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Defensive behaviors of lower mammals confronted with a predatory stimulus provide an appropriate laboratory model for investigating behavior relevant to human emotional disorders. The mouse defense test battery (MDTB) has been developed because it combines many of the aspects of defense. Briefly, it consists of five tests either associated with potential threat (contextual defense) or the actual presence of an approaching threat (a rat). These latter focus on changes in flight, risk assessment and defensive threat and attack behaviors. Investigations with anxiolytic compounds have shown that these defense reactions may be used to differentiate between several classes of anxiolytic drugs. Here we used the MDTB to compare the behavioral profile of the benzodiazepine diazepam with that of neuropeptide receptor antagonists which have been shown to be involved in the modulation of stress response, namely the NK2receptor antagonists, SR48968 (0.01–1mg/kg) and SR144190 (1–10mg/kg), and the NT1receptor antagonist, SR48692 (1–30mg/kg). Results showed that all compounds decreased defensive threat/attack, but only diazepam and, to a lesser extent, SR48692 significantly modified risk assessment or flight. Further, none of the neuropeptide receptor antagonists modified contextual defense. Overall, the behavioral profile displayed by diazepam and these latter compounds in the MDTB are consistent with an anxiolytic-like action. However, our results suggest that, while NK2and NT1receptor antagonists may have limited efficacy on anxiety-related responses including cognitive aspects (i.e. risk assessment), they may have a potential against some forms of anxiety disorders which involve adaptative responses to extreme stress stimuli (e.g. direct confrontation with the threat stimulus).

Background: Chronic ethanol administration results in neurobiological alterations similar to those observed after chronic cannabinoid exposure. The purpose of this study was to investigate alcohol drinking and the withdrawal responses after pulmonary chronic alcoholization with intraperitoneal or oral administration of a cannabinoid CB1receptor antagonist.

Using anaesthetized adult rats, we compared the effects of i.v. injections of neurotensin receptor antagonists (SR48692 and SR142948), haloperidol and clozapine on neuronal firing rate in the two ventral pallidal areas. SR48692 (0.5, 1 and 2 mg/kg, i.v.) induced a dose-dependent inhibition of firing rate in two thirds of neurons in the ventromedial part without any effect in the ventrolateral part. These effects are in keeping with the preferential neurotensin immunoreactivity distribution reported in the ventral pallidum. The classical antipsychotic drug haloperidol (0.5 mg/kg, i.v.) induced an inhibition of neuronal firing rate in both ventral pallidal areas whereas the atypical antipsychotic drug clozapine (20 mg/kg, i.v.), like the neurotensin receptor antagonist SR48692, inhibited cell firing only in the ventromedial part.

In vivo extracellular recording techniques were used to investigate the effects of neurokinin3 (NK3) receptor blockade on the pharmacological activation of midbrain dopamine (DA) neurons in the guinea pig substantia nigra (A9) and ventral tegmental area (A10). The number of spontaneously active DA cells (population response) was largely increased in A10 and A9 by acute administration of haloperidol (1 and 0.5 mg/kg i.p., respectively) and this effect was dose-dependently prevented in both areas by the selective NK3 receptor antagonist SR142801 (0.3, 1, 3, and 1, 3, 10 mg/kg i.p., respectively). This compound, which was totally inactive by itself, also antagonized the increase of population response induced in A10 cells by the neurotensin receptor antagonist SR142948 (1 mg/kg i.p.) and in A9 cells by the NK2 receptor antagonist SR144190 (1 mg/kg i.p.). None of the effects of SR142801 were reproduced by SR142806, its (R)-enantiomer with 240-fold lower affinity for NK3 receptors. In addition, neither SR144190 (0.3 mg/kg i.p.) nor the NK1 receptor antagonist GR205171 (1 mg/kg i.p.) affected the haloperidol-induced response. The antagonistic effects of SR142801 (3 mg/kg i.p.) were also observed on the depolarization block-related decrease of A10 cell population response evoked by repeated administration (22 days) of haloperidol. Finally, SR142801 (3 mg/kg i.p.) prevented depolarization block induced in A10 cells by acute co-administration of SR142948 and haloperidol, both on population response and on single cell firing. These results on pharmacologically induced activation and depolarization block of dopamine neurons suggest that NK3 receptors play a key role in the midbrain DA function, presumably through activation by neurokinin B. Synapse 33:71–79, 1999. © 1999 Wiley-Liss, Inc.

In vivo extracellular recording techniques were used to investigate the effects of neurokinin3(NK3) receptor blockade on the pharmacological activation of midbrain dopamine (DA) neurons in the guinea pig substantia nigra (A9) and ventral tegmental area (A10). The number of spontaneously active DA cells (population response) was largely increased in A10 and A9 by acute administration of haloperidol (1 and 0.5 mg/kg i.p., respectively) and this effect was dose‐dependently prevented in both areas by the selective NK3receptor antagonist SR142801 (0.3, 1, 3, and 1, 3, 10 mg/kg i.p., respectively). This compound, which was totally inactive by itself, also antagonized the increase of population response induced in A10 cells by the neurotensin receptor antagonist SR142948 (1 mg/kg i.p.) and in A9 cells by the NK2receptor antagonist SR144190 (1 mg/kg i.p.). None of the effects of SR142801 were reproduced by SR142806, its (R)‐enantiomer with 240‐fold lower affinity for NK3receptors. In addition, neither SR144190 (0.3 mg/kg i.p.) nor the NK1receptor antagonist GR205171 (1 mg/kg i.p.) affected the haloperidol‐induced response. The antagonistic effects of SR142801 (3 mg/kg i.p.) were also observed on the depolarization block‐related decrease of A10 cell population response evoked by repeated administration (22 days) of haloperidol. Finally, SR142801 (3 mg/kg i.p.) prevented depolarization block induced in A10 cells by acute co‐administration of SR142948 and haloperidol, both on population response and on single cell firing. These results on pharmacologically induced activation and depolarization block of dopamine neurons suggest that NK3receptors play a key role in the midbrain DA function, presumably through activation by neurokinin B. Synapse 33:71–79, 1999. © 1999 Wiley‐Liss, Inc.

The neurotrophic factor promoting activity of the neuroprotective compound SR57746A was evaluated in primary cultures of neonatal rat cortical astrocytes by studying the synthesis of nerve growth factor (NGF) and brain‐derived neurotrophic factor (BDNF).A concentration‐ and time‐dependent increase of nerve growth factor mRNA was induced by SR57746A (10 nM–1 μM). In these astrocytes, BDNF mRNA contents were increased to a significant but smaller extent, and β‐actin mRNA showed no variation.SR57746A (1 μM) induced increases of both de novoprotein translation after 6 h of incubation and NGF release into the extracellular medium after 6–24 h.These effects were preceded by a transient augmentation of junB, c‐fosand c‐junmRNA contents. These increases of AP‐1 family mRNA were associated with increased nuclear AP‐1 binding activity.The results show that SR57746A can increase the synthesis and release of NGF in rat cortical astrocytes. Such effects may contribute to the drug's previously described neuroprotective effects.

Summary We have investigated the effect of SR 57227A, a selective 5-HT3 receptor agonist which crosses the blood brain barrier, on three rodent models in which antidepressants are active. In the forced swimming test, SR 57227A dose-dependently reduced the duration of immobility in mice and rats after i.p. administration. (ED50=14.2mg/kg i.p. in mice, and 7.6 mg/kg i.p. in rats.) The compound was also active in both species after oral administration. In a time-course study in mice, SR 57227A (20 mg/kg p.o.) produced a significant effect lasting 6 h. SR 57227A (1 and 3 mg/kg i.p.) reduced the elevation of the escape failures in the learned helplessness model in rats by 50–60% on the last two days of the avoidance task, and reduced isolation-induced aggressivity in mice by 50 to 85%, an effect which was antagonised by zacopride (1 mg/kg i.p.). These results suggest that the stimulation of 5-HT3 receptors can produce antidepressant-like effects in behavioural tests in rodents.

In order to further assess the role of endogenous neurotensin on midbrain dopaminergic neuronal function, the effects of the selective neurotensin receptor antagonists SR 48692 and SR 48527 were investigated on the number of spontaneously active A9 and A10 dopaminergic neurons in rats. Single intraperitoneal administration of SR 48692 (0.1–3 mg/kg) dose-dependently increased the number of active A10, but not A9 cells. SR 48527 (1 mg/kg) had a similar profile, but not SR 49711, its low affinity R-enantiomer, indicating that the effects observed were mediated through neurotensin receptor blockade. Five-week treatment with SR 48692 (3 mg/kg/day) produced a significant decrease of the number of active A10, but not A9 cells, which was reversed by apomorphine, suggesting that these cells were under depolarization block. Single co-administration of inactive doses of SR 48692 (0.1 mg/kg) and haloperidol (0.0625 mg/kg) significantly increased the number of active A10 cells. Conversely, co-administered active doses of SR 48692 or SR 48527 and haloperidol (1 and 0.25 mg/kg, respectively) induced an apomorphine-sensitive decrease of the number of A10 active cells. Finally, SR 48692 (10 mg/kg) modified neither accumbal nor cortical basal DA release. Local micro-injection of SR 48692 (10^-11–10^-9 M), but not that of SR 49711 (10^-9 M), into the prefrontal cortex, increased the number of active A10 cells in a concentration-dependent manner. These results suggest that neurotensin receptor blockade counteracts a tonic inhibitory regulation by endogenous neurotensin of mesolimbic dopaminergic function and indicate that the prefrontal cortex is critically involved in this regulation. Synapse 26:370–380, 1997. © 1997 Wiley-Liss Inc.

CB1receptors and their putative natural ligand anandamide, have been tentatively involved in the control of midbrain extrapyramidal function. Electrophysiological activity of dopamine neurones was measured after acute and repeated administration of the CB1receptor antagonist SR 141716A (0.3–3 mgkg-1) in rats. Acute SR 141716A increased A9, but not A10cell population response without affecting either their spontaneous firing rate or apomorphine-induced rate inhibition and prevented amphetamine-induced inhibition of A9, but not of A10cell firing. After repeated administration SR 141716A (1 or 5 mg kg-1) decreased population response of A9cells, which was reversed by apomorphine. These results suggest that CB1receptor blockade by SR 141716A interrupts a cannabinoid-like endogenous tone controlling extrapyramidal function.

SR141716A is the first selective and orally active antagonist of the brain cannabinoid receptor. This compound displays nanomolar affinity for the central cannabinoid receptor but is not active on the peripheral cannabinoid receptor. In vitro, SR141716A antagonises the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and adenylyl cyclase activity in rat brain membranes. After intraperitoneal or oral administration SR141716A antagonises classical pharmacological and behavioural effects of cannabinoid receptor agonists. This compound should prove to be a powerful tool for investigating the in vivo functions of the anandamide/cannabinoid system.

The effects of tachykinin receptor agonists and antagonists were investigated using intra- and extracellular recordings on spontaneously firing nigral neurons in guinea-pig brain slices. In 70 of 76 electrophysiologically identified dopaminergic neurons, a concentration-dependent increase in firing rate was induced by the selective neurokinin-3 tachykinin agonist senktide and by the natural tachykinin agonists neurokinin B and substance P, with ec50values of 4.7, 31.2 and 12 200nM respectively. These responses were inhibited in a concentration- and time-dependent manner by the selective non-peptide neurokinin-3 receptor antagonist SR 142801 (1–100nM; n=23), but neither by its S-enantiomer SR 142806 (100nM; n=4) nor by selective antagonists of neurokinin-1 (SR 140333) or neurokinin-2 (SR 48698) receptors (both at 100nM; n=3). The selective neurokinin-1 agonist [Sar9,Met(O2)11]substance P (30–100nM; n=23) and the selective neurokinin-2 agonist [Nle10]neurokinin A(4–10) (30–100nM; n=13) were without any effect on dopaminergic cells. In 13 of 21 electrophysiologically identified, presumably GABAergic neurons located in the pars compacta of the substantia nigra, excitatory responses were evoked concentration dependently by substance P and [Sar9,Met(O2)11]substance P, with ec50values of 18.6 and 41.9nM respectively. These responses were inhibited by SR 140333 (100nM; n=3), but neither by its R-enantiomer SR 140603 nor by SR 142801 (both at 100nM; n=3). Senktide and [Nle10]neurokinin A(4–10) (both at 30–100nM; n=10) were without effect on these presumed GABAergic neurons. A small population (12%) of pars compacta neurons was insensitive to any of the three selective tachykinin agonists. In the nigral pars reticulata, 12 neurons were recorded which had an electrophysiological profile similar to that of presumed GABAergic neurons in the pars compacta. Of these 12 cells, seven did not respond to any of the selective tachykinin agonists tested, while five were excited by senktide in a concentration-dependent manner (ec50=98.5nM). Although this value was significantly higher than that found for dopaminergic neurons in the pars compacta, senktide-evoked responses were inhibited by SR 142801 (100nM; n=3).

The effects of SR142801, a nonpeptide tachykinin neurokinin (NK3) receptor antagonist, were investigated on the functional events linked to NK3 receptor activation by using Chinese hamster ovary (CHO) cells transfected with the human NK3 receptor. Radioligand binding conducted with [125I]iodohistidyl-[MePhe7]-NKB revealed a competitive inhibition by SR142801 and its (-)-antipode SR142806 with Ki values of 0.21 +/- 0.03 and 32.0 +/- 5.0 nM, respectively. NK3 agonists such as [MePhe7]-NKB and senktide stimulated inositol monophosphate formation with EC50 values of 2.0 +/- 1.4 and 2.1 +/- 0.7 nM, respectively. SR142801 antagonized the stimulatory effect of [MePhe7]-NKB (10(-8) M) with an IC50 of 14.3 +/- 2.6 nM and of senktide (10(-8) M) with an IC50 of 4.8 +/- 1.5 nM. The [3H]arachidonic acid release induced by either [MePhe7]-NKB (EC50 of 2.6 +/- 0.2 nM) or senktide (EC50 of 4.2 +/- 2.9 nM) also was inhibited by SR142801 with IC50 values of 16.1 +/- 0.5 and 8.0 +/- 1.7 nM, respectively. The cyclic AMP accumulation induced by 10(-7) M [MePhe7]-NKB (EC50 of 54 +/- 2 nM) also was antagonized by SR142801 with an IC50 value of 4.0 +/- 0.7 nM. These antagonistic effects were stereospecific and NK3 receptor specific because the (-)-antipode, SR142806, was much less effective than SR142801 in NK3 agonist-evoked responses, whereas the nonpeptide NK1 (SR140333) and NK2 (SR48968) receptor antagonists were almost inactive. The activity of SR142801 also was evaluated on the [Ca++]i increase induced by 10(-9) M [MePhe7]-NKB.(ABSTRACT TRUNCATED AT 250 WORDS)

This study investigated in rats the action of a variety of antidepressants in two behavioral models. In model 1, animals trained in a T-maze were allowed to choose between 2 magnitudes of reward: immediate but small reward (2 pellets) vs. a 25-sec delayed but large reward (10 pellets). Under this alternative, vehicle-injected rats selected the large-but-delayed reward in less than 40% of the trials. Desipramine 8 mg/kg, clomipramine 8 mg/kg, maprotiline 8 mg/kg, indalpine 2 to 4 mg/kg, zimelidine 8 to 16 mg/kg, nialamide 16 to 32 mg/kg and clenbuterol 0.03 to 0.06 mg/kg significantly increased the number of choices of the large-but-delayed reward. In model 2, rats were subjected to a fixed ratio 48 schedule of food reinforcement; after completion of a series of exactly 48 presses a food pellet was delivered, and if no further press occurred, a sequence of free pellets was initiated according to fixed, increasing intervals (from 5-80 sec). Pressing during the sequence stopped it and required the rat to complete again the fixed ratio 48 to be reinforced and to reintiate the sequence. Waiting for free reward was significantly lengthened by desipramine 8, clomipramine 16, indalpine 8, zimelidine 8 to 16, nialamide 32 and clenbuterol 0.007 to 0.06 mg/kg. These results suggest that, possibly through noradrenergic and serotonergic mechanisms, antidepressants markedly enhanced rats' ability to wait for food reward, an affect which might reflect the ability of these drugs to improve impulse control. The relevance of such a property in the therapeutic action of antidepressants remains to be delineated.

1CB‐1 cannabinoid receptors are strongly expressed in the molecular layer of the cerebellar cortex. We have analysed, in patch‐clamped Purkinje cells (PCs) in rat cerebellar slices, the effect of the selective CB‐1 agonists WIN55,212‐2 and CP55,940 and of the selective CB‐1 antagonist SR141716‐A on excitatory synaptic transmission and synaptic plasticity.2Bath application of both agonists markedly depressed parallel fibre (PF) EPSCs. This effect was reversed by SR141716‐A. In contrast, responses of PCs to ionophoretic application of glutamate were not affected by WIN55,212‐2.3The coefficient of variation and the paired‐pulse facilitation of these PF‐mediated EPSCs increased in the presence of WIN55,212‐2.4WIN55,212‐2 decreased the frequency of miniature EPSCs and of asynchronous synaptic events evoked in the presence of strontium in the bath, but did not affect their amplitude.5WIN55,212‐2 did not change the excitability of PFs.6WIN55,212‐2 impaired long‐term depression induced by pairing protocols in PCs. This effect was antagonized by SR141716‐A. The same impairment of LTD was produced by 2‐chloroadenosine, a compound that decreases the probability of release of glutamate at PF‐PC synapses.7The present study demonstrates that cannabinoids inhibit synaptic transmission at PF‐PC synapses by decreasing the probability of release of glutamate, and thereby impair LTD. These two effects might represent a plausible cellular mechanism underlying cerebellar dysfunction caused by cannabinoids.

SR 57746A (1‐(2β‐naphthylethyl)‐4‐(3‐trifluoromethylphenyl)‐1,2,5,6‐tetrahydropyridine hydrochloride) is a neuroprotective compound which potentiates nerve‐growth factor (NGF)‐induced differentiation in PC12 cells. We have evaluated the interaction of SR 57746A with the other members of the neurotrophin family in this cell‐line.

In 22 chronic bronchopulmonary patients with respiratory insufficiency and varied degrees of dyspnoea the functional modifications after intravenous or intramuscular para-aminobenzoic acid administration were established. Fifteen minutes after the intravenous injection (10 cc. of sodium salt at 5 per cent) an increase of oxygen in arterial blood and the hemoglobin saturation (from 85.9 to 92.6) could generally be observed, and the oxygen consumption decreased (from 301 cc. to 241 cc. average per minute). The apnoeic inspiratory pause increased (from 26 to 30 seconds), the vital capacity (from 2046 cc. to 2132 cc. average), the reserve air (from 502 to 624 cc.) the respiratory minute volume (from 11.4 to 13.1 liters), the respiratory maximum volume (from 39.5 to 42.3 liters) and the number of respirations diminished (from 28 to 24 per minute). It is being considered that the favourable action of PAB on the anoxic states of bronchopulmonary origin is principally due to its antioxidizing capacity.

Quinacrine has been reported as an antiprion agent and proposed as an immediately applicable treatment for Creutzfeldt–Jakob disease (CJD). The authors report the results of an open compassionate procedure to which 32 CJD patients had access. In some genotypic subgroups, a slight but nonsignificant increase in survival was observed, likely due to biased inclusion of long-term surviving patients. There was no pathologic evidence of a beneficial effect of quinacrine treatment.