Extinction of fear I: Effects of amylobarbitone and dexamphetamine given separately and in combination on fear and exploratory behaviour in rats

Passive avoidance by rats of an environment previously associated with inescapable electric shocks, was taken as an index of the level of fear on repeated, unpunished tests. Locomotor and non-locomotor exploratory activity was also recorded during these tests. Although amylobarbitone diminished fear it did not accelerate its extinction; the amounts of locomotion were increased in both shocked and unshocked rats and tolerance did not develop to these effects of amylobarbitone.Dexamphetamine retarded extinction, with the result that the level of fear remained high even when the drug was withheld. At the same time as maintaining the level of fear dexamphetamine also increased locomotor activity, but this was confined to safe areas of the apparatus.Mixtures of amylobarbitone and dexamphetamine produced greater increases in locomotor activity than did the separate drugs, and their effects on fear were intermediate. In both cases the interactions between the effects of the constituent drugs did not appear to be other than additive. The inhibitory effects of dexamphetamine on the extinction of fear were not modified by adding amylobarbitone.     

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.     

N-Allyl-derivative of clonidine,a substance with specific bradycardic action at a cardiac site

Summary The most prominant action of a new substance 2-[N-allyl-N-(2,6-dichlorophenyl)-amino]-2-imidazoline, St 567 is bradycardia. As shown by ECG recordings in anaesthetized rats and cats, the bradycardia (doses 0.5 mg/kg) is of the sinus type, changes in PQ- and QT-intervals were neglegible, there were no changes in the QRS-complex. The bradycardic action could be localized in the heart, as was observed in spinal rats and isolated guinea-pig atria, and is of high specificity — in the isolated atria the heart rate was decreased by much smaller concentrations (EC30=2.9 g/ml) than contractility (EC30=155 g/ml) and maximal driving frequency (EC30=40 g/ml). Ratios between these 3 values were calculated and revealed a profile different from those of antiarrhythmics, so called calcium antagonists, and cholinergic drugs. In isolated guinea-pig atria the bradycardic effect of St 567 was not affected by phentolamine (1g/ml) or atropine (0.05 g/ml); the tachycardic action of isoprenaline (10^–4–10^–1 g/ml) was not affected by St567 (3 g/ml) in a way that indicates competitive antagonism. Thereby an involvement of -adrenoceptors, muscarinic receptors of -adrenoceptors was excluded. With 30 mg/kg St 567 no gross changes in behaviour of rats were observed, allowing a differentation from other bradycardic drugs such as harmala alkaloids and veratramine. The hitherto unknown pharmacologic pattern of St567 is discussed, its possible therapeutic use in coronary heart disease is considered.A preliminary report of this work was presented at the 5. Österreichisches Kardiologentreffen, Badgastein, Austria, January 11–14, 1979This paper is dedicated to the 60th birthday of Prof. Dr. Hans Klupp, Ingelheim am Rhein     

Biphasic and long-lasting effect of ceruletide on tardive dyskinesia

A 55-year-old schizophrenic inpatient with buccolingual dyskinesia was treated with a single dose of ceruletide 0.8 g/kg IM. Time-course effects of the drug were then followed for up to 6 weeks after injection. To assess changes in severity of bucco-lingual dyskinesia objectively, electromyogram (EMG) and microvibration (MV) were recorded. Simultaneously, bucco-lingual dyskinesias were also evaluated by using a five-point rating scale. Before injection of ceruletide, severity of dyskinesia was moderate and 3–4 Hz of dyskinetic oral movements were dominant. Extremely severe and repetitious gross oral movements (around 1 Hz) were observed within a few minutes after injection and continued for up to 1 h. Thereafter, oral movements tended to decrease, and they disappeared completely 3 weeks after injection. This biphasic and long-lasting effect of ceruletide on tardive dyskinesia might contribute to further understanding of the physio-pathophysiological role of cholecystokinin-like peptides in the brain, and provide a basis for practical treatment of tardive dyskinesia.     

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.     

Short-, medium-, and long-term effects of prenatal oxazepam on neurobehavioural development of mice

A benzodiazepine (oxazepam) was given to nulliparous mice on days 12–16 of pregnancy, and the development and young adult behaviour of the offspring were studied. Experiment 1, using 5, 15, and 50 mg/kg doses given PO twice daily, showed a dose-dependent retardation of postnatal development of several responses such as righting, bar holding, limb placing, and auditory startle. These changes were maximal in the first 2 postnatal weeks and then were markedly attenuated, or disappeared, being apparently related to a temporary retardation of body growth. A reduction of locomotor activity at 60 days was found only in the 50 mg/kg group. The effects of the 15 mg/kg dose on postnatal body growth and neurobehavioural development were replicated in Experiments 2 and 3. Moreover, in these experiments prenatal oxazepam reduced open field activity at 14–16 days and attenuated the hyperactivity induced by dl-amphetamine sulphate (2 mg/kg IP). On the other hand activity, habituation, and response to a scopolamine challenge (2 mg/kg IP) at 21–23 days were not significantly different from those of appropriate controls. Experiment 3, using a cross-fostering procedure, showed that postnatal maternal effects were not responsible for the changes so far mentioned. Experiment 2 also investigated the acquisition of several go-no go avoidance discriminations in a shuttle-box, using either light (L) or buzzer noise (N) as the go signal, a compound no go signal (NL in the L-go groups and LN in the N-go groups), and either an extinction or a passive avoidance contingency during the no go signal (4 weeks of training, starting at 60 days). The main effect of prenatal oxazepam was an impairment of active avoidance responding, while the treatment effects on overall discrimination performance were less marked and limited to the later stages of training.     

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.     

Toxicological studies with the herbicide 2,6-dichloro-thiobenzamide (chlorthiamid, “Prefix”)

Summary Prefix (chlorthiamid) has been shown to have single dose acute oral LD₅₀ values of 757 mg/kg (691–801) to rats, 500 mg/kg (455–548) to mice, between 100 and 125 mg/kg to sheep, about 300 mg/kg to rabbits, and over 1,000 mg/kg to domestic fowl and to Beagle hounds. The single dose acute percutaneous LD₅₀ to rats is greater than 1,000 mg/kg. Using a two hour experiment the LC₅₀ to Harlequin fish is 50 to 100 ppm and to Guppies over 100 ppm, but in 24 and 48 hour experiments using Harlequin fish the LC₅₀ values were 33 and 41 ppm (sic).The no-effect level for Prefix fed to rats in the diet was found to be 100 ppm. Rats also survived repeated oral dosing with half the LD₅₀ but rabbits were shown to be more susceptible in this test.Prefix has been shown to be non-irritant to skin and eyes and does not sensitize susceptible guinea-pigs.     

Comparative behavioral characterization of the neuroactive steroids 3α-OH,5α-pregnan-20-one and 3α-OH,5β-pregnan-20-one in rodents

Pregnan steroids have been shown to possess anesthetic, hypnotic, anticonvulsant and anxiolytic properties. In this study, two endogenous neuroactive steroid isomers, 3-hydroxy-5-pregnan-20-one (3,5-P) and 3-hydroxy-5-pregnan-20-one 3,5-P), were studied for differences in their pharmacological properties using behavioral assays. 3,5-P and 3,5-P were similar in their potencies and efficacies in blocking pentylenetetrazol-induced seizures in mice (ED₅₀: 3,5-P=2.8 mg/kg and 3,5-P=3.0 mg/kg). Similarly, both neuroactive steroids produced roto-rod deficits within the same range of potency (TD₅₀:3,5-P=18.8 mg/kg and 3,5-P=21.2 mg/kg). However, in animal models of anxiety, subtle differences were observed between the two isomers. In both the light/dark transition test and elevated plus-maze, 3,5-P was more efficacious than 3,5-P, though both compounds had similar potencies. In the Geller-Seifter test, 3,5-P was more potent and efficacious than 3,5-P. Neither compound had significant effects on unpunished responding within the dose range tested. Both compounds produced similar biphasic curves in the locomotor test. All together, the data indicate that 3,5-P and 3,5-P have similar anticonvulsant activity, but the 5-isomer possesses more potent and efficacious anxiolytic properties than the 5-isomer.     

Rewarding properties of β-endorphin as measured by conditioned place preference

The role of -endorphin as a possible mediator in the reinforcing properties of opiates was investigated using a conditioned place preference paradigm. Heroin, a synthetic opiate known to have reinforcing properties, produced a strong preference for an environment previously paired with heroin injection at all doses tested (0.25, 0.5, 1.0, 2.0 mg/kg SC). No such place preference was observed following saline injections. Rats also showed dose-dependent place preference for the environment paired with -endorphin when injected intracerebroventricularly (significant dose was 2.5 g). At higher doses (5.0 and 10.0 g) rats showed no preference for the paired environment, but were catatonic. Pretreatment with naloxone (0.04, 0.2, 1.0 mg/kg SC) attenuated the rewarding effect of -endorphin (2.5 g) at all doses tested. The lowest dose of naloxone which had no aversive effect when tested alone could also significantly block the positive effect of -endorphin. The reinforcing dose of -endorphin (2.5 g) also produced an increase in locomotor activity, when tested in photocell cages. This suggests that the hyperactivity induced by -endorphin may contribute to the preference for an environment previously paired with the same drug. The reinforcing effect of -endorphin is most probably mediated by the mu and/or delta opioid subtype receptor, since -endorphin has a high affinity for these receptors. These results demonstrate positive reinforcing properties of -endorphin in the central nervous system.     

Bioavailability assessment: Methods to estimate total area (AUC 0-∞) and total amount excreted (A e ∞ ) and importance of blood and urine sampling scheme with application to digoxin

Five methods are compared to estimate the total area under the digoxin plasma or serum concentrationtime curve (AUC0-) after a single dose of drug. To obtain accurate estimates of AUC0-, data required are concentrations at a sufficient number of sampling times to define adequately the concentration-time curve prior to the log-linear phase, and at least three, but preferably four or more equally spaced points in the terminal loglinear phase. One method (designated Method I) requires a digital computer; another (Method III) is the classical method (these two methods do not require equally spaced points in the loglinear phase). Method IIA is the accelerated convergence method of Amidon et al.; Methods IIB and IIC are modifications of this method, but incorporate usual and orthogonal least squares, respectively, which make them more accurate with real (noisy) data. Methods I and IICgave very comparable estimates of AUC0-. Results indicate that digoxin administered orally in aqueous solution was completely (100%) absorbed when bioavailability estimates were based on oral and intravenous AUC0- estimates and the actual doses, whereas formerly only about 80% absorption was reported, based on areas, under plasma concentration curves which were truncated at 96 hr. It is shown that the sampling scheme of blood can produce biased apparent bioavailability estimates when areas under truncated curves are employed, but an appropriate sampling scheme and application of method IIyield accurate bioavailability estimates. This is important particularly in those bioavailability studies where one is attempting to determine the appropriate label dose for a new fastrelease digoxin preparation relative to the label dose and bioavailability of currently marketed tablets. It is shown that the magnitudes and variability of apparent elimination rate constants and halflives of digoxin, estimated from urinary excretion data by the ^– method, depend on which value of A _e is used. The formerly reported greater interindividual variability of AUC data compared to At data for digoxin is explained in that the AUCs, but not the A_e,'s, involve the renal clearance, which exhibits considerable inter- and intraindividual variation.     

A comparison of the effects of TMB-8 and nifedipine on pressor responses to α1- and α2-adrenoceptor agonists in pithed rats

TMB-8 has been characterized as an inhibitor of the release of Ca⁺ from intracellular pools. We have studied the modification of the pressor responses to selective _l-adrenoceptor agonists (methoxamine and phenylephrine), and to selective ₂-adrenoceptor agonists (B-HT 920 and B-HT 933) in pithed rats, produced by TMB-8. We have compared this modification with that produced by the calcium antagonist nifedipine. Nifedipine (100 g/kg, 300 g/kg, and 1000 g/kg) inhibited in a dose-dependent manner the pressor responses to the ₁- and ₂-adrenoceptor agonists, the dose-response curves to the ₂-adrenoceptor agonists being shifted further to the right. TMB-8 at a dose of 3000 g/kg did not modify the pressor effects of the _l-adrenoceptor agonists, and neither did it reinforce the inhibition of such responses produced by nifedipine. By contrast, TMB-8 pretreatment (0.03 g/kg, 0.3 g/kg, 3 g/kg, 30 g/kg, 300 g/kg and 3000 g/kg) inhibited the responses to both ₂-adrenoceptor agonists, the inhibition being more pronounced with B-HT 920. A similar effect was obtained with 0.03 g/kg TMB-8 and 0.3 g/kg TMB-8, particularly in the case of B-HT 920. It was stronger with higher doses, but similar for all doses over 3 g/kg. The inhibition of the pressor responses mediated by the stimulation of ₂-adrenoceptors by TMB-8 was less in rats treated with the Ca²⁺ entry promoter BAY K 8644 (300 g/kg), and could also be reduced by the continuous infusion of CaCl₂ (0.25 g/min). These results suggest that in pithed rats TMB-8 may also behave as an inhibitor of the Ca⁺ influx into vascular smooth muscle.     

Opioid peptides decrease noradrenaline release and blood pressure in the rabbit at peripheral receptors

Summary Effects of dynorphin-(1–13), Leu⁵-enkephalin,d-Ala²,d-Leu⁵-enkephalin (DADLE), and for comparison bremazocine, on plasma noradrenaline concentration and mean arterial pressure (MAP) were studied in pithed rabbits. In the first series of experiments, the sympathetic outflow was stimulated electrically via the pithing rod at 2 Hz twice for 3 min each (S₁, S₂). Drugs were administered before S₂. Bremazocine 10 g/kg+2g/kg/h and 100 g/kg+20 g/kg/h, dynorphin 1 and 3 g/kg/min, Leu⁵-enkephalin 100 g/kg/min and DADLE 10 and 30 g/kg/min all diminished the electrically-evoked increase in plasma noradrenaline and MAP. The effects were antagonized by naloxone. In the second series, an infusion of noradrenaline (2 g/kg/min) was given twice for 3 min each (N₁, N₂). Drugs were administered before N₂. Bremazocine 100 g/kg+20 g/kg/h slightly enhanced the pressor effect of exogenous noradrenaline, whereas dynorphin 3 g/kg/min, Leu⁵-enkephalin 100 g/kg/min and DADLE 30 g/kg/min caused no significant change. In the third series, the sympathetic outflow was stimulated continuously at 2 Hz, and the interaction of dynorphin and DADLE was studied. Dynorphin 1 g/kg/min and DADLE 10g/kg/min initially decreased MAP to a similar extent. The effect of DADLE faded with time. When, during continuous infusion of DADLE 10 g/kg/min, and after return of MAP to the pre-DADLE level, dynorphin 1 g/kg/min or DADLE 10 g/kg/min was infused additionally, the effect of dynorphin was unchanged, whereas that of DADLE was almost abolished. We conclude that the opioid peptides as well as bremazocine decrease action potential-evoked release of noradrenaline and, secondarily, blood pressure. They act at peripheral sites, presumably prejunctional opioid receptors at postganglionic sympathetic axons. Dynorphin on the one hand, and Leu⁵-enkephalin and DADLE on the other hand, appear to act at different receptors, dynorphin probably at a - and DADLE and Leu⁵-enkephalin at a -receptor.     

Effects of morphine on release of acetylcholine in the rat striatum: an in vivo microdialysis study

Summary We examined the effect of morphine on the release of acetylcholine (ACh) in the striatum of freely moving rats using the in vivo microdialysis method. The basal level of ACh was 3.01 ± 0.51 pmol/30 l/15 min in the presence of neostigmine (10 M). Tetrodotoxin (1 M), a selective blocker of voltage-dependent Na⁺ channels, rapidly decreased the release of ACh in the striatal perfusates. Morphine at a dose of 10 mg/kg (i.p.) caused a reduction of ACh release in the striatum at 90–150 min. However, a lower dose of morphine (5 mg/kg, i.p.) did not affect ACh release in the striatum. The reduction following intraperitoneal administration of morphine was abolished by naloxone (1.0 mg/kg).After microinjection of the neurotoxin 6-hydroxydopamine (6 g/3 l, 7 days before) in the substantia nigra, the morphine (10 mg/kg)-induced decrease of ACh was attenuated, and a similar result occurred following reserpine (2 mg/kg, i.p.) 24 h before combined with -methyl-p-tyrosine (300 mg/kg, i. p.) 2.5 h before.These findings indicate that morphine exerts an inhibitory influence on striatal ACh release in freely moving rats and that this inhibitory effect is mediated by the nigro-striatal dopaminergic system.Correspondence to K. Taguchi at the above address     

Bidirectional effects of benzodiazepine binding site ligands on active avoidance acquisition and retention: differential antagonism by flumazenil and β-CCt

Rationale The pharmacological approach, using subtype selective ligands, complements genetic studies on the specific contribution of individual receptor subtypes to the various effects of benzodiazepines.Objective The aim of this study was to examine the relative significance of ₁-containing GABA_A receptors in the effects of modulators at the benzodiazepine site on anxiety and memory processes.Methods We tested the effects of the nonselective antagonist flumazenil, the preferential ₁-subunit selective antagonist -carboline-3-carboxylate-t-butyl ester (-CCt), the nonselective agonist midazolam, the preferential ₁-subunit selective agonist zolpidem, and the nonselective inverse agonist methyl 6,7-dimethoxy-4-ethyl--carboline-3-carboxylate (DMCM) in a two-way active avoidance task in rats. The influence of flumazenil (10.0 mg/kg) and -CCt (30.0 mg/kg) on the effects of the two agonists were also examined. In the schedule 2×30 trials, drugs were administered i.p. 20 min before the training session. Avoidance responses in the training session are an anxiety-mediated behavior, whereas performance in the retention session relates to the effects on memory.Results Flumazenil and -CCt did not affect behavior. Midazolam (2.0 mg/kg) facilitated acquisition performance, while DMCM (1.0 and 2.0 mg/kg) induced the opposite effect. Flumazenil antagonized both effects. -CCt potentiated the effect of midazolam, and partly antagonized the effect of DMCM. Midazolam (0.5 and 1.0 mg/kg) and zolpidem (1.0–3.0 mg/kg) impaired, while DMCM (0.1 mg/kg) facilitated the subjects performance in the retention test. The amnesic effects were attenuated but not fully reversed, while the effect of DMCM was counteracted by both antagonists.Conclusion The results indicate the ₁-subunit interferes with the anxiolytic effect of a benzodiazepine site agonist and may contribute to the DMCM-induced anxiogenic effect. It is also substantially involved in the bidirectional memory processing in the active avoidance paradigm.     

Antagonism of the anticonflict effects of chlordiazepoxide by β-carboline carboxylic acid ethyl ester,Ro 15-1788 and ACTH(4–10)

The antagonism of the anticonflict effect of chlordiazepoxide (CDP) by -carboline carboxylic acid ethyl ester (BCCE), Ro 15-1788 and ACTH(_4–10) has been evaluated in the Geller-Seifter rat conflict test in which CDP increases punished (conflict), but not unpunished responding. BCCE (0.5–10 g ICV) produced a dose-dependent reduction in the anticonflict activity of CDP. This was also significantly reduced by Ro 15-1788 (25 mg/kg IP) and a high dose of ACTH(_4–10) (5 g ICV). None of these test compounds had a marked direct effect on punished or unpunished responding in the doses used. These experiments provide further physiological support for the suggestion from binding studies that BCCE and Ro 15-1788 act on benzodiazepine receptors. However, the ability of ACTH(_4–10) to reduce the anticonflict effect of CDP may be by some other, possibly opioid, mechanism.     

Diazepam withdrawal: effects of diazepam and gepirone on acoustic startle-induced 22 kHz ultrasonic vocalizations

It has proven difficult to demonstrate and study the anxiogenic quality of drug withdrawal states in animals. Ultrasonic vocalizations (USV) in response to acoustic startle stimuli have shown promise as a measure of affect and may represent distress responses during diazepam withdrawal. Three experiments evaluated the association between USV and distress by comparing the effects of diazepam as a prototypic benzodiazepine agonist and the putative anxiolytic gepirone with affinity for 5-hydroxytryptamine (5-HT_1A) receptors in naive and diazepam-withdrawn subjects. Adult male Long-Evans rats were exposed to acoustic startle sessions consisting of nine 105 dB and nine 115 dB stimuli. USV at 20–30 kHz were readily emitted during startle and often commenced after the third or fourth stimulus presentation. Acutely, intraperitoneal (IP) administration of diazepam (0.1–3 mg/kg) and gepirone (0.1–1 mg/kg) decreased USV dose-dependently without affecting the startle reflex; gepirone also decreased tail flick latency. Startle-induced USV were also sensitive to the anxiogenic effects of withdrawal from diazepam exposure (0, 2.5, 5, 10 mg/kg b.i.d. IP×5 days). Twenty-four hours after the last diazepam injection, rats were hyperreactive to startle stimuli and doubled their rate of USV over vehicle-treated controls. Gepirone (0.1–1 mg/kg IP), but not diazepam (3–20 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 10 mg/kg b.i.d. diazepam. Diazepam (2.5–10 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 2.5 mg/kg b.i.d. diazepam. USV induced by acoustic startle stimuli are sensitive to the anxiolytic effects of benzodiazepine and 5-HT_1A receptor agonists and permit the assessment of the anxiogenic properties of diazepam withdrawal. The potent effect of gepirone on USV suggests a serotonergic amelioration of the anxiogenic aspects of diazepam withdrawal.     

Effect of haloperidol on reflex activation of rat α-motoneurones

Summary Effects of haloperidol on rat flexor and extensor -motoneurones were studied in ventral roots of laminectomized rats under halothane anesthesia. The -motoneurones were activated by tetanic stimulation of low-threshold afferents (group I and II), either of the ipsilateral peroneal nerve (flexor -motoneurones) or gastrocnemius-soleus nerve (extensor -motoneurones).Haloperidol, given in the doses of 0.075, 0.15 and 0.30 mg/kg i.p. inhibited the reflex activation of flexor -motoneurones; higher doses seemed to be more effective than lower ones. Apomorphine (2 mg/kg s.c.) partially antagonized the inhibitory action of haloperidol with some latency. Higher doses of haloperidol (0.15–0.60 mg/kg i.p.) also inhibited the reflex activation of extensor -motoneurones; this inhibitory effect was, at least for a short time, antagonized by apomorphine (2 mg/kg s.c.).The threshold for reflex activation both of flexor and extensor -motoneurones was raised by haloperidol and lowered by a subsequent administration of apomorphine.Our results suggest that akinesia and catalepsy, induced in rats by haloperidol might be, at least in part, due to a decrease in sensitivity of -motoneurones to proprioceptive stimuli.     

Benzodiazepine ligands,nociception and ‘defeat’ analgesia in male mice

Recent studies have indicated that defeat experience induces acute non-opioid analgesia in intruder mice. To investigate the potential involvement of benzodiazepine receptors in this biologically-relevant form of environmentally-induced antinociception, we initially assessed the effects of some benzodiazepine ligands on basal nociception (tail-flick assay). Chlordiazepoxide (5–30 mg/kg), midazolam (0.625–5 mg/kg), diazepam (0.5–4 mg/kg), Ro15-1788 (5–80 mg/kg) and CGS8216 (5 mg/kg) were found to be ineffective in altering basal nociception. However, higher doses of CGS8216 (10–20 mg/kg) induced significant analgesia, an effect also observed with the -carboline derivatives FG7142 (5–20 mg/kg) and DMCM (1–2 mg/kg). Time-course analyses revealed that the onset of CGS8216 analgesia was slower than for FG7142 and DMCM, but that all three drugs produced long-lasting elevations in tailflick latencies. The analgesic effects of FG7142 and DMCM were completely reversed by Ro15-1788 (20 mg/kg) and by chlordiazepoxide (20 mg/kg), suggesting mediation by benzodiazepine receptor mechanisms. Although CGS8216 analgesia was also reversed by Ro15-1788, it was unaffected by chlordiazepoxide; however, diazepam (5 mg/kg) did significantly attenuate the reaction. Further studies indicated that the antinociceptive consequences of defeat experience were dose-dependently blocked by Ro15-1788 (10–40 mg/kg) and by diazepam (0.5–2 mg/kg). Surprisingly, however, neither chlordiazepoxide (5–20 mg/kg) nor midazolam (1.25–2.5 mg/kg) blocked defeat analgesia under present test conditions. Although several issues remain unresolved, present findings would not be inconsistent with the proposal that stimuli associated with the acute stress of defeat experience release an endogenous ligand which acts in an inverse agonist-like manner at benzodiazepine sites.     

Anti-nociceptive effect of morphine,opioid analgesics and haloperidol injected into the caudate nucleus of the rat

Summary The effect of intracaudate (i.c.) microinjections of morphine, opioid analgesics and haloperidol was determined on the tail-flick response evoked by radiant heat in rats. Bilateral injections (0.2 l on each side) into the caudate nuclei of morphine 5 g, pethidine 50 g, levorphanol 4 g, dextrorphan 10 g and haloperidol 5 g significantly increased the reaction time of the tail-flick response. The antinociceptive effect of an i.c. injection of morphine or levorphanol was abolished by an intraperitoneal (i.p.) injection of naloxone 0.2 mg/kg or apomorphine 2 mg/kg. The anti-nociceptive effect of pethidine, dextrorphan and haloperidol was reduced but not abolished by an i.p. injection of naloxone 0.2 mg/kg. An i.p. injection of apomorphine 2 mg/kg abolished the effect of an i.c. injection of haloperidol. A bilateral i.c. injection of naloxone 5 g or apomorphine 10 g reduced the anti-nociceptive effect of an i.p. injection of morphine 2 mg/kg or haloperidol 2 mg/kg, but did not abolish it. It is concluded that (1) an anti-nociceptive effect can be achieved by an action on the caudate nucleus of the drugs tested; (2) the anti-nociceptive effect exerted by morphine and levorphanol in the caudate nucleus is due to a specific action mediated by opiate receptors, whilst that produced by pethidine and dextrorphan is due to a specific and/or unspecific action; (3) the anti-nociceptive effect of haloperidol in the caudate nucleus is due to an impairment of dopaminergic impulse transmission, which is also involved in the effect of morphine and levorphanol.Supported by the Sonderforschungsbereich 38 Membranforschung