. one of the four pain-levels, b) that in the Non Benzoctadiene Group the analgesics were not differentiated from placebo, and c) that within the Benzoctadiene Group each analgesic was more effective than placebo on two pain-levels.     

Toxic effects of some “mono-n-butyl-tin compounds” on white mice

The toxic effects of mono-n-butyl-tin-trichloride, mono-n-butyl-tin-tris-(2-ethyl-hexyl-mercaptoacetate), mono-n-butyl-tin acid and mono-n-butyl-thiotin acid on white mice were investigated. These compounds were administered to white mice by means of a stomach tube in a single dose of 4000 mg/ kg b.w. at the start of the experiment. All mice were sacrificed 24 hours after the administration.The clinical course as well as the macroscopic findings in all experimental groups indicated general signs of an acute intoxication. The histological findings in the mono-n-butyl-tin-trichloride group showed pronounced changes in the digestive tract, where haemorrhages in the mucous membrane and in the inner layer of the gastric and intestinal walls had been found. In the mice of the other experimental groups, steatosis of the hepatocytes and an irregular steatosis of the renal tubular epithelium were observed.     

Failure of “antigastrin” (SC-15 396) to inhibit gastric acid and pepsin secretion in anaesthetized gastric fistula cats

Summary 1. The effect of antigastrin (SC-15 396) on gastric acid and pepsin secretion produced by the gastrin-analogue tetrapeptide amide Try. Met. Asp. Phe-NH₂ and by electrical stimulation of the vagus was investigated in anaesthetized gastric fistula cats.2. Antigastrin failed to inhibit both acid and pepsin response stimulated by either the tetrapeptide or vagus excitation.3. It was concluded that the ineffectiveness of antigastrin in cats is due to a species difference between rats and dogs on the one hand and cats on the other, and that antigastrin is not a specific gastrin antagonist.Supported by the Deutsche Forschungsgemeinschaft and by the Alfred Teufel-Stiftung.     

Role of brain amines in learning associated with “amphetamine-state”

Conditional avoidance responses acquired under amphetamine were recalled without deficit only when tested under amphetamine (amphetaminestate dependent learning). Hydroxyamphetamine was devoid of this property. Dihydroxyphenylalanine (DOPA) but not 5-hydroxytryptophan (5-HTP) substituted for amphetamine while reserpine but not syrosingopine eliminated the amphetamine-state. DOPA and 5-HTP, only when given together, restored the amphetamine-state in reserpinized animals. DOPA alleviated the deficit in retention which was caused by methyl-p-tyrosine. 5-HTP alleviated the similar deficit caused by p-chlorophenylalanine. Chlorpromazine or cyproheptadine antagonized the amphetamine-state. It is suggested that amphetamine, but not hydroxyamphetamine is capable of producing an asymmetric behavior-controlling state. The amphetamine-state is related to the stimulation of central and not peripheral amine-receptors and depends on newly synthesized catecholamines which stimulate central catecholamine receptors through serotonin modulation in this case.     

The effect of midazolam and β-carboline carboxylic acid ethyl ester on behaviour,steroid hormones and central monoamine metabolites in social groups of talapoin monkeys

Established social groups of talapoin monkeys show rank-related differences in aggressive, social and sexual behaviours and visual monitoring, as well as in endocrine and monoamine profiles. Here we describe the effects on these variables of an anxiogenic drug, -carboline carboxylic acid ethyl ester (-CCE), and an anxiolytic drug (midazolam) given to either dominant or subordinate male talapoins. In dominant animals -CCE increased aggression and visual monitoring but reduced sexual behaviour. Treatment of subordinate animals with -CCE served only to increase visual monitoring. Conversely, treatment with a non-sedative acute dose of midazolam in dominants reduced aggressive behaviour and increased sexual behaviour, whereas in subordinates no behavioural changes were noted. Significant effects on endocrine and neurochemical variables were not seen with the acute drug treatments employed. Nevertheless, the results show that drugs which modulate anxiety produce status-dependent behavioural effects.     

Liberation of α-methyldopamine as a “false” sympathetic transmitter after pretreatment of cats with α-methyldopa and disulfiram

Summary Pretreatment of cats with -methyldopa (3×200 mg/kg i.p. given over a period of 28 hrs) and simultaneous inhibition of dopamine -hydroxylase by disulfiram (4×400 mg/kg p.o. given over a period of 44 hrs) diminished the norepinephrine content of the heart to 31% and of the spleen to 15% of control levels. The missing norepinephrine was only partially replaced by -methyldopamine and the total catecholamine content of spleen and heart amounted to 51 and 70% respectively of untreated controls. In spinal cats the response of the nictitating membrane to sympathetic nerve stimulation was markedly diminished, whereas the effect of intravenously injected norepinephrine on blood pressure and nictitating membrane was considerably potentiated. In the isolated perfused spleen the contractile response to sympathetic nerve stimulation was also diminished and the pressor activity (expressed in terms of norepinephrine) of the venous effluent was reduced to 40% at a stimulating rate of 6/sec and to 39% at 10/sec. Together with the diminished amounts of norepinephrine -methyldopamine appeared as a false sympathetic transmitter in the perfusion fluid. The two amines were liberated by sympathetic nerve stimulation in the same proportions in which they were stored in splenic tissue.From this and previous studies it becomes apparent that several aspects must be considered in correlating biochemical and functional findings: amounts of normal transmitter in tissues versus amounts liberated by sympathetic nerve stimulation, quantitative aspect of replacement of the physiological by the false transmitter in tissues and in the output from stimulated nerves, potency of the false transmitter at adrenergic receptors and its possible interference with transmitter inactivation.Preliminary results of this report have been communicated to the German Pharmacological Society in Mainz at the Spring meeting 1966.     

Behavioral and autonomic responses to intermittent social stress: differential protection by clonidine and metoprolol

The present study investigated physiological and pharmacological characteristics of socially stressed animals. Specifically, we examined (1) to what degree autonomic and behavioral stress reactions during intermittent confrontations between an intruder male adult Long-Evans rat with an aggressive resident undergo habituation, and (2) to what extent the defeat-experienced animal can be protected against these stress reactions with clonidine or metoprolol, two adrenergic agents with clinical anxiolytic effects. We developed an acute social stress situation that consisted of initially placing an experimental rat as an intruder into the homecage of a resident while the resident was not present, thereafter permitting brief physical agonistic interactions with the reintroduced resident until the intruder was forced into a submissive supine posture and emitted ultrasonic vocalizations (USV), and eventually exposing the intruder to the resident's threats for one hour, while being shielded from potentially injurious attacks (threat encounter). Over the course of the initial 4-weekly threat encounters the acute tachycardia but not the hyperthermic stress responses decreased in magnitude. Following the first three threat encounters core temperature (T_c) was significantly elevated for at least 3 h. The T_c was already elevated when the repeatedly defeated intruder was confronted with the olfactory cues of the resident's cage. This conditioned anticipatory hyperthermia developed in the course of the first three confrontations and was paralleled by a decrease in exploratory and motor behavior and by an increase in defensive behaviors and in both types of USV emitted in the low (20–30 kHz) and the high (31–70 kHz) frequency range. Clonidine (0.01–0.1 mg/kg, IP), an ₂-adrenergic agonist and metoprolol, a -adrenergic blocker (1.0–10.0 mg/kg, IP), dose-dependently prevented the tachycardic response to stress. Only clonidine, but not metoprolol, also attenuated the rise in T₀ during the 1-h agonistic interaction. Clonidine decreased those aspects of motor behavior (e.g. rearing, walking) that are of lesser cost for the individual but maintained high levels of defensive reactions and increased the duration of low USV. The high doses of clonidine (0.06, 0.1 mg/kg) attenuated the homeostatic regulation and sedated the intruder while exposed to threats during a social confrontation. The absence of attenuation of the high level of defensive behavior and the prolonged low USV suggest a stress intensification by the higher doses of clonidine. In conclusion, after the fourth encounter, the autonomic, behavioral and vocal response pattern prior to and during repeated weekly confrontations show no evidence for habituation for the following 6 weeks. Moreover, adrenergic therapeutic agents that are applied to treat symptoms of anxiety block the tachycardic response but may actually intensify defensive behavior and certain stress vocalizations.     

Inhalation pharmacokinetics based on gas uptake studies

On the basis of previous determinations of pharmacokinetic parameters for inhaled vinyl chloride in men, rhesus monkeys, and rats, and on improved pharmacokinetic models a pharmacokinetic treatment of the problem of peak concentrations of vinyl chloride, as occuring in industrial practice, became possible. For the calculations, metabolic elimination kinetics of vinyl chloride was assumed to be first order as experiments in different species including rhesus monkeys showed linear pharmacokinetics up to atmospheric exposures of 200–300 ppm. The distribution of vinyl chloride between atmosphere and organism under different conditions was evaluated using steady-state-kinetics. After treating the processes of influx, efflux, and metabolism, the numerical values for the parameters derived from a human kinetic experiment were used to theoretically calculate the time courses of concentration of vinyl chloride in the organism and of the cumulative amount of vinyl chloride metabolized, under the conditions of (a) a 2 h constant exposure to 5 ppm vinyl chloride and (b) two subsequent peaks of 50 ppm with a duration of 5 min each. This model calculation suggested that, regardless of the exposure profile, the amount of (reactive) metabolites formed from vinyl chloride would soleley be a function of the mean atmospheric vinyl chloride concentration over time. The general validity of this suggested rule could subsequently be demonstrated. As the concentration of the reactive metabolite of vinyl chloride responsible for the carcinogenic effect at the target site must be a resultant of both formation and inactivation, an evaluation of the differential risk of different exposure profiles can reasonably be based on biochemical examinations of the detoxifying pathways. This points out the relevance of studies of the patterns of different metabolites of vinyl chloride in man under varying exposure profiles.     

Chronic anorexic and behavioural effects of the fenfluramine derivative SE 780 in rats

The behavioural and anorexic effects of the fenfluramine derivative SE 780 in rats were studied after chronic administration over 35 days. Behavioural effects of the compound were assessed by time sampling behavioural categorisation, on days 1, 14 and 28 of administration. An initial sedative effect observed after acute administration was absent on days 14 and 28 of observation, when the drug had no behavioural effects at all. The anorexic properties of the drug were investigated in two ways. Firstly, by measuring daily body weights; and secondly by measuring intake of food over a 2 h period on observation days. The drug appeared to be a highly potent anorexiant in that tolerance to its effects built up very slowly. It is suggested that SE 780 may be an anorexic agent which is superior to Fenfluramine in two ways; firstly, it lacks stimulant properties after chronic administration, and secondly it is active over longer periods of time; as such it merits further study in humans.This compound has also been referred to as S 992.     

Induction of skeletal malformations in organ cultures of mammalian embryonic tissues

Summary Abnormalities of the cartilaginous limb bone anlagen resembling syndactyly and phocomelia can be mimicked entirely in vitro, using an organ culture system which allows the differentiation of mouse limb buds from the blastema stage (day 11.0 of gestation) to well recognizable cartilaginous anlagen of the long bones and the hand (or foot) skeleton (metacarpal anlagen) within 6 to 7 days. As reported here such malformations as triggered in vitro by 6-mercaptopurine (6-MP) should be distinguished from less specific effects, such as failure of the explant to develop typically in a proximodistal direction and to grow or form cartilage, which are produced by a variety of drugs or by altering the medium composition or other culture conditions. When culturing limb buds from embryos exposed in utero to 5-bromodeoxyuridine (BUdr) in a normal medium it was possible to obtain polydactyly in about 30% of the explants. The test system used provides another way of elucidating the mode of action of teratogenic agents, and of mechanisms involved in an abnormal mammalian development.     

The effect of phloxin on bethanechol and histamine stimulated gastric acid secretion in rats

Summary The effect of phloxin (Na salt of tetrabromo-tetrachlorofluorescein) on histamine- and bethanechol-stimulated gastric acid secretion was studied in anaesthetized rats. Concentrations of phloxin, equimolar with those of the stimulants, depressed the secretory response to histamine and had no influence on the bethanechol effect. The results suggest that histamine is not involved in the events triggered by bethanechol which stimulate gastric acid secretion in rats.Supported by the Deutsche Forschungsgemeinschaft and the Gesellschaft der Freunde der Universität Tübingen.     

Comparison of measured and FTC-predicted nicotine uptake in smokers

Cigarette smokers have a wide variety of tar and nicotine yields to choose from in the current market, ranging from 0.5 mg tar and less than 0.05 mg nicotine to 27 mg tar and 1.8 mg nicotine by the Federal Trade Commission (FTC) method. To understand better the relationship between FTC nicotine yields and actual nicotine uptake in smokers, we have studied nicotine uptake in 33 smokers of self-selected products representing four tar groupings: 1 mg tar (1 MG), ultra-low tar (ULT), full-flavor low tar (FFLT), and full flavor (FF) cigarettes. These cigarette categories had mean FTC nicotine yields of 0.14, 0.49, 0.67, and 1.13 mg/cigarette, respectively. The subjects smoked their usual brand of cigarette ad libitum and provided a 24-h urine sample for total nicotine uptake analysis over a period during which the number of cigarettes smoked was recorded. Nicotine uptake was determined by monitoring urinary nicotine and its metabolites, including the glucuronide conjugates. Daily nicotine uptake was 9.1±7.3 mg (range 1–21 mg) for 1 MG, 19.2±10.0 mg (range 4–42 mg) for ULT, 21.8±9.4 mg (range 13–38 mg) for FFLT, and 37.1±14.4 mg (range 21–60 mg) for FF smokers. On a per cigarette basis, yields were 0.23±0.11, 0.56±0.23, 0.60±0.18, and 1.19±0.43 mg nicotine, respectively. Although individual variability was fairly large (CVs of 0.39–0.80), means for the different groups showed that lower FTC yield smokers not only absorb less nicotine per 24-h period, but also per cigarette smoked. These data suggest that nicotine uptake is a function of individual smoking behavior within product design limits. We conclude from these data that, while FTC yield cannot precisely predict nicotine uptake for an individual smoker, it is useful in predicting and comparing actual nicotine uptake by smokers who select cigarettes with a particular FTC yield.     

Is there a need for more precise definitions of bioavailability?

Summary After evaluation of the present definitions in a set of particular cases, it was agreed that there was no need for more precise definitions and that the current ones were adequate in the majority of cases. However, it was felt that the present definitions might be improved, in particular in view of the existence of non-systemically acting drugs and future targeted drugs. Thus, the FDA definition might be modified as follows: Bioavailability means the rate and extent to which the active drug ingredient or therapeutic moiety from a drug product becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action.     

Alcohol,anxiolytics and social stress in rats

The main objective was to compare the anxiolytic-like profiles of alcohol, diazepam and gepirone along the stress intensity gradient which characterizes consecutive phases of a social confrontation. The acute social stress situation consisted of initially placing the experimental rat as an intruder into the homecage of a resident while the resident was not present, termed the anticipatory phase, thereafter permitting brief physical agonistic interactions with the re-introduced resident until the intruder was forced into a submissive supine posture and emitted ultrasonic vocalizations (USV), and eventually exposing the intruder to the resident's threats for 1 h, while being shielded from potential injurious attacks. The hyperthermia, measured via telemetry, in the anticipatory phase prior to defeat and in reaction to threats, was decreased by alcohol, gepirone and diazepam; alcohol and gepirone were also effective in attenuating anticipatory tachycardia. Alcohol, like gepirone and diazepam, also decreased defensive responses and ultrasonic vocalizations in the anticipatory phase of the confrontation, but none of these drugs affected defensive reactions to threats which immediately followed defeat. Gepirone had no systematic sedative effects throughout the confrontation; infact, it dose-dependently reduced the stress-induced suppression of locomotor activity during the anticipatory phase. In contrast, at higher doses, alcohol as well as diazepam had marked sedative effects as evidenced by several behavioral parameters (i.e. lie, crouch, walk). The anxiolytic-like profile of hyperthermia, tachycardia, USV and defensive behavior in the anticipatory phase of the confrontation by alcohol, gepirone and diazepam contrasted with the lack thereof during the more intense reactive phase. This differential pattern of effects appears to be relevant to the clinical distinctions between anticipatory anxiety and other affective disturbances.     

Opioid receptors in the caudate nucleus can mediate EMG-recorded rigidity in rats

Summary Systemic administrations of opioids are known to induce catatonia or lead pipe rigidity in rats. The relevance of the caudate nucleus in inducing rigidity was tested. For this purpose, several opioids (or saline) were injected into the head of the caudate nucleus (intrastriatal injection) through an implanted cannula, and the electromyographical activity (EMG) was recorded in the gastrocnemius-soleus muscle (GS). Morphine (7.5–30 g), injected unilaterally, induced a continuous EMG activity in the ipsilateral GS muscle. This effect could be antagonized by systemic administration of naloxone (1 or 2 mg/kg i.p.). D-ala²-met⁵-enkephalinamide (3 g) and levorphanol (22.5 g) induced an EMG activity, too, whereas an equimolar dose of dextrorphan was ineffective, indicating that this effect was stereospecific and mediated via opioid receptors in the caudate nucleus. The EMG activity observed after systemic morphine administration (15 mg/kg i.p.) was antagonized by intrastriatal injection of naloxone (5 g). From our results, it can be concluded that the striatum — at least the head of the caudate nucleus — plays an important role in mediating the rigidity observed after systemic administration of morphine and other opioids.with technical assistance of Ch. Bode and H. Kügler