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 nicotine on the swimming speed of pre-trained rats through a water alley

Summary In sessions of ten runs each, swimming time of rats through a 4 m long water alley was measured. Four doses of nicotine (0.05; 0.1; 0.2; 0.4 mg/kg given intraperitoneally 30 minutes before testing) were tested in sessions with a braking load on the tails of the animals either in all 10 runs of a session, or in every second run, or in none of the 10 runs. Regardless of the swimming condition, nicotine produced a considerable, and at doses of 0.1 mg/kg and over, significant decrease of performance in the first two runs. From the third to the 10th run, the changes caused by nicotine were smaller and differed depending on the swimming conditions.A dose of 0.1 mg nicotine/kg improved performance in the without-load-sessions and the without-load-runs of the alternating sessions, while both 0.1 and 0.2 mg/kg improved performance of the with-load-runs of the alternating sessions. Performance in the without-load-sessions and the without-load-runs was depressed by 0.4 mg/kg and that in the with-load-sessions by 0.2 and 0.4 mg/kg.     

Potentiation of catalepsy induced by narcotic agents during Haffner's test for analgesia

Potentiation of morphine catalepsy in the mouse during Haffner's (tail-clip) test for analgesia has been investigated. Very marked potentiation occurred in the presence of the clip. Both native and clip catalepsy were antagonised by nalorphine. Atropine antagonised morphine native catalepsy in a dose-dependent fashion, but produced a parallel increase in both analgesia and clip catalepsy at higher doses. Haloperidol catalepsy was abolished in the presence of the clip but reappeared on its removal. It is suggested that morphine must have at least two sites of action in producing catalepsy to account for these results.     

Structure-activity relationship studies on mescaline: II. Tolerance and Cross-tolerance between mescaline and its analogues in the rat

Summary Using the CAR shuttle box technique, with male hooded rats as subjects, the development of tolerance to mescaline, 3,4-dimethoxyphenyl-ethylamine (DMPE) and NN-dimethylmescaline (DMM) and possible cross-tolerance between these drugs was studied. It was found that seven successive daily doses of mescaline induced tolerance to its inhibitory effect, but that the excitatory effect was increased. Tolerance developed to the predominantly inhibitory effect of DMPE, and to the excitatory effect of DMM.Partial cross-tolerance existed between DMPE and mescaline, and when the procedure was reversed, between mescaline and DMPE. Cross-tolerance was shown in the same manner between DMM and mescaline, and mescaline and DMM.The problems of quantification and interpretation of these results is discussed. It was concluded, on the basis of subsidiary experiments, that the inhibitory effect of mescaline was probably not caused by ataxia or by a peripheral effect.     

Drug,doctor warmth,and clinic setting in the symptomatic response to minor tranquilizers

An NIMH-PRB collaborative double-blind clinical trial, concerned with the importance of the doctor variable for drug treatment outcome, was conducted with 485 anxious neurotic outpatients receiving either chlordiazepoxide, meprobamate, or placebo. The participating clinics were located at the Johns Hopkins Hospital, Philadelphia General Hospital, and the Hospital of the University of Pennsylvania. The doctor variable selected for presentation was doctor warmth. Data on the 169 patients completing the 4 week study according to protocol were analyzed using a factorial analysis of covariance procedure, and the main findings were as follows: 1. several main drug effects, present only at 2 weeks, indicated chlordiazepoxide to produce significantly more improvement than either meprobamate or placebo; 2. several main warmth effects, present only at 4 weeks, showed patients rating their physicians at the initial visit as warm to improve significantly more than patients rating their physicians as non-warm; and 3. several significant drug X clinic interaction effects at 4 weeks reflected the fact that while hardly any drug differences were seen in 2 clinics, at Philadelphia General Hospital, patients strongly favored chlordiazepoxide. Drug and warmth effects were particularly marked in initially sicker patients, and warmth appeared especially important in the improvement of initially sicker placebo patients.     

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.     

“A” esterases and their role in regulating the toxicity of organophosphates

Esterases which can hydrolyse organophosphates without being inhibited by them are termed A esterases. Using paraoxon and pirimiphos-methyl oxon as substrates, high A esterase activity is found in the liver and plasma or serum of a range of mammalian species. In a study of serum A esterases of sheep and humans, over 80% of the activity separated into the high density lipoprotein (HDL) fraction following ultracentrifugation. When HDL fractions from sheep serum were run on Sepharose gel columns, most of the paraoxonase activity separated as a single peak of estimated molecular weight 360000, which corresponds to that of HDL₂ of humans.During the course of purification of A esterases by three different column procedures, contrasting esterase elution profiles were obtained with organophosphate and pyrethroid substrates. This was strong evidence for the existence of multiple forms of HDL A esterases.Levels of A esterase activity in plasma and liver of birds were much lower than those of mammals. This appears to be the main reason why birds are much more susceptible than mammals to organophosphates such as pirimiphos-methyl and diazinon which form active oxons that are good substrates for mammalian A esterases.No A esterase was detected in strains of rust red flour beetle (Tribolium castaneum) which were resistant to organophosphates. Similar observations have been made with strains of other insects resistant to organophosphates, raising the question to what extent esterases of this type are present in insects.Dedicated to Professor Dr. med. Herbert Remmer on the occasion of his 65th birthday     

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.     

Relation between morphine pharmacokinetics and analgesia

The relationship between the multicompartmental behavior of morphine and the kinetics of the analgesic effect has been investigated using a digital computer compartment analysis program. The results obtained indicate that the concentrations of morphine in the brain are not related to the analgesic effect in a direct manner but rather in an indirect way. A compartment model describing the kinetics of such an indirect pharmacological effect was found to yield a good correlation between the Pharmacokinetics of morphine and the kinetics of the analgesic effect.     

Cocaine-induced cocaine craving

In nine experienced users of cocaine, we examined the urge to use cocaine or other drugs following a 40 mg dose of intravenous (IV) cocaine with and without oral pretreatment with 2.5 mg bromocriptine. The urge to use cocaine was assessed with a questionnaire constructed to assess both wanting and craving for cocaine or other drugs. Fifteen minutes after the administration of cocaine (but not after placebo), subjects' ratings for both drug wanting and drug craving were significantly increased. Our results provide a laboratory demonstration of cocaine-induced increases in the urge to use drugs in humans. The findings, stressing the role of internal stimuli associated with drug administration, suggest the possibility of distinguishing among related, but perhaps distinct, components of the fluctuating levels of motivation to reuse drugs.     

The saturability of a site of loss and the degree of supersensitivity to agonists which are substrates of this site of loss

Summary The present investigation was undertaken to test the hypothesis that the experimentally determined degree of supersensitivity to an agonist caused by inhibition of a site of loss depends on the ratio K _m of the site of loss/ED₅₀ of the agonist.The influence of inhibition of neuronal uptake by cocaine on the -adrenoceptor-mediated effect of noradrenaline was studied on the dog saphenous vein; the influence of inhibition of COMT by U-0521 on the -adrenoceptor-mediated effect of isoprenaline was studied on the dog saphenous vein and on the guinea-pig trachea; the influence of inhibition of acetylcholinesterase by physostigmine on the effect of acetylcholine was studied on the guinea-pig ileum. To further extend the range of values of the ratio K _m/ED₅₀, several concentrations of phentolamine, propranolol or atropine were used to increase the ED₅₀ of the respective agonist. It was thus possible to determine the degree of supersensitivity caused by inhibition of a site of loss over a range of K _m/ED₅₀ values of 0.02 to 2,307.In seven situations the ratio K _m/ED₅₀ was higher than 10. In all of these cases the supersensitivity caused by inhibition of the site of loss was maximal. In eleven situations the ratio K _m/ED₅₀ was less than 10 and higher than 0.1 and the supersensitivity obtained was sub-maximal but was closer to the maximum, the closer the ratio was to 10. In two situations the ratio was less than 0.1 and no supersensitivity was obtained.The results confirm the hypothesis.     

A comparison of the analgetic potency of some analgesics as measured by the “flinch-jump” procedure

Summary The effects of various doses of morphine, dl-methadone, nalorphine, codeine, meperidine and saline on the flinch-jump thresholds of rats were measured by a procedure described previously. While none of the drugs influenced the flinch threshold, the group slopes of elevation of jump thresholds were significant for all drugs studied. In order of potency as revealed by this method, nalorphine ranked with morphine and methadone, while codeine and meperidine were less potent, suggesting that the procedure may be useful as a screening test for analgesic drugs.     

Clockwise hysteresis or proteresis

The authors propose the word proteresis to designate the clockwise hysteresis, i.e., when an effect increases more rapidly than the observed drug concentrations. Such a phenomenon has been recently described for aspirin and nicotine. Indeed hysteresis means which comes after, while proteresis, the greek symmetrical word, means which comes earlier, a more appropriate term for the described situation.     

A new technique for the investigation of some analgesic drugs on a reflexive behavior in the rat

Summary The analgetic action of a series of analgesic and psychotropic agents was tested in a situation in which variable intensities of electric shock to a rat's feet were used to elicit two distinguishable reflexive responses: a flinching response at low shock values, and a jumping response at higher shock values,By using a modified method of limits, reliable threshold for the two responses were obtained.Chlorpromazine, perphenazine, morphine, codeine, nalorphine and acetylsalicylate were found to raise the threshold to jump, but had little or no effect on the threshold to flinch.PIH, JB 835, iproniazid, reserpine, tetrabenazine, and amphetamine were found to have no effect on either the jump or the flinch thresholds.A combination of amphetamine and codeine was found to produce a synergistic potentiation. A combination of morphine and nalorphine was found to produce an antagonism.The results were discussed in terms of Beecher's hypothesis that the analgetic action of drugs is due to a diminution of the emotional components of an animal's reaction to pain and in terms of the relationship of brain amine change to analgetic action.     

Blockade of hoarding in rats by diazepam: an analysis of the anxiety and object value hypotheses of hoarding

The security hypothesis suggests food hoarding by rats serves to preempt attack and therefore might be motivated by anxiety. The object value hypothesis suggests rats hoard objects that they perceive as valuable as related to some state or need. These hypotheses were evaluated with the anxiolytic drug diazepam, which is purported to both decrease anxiety and increase motivation to eat, and which accordingly either may decrease or increase hoarding. Using a new hoarding paradigm, diazepam (Valium: 0.25–5 mg/kg), was found to produce a dose-related reduction in hoarding that was dependent upon food pellet size and that was reversed by flumazenil (Ro 15-1788), a benzodiazepine receptor antagonist. Diazepam also slowed eating speed, blocked dodging, a movement used to initiate hoarding, and impaired spatial navigation in a learning-set swimming pool task. The results fail to support the object value hypothesis of hoarding. Since perception of food size, motivation, motor ability and spatial abilities all probably contribute to successful food hoarding, the results provide several explanations other than, or in addition to, anxiety reduction for the drug's effects on hoarding. Nevertheless, the study provides a number of new sensitive measures of the effects of anxiolytic drugs and new insights into their behavioral effects.     

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.     

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.     

The influence of learning on morphine analgesia and tolerance development in rats tested on the hot plate

The influence of learning on the development of tolerance to the analgesic effect of morphine in rats was examined employing the hot plate procedure. A tested-reinforced (Tr) group and its yoked-control, a tested-non-reinforced (Tnr) group, received identical exposure to the testing procedure; the Tr group was reinforced daily for its behavior on the heated plate whereas the Tnr group was reinforced only on the last day of the experiment. Paired statistical comparisons between these two groups on the last day of the experiment revealed that: 1. premorphine control reaction times on the heated plate were significantly lower in Tr than in Tnr animals; and 2. post-morphine increases in reaction time did not differ between Tr and Tnr animals. It was concluded that whereas some learning does occur in this testing procedure, learning does not influence the behavioral tolerance to morphine which develops in this analgesiometric method. An hypothesis which accommodates this behavioral tolerance and a mechanistic scheme is offered.     

The subjective,behavioral and cognitive effects of subanesthetic concentrations of isoflurane and nitrous oxide in healthy volunteers

A prospective, crossover, double-blind trial was conducted in nine healthy volunteers in which the subjective, psychomotor and memory effects of isoflurane (0.0, 0.3 and 0.6%) and nitrous oxide (N₂O) (0, 20 and 40%) were examined. Dependent measures included visual analog scales and a standardized drug effects inventory (subjective effects), reaction time and eye-hand coordination (e.g., psychomotor performance), and immediate and delayed free recall (memory). There were some similarities in subjective effects between the two inhaled drugs (e.g., increased ratings of drunk and spaced out), but isoflurane had effects which N₂O did not have. Isoflurane but not N₂O increased visual analog scale ratings of confused, sedated, and carefree, and decreased ratings of in control of thoughts and in control of body. An odor was detected with isoflurane and it was disliked. Psychomotor performance was more grossly impaired during isoflurane inhalation than during N₂O inhalation. Psychomotor recovery from both agents was rapid and complete so that 5 min after the inhalation period had ceased, performance had returned to baseline levels. Both isoflurane and nitrous oxide impaired immediate and delayed free recall. The feasibility of using isoflurane in conscious sedation procedures is discussed.     

A novel diterpenoid with a rearranged neoclerodane skeleton from Salvia leucantha CAV.

A new diterpenoid with a rearranged neoclerodane skeleton, spiroleucantholide (compound S1), along with four known diterpenoids—salvifaricin (compound S2), isosalvipuberulin (compound S3), salvileucantholide (compound S4), and salviandulin E (compound S5)—was isolated from the aerial parts of Salvia leucantha CAV.. The structures were established by spectroscopic methods, including the X-ray analysis of spiroleucantholide (S1).