C. de Montigny

Rhythmic activity induced by harmaline in the olivo-cerebello-bulbar system of the cat

Abstract Unitary extracellular recordings were obtained from brain stem and cerebellar neurons following administration of harmaline in decerebrate paralyzed cats. Rhythmic discharges at 8–12/sec in the inferior olive generated synchronous climbing fiber responses in Purkinje cells associated with an almost complete suppression of simple spike activity. Rhythmic bursting was also recorded from neurons of the fastigial, the bulbar reticular and the lateral vestibular nuclei. This central rhythmic activity was not modified by spinal section at the C 2 level. After total cerebellectomy the rhythmic activity persisted in the inferior olive but not in the other bulbar nuclei. These data indicate that the rhythmicity induced by harmaline in the inferior olive is not generated within loops involving the cerebellum or the bulbar nuclei and that the olivo-cerebellar system is responsible for the rhythmic activation of the bulbar reticular and vestibular nuclei. From simultaneous recordings along the olivo-cerebello-bulbar system, it appears very likely that the bulbar reticular and vestibular rhythmic activity is primarily the consequence of the periodic interruption of fastigial cells firing by the rhythmic climbing fiber responses.

Monoaminergic denervation of the rat hippocampus: Microiontophoretic studies on pre- and postsynaptic supersensitivity to norepinephrine and serotonin

The responsiveness of hippocampal CA3 pyramidal neurons to microiontophoretic applications of serotonin (5-HT), norepinephrine (NE), gamma-aminobutyric acid (GABA) and isoproterenol (ISO) was assessed in rats following 5,7-dihydroxy-tryptamine (5,7-DHT) and 6-hydroxydopamine (6-OHDA) pretreatments and bilateral locus coeruleus lesions. The intraventricular administration of 200 micrograms (free base) of 5,7-DHT and of 6-OHDA produced 89% and 93% decreases of 5-HT and NE respectively. None of these pretreatments modified the inital responsiveness to, or recovery from iontophoretic application of 5-HT. In 6-OHDA pretreated and locus-lesioned rats, the initial effectiveness of NE was not altered but its effect was markedly prolonged. However, there was no such prolongation of the effect of ISO which is not a substrate for the high affinity NE reuptake. The effect of GABA was not affected by these pretreatments. Acute pharmacological blockade of the NE reuptake with desipramine (5 mg/kg, i.p.) similarly induced a prolongation of the effect of iontophoretically applied NE, while fluoxetine (10 mg/kg, i.p.) a 5-HT reuptake blocker, failed to alter the recovery of pyramidal cells from iontophoretic application of 5-HT. It is concluded that 5-HT denervation induces neither pre- nor postsynaptic types of supersensitivity in hippocampal pyramidal cells, contrasting with the previously shown supersensitivity of ventral lateral geniculate and amygdaloid neurons following 5-HT denervation. NE denervation fails to induce a postsynaptic type of supersensitivity but leads to a marked prolongation of the response to NE indicative of a presynaptic mechanism. These results underscore the necessity for regional studies of neurotransmitters and drug action.

Pre- and postsynaptic effects of zimelidine and norzimelidine on the serotoninergic system: single cell studies in the rat.

The pre‐ and postsynaptic effects of zimelidine and norzimelidine were studied in adult male Sprague‐Dawley rats. The potency of the presynaptic effect was estimated from their ability to depress the rate of firing of serotonin (5‐HT)‐containing raphe neurons. Chronic administration of tricyclic antidepressant drugs has been shown to sensitize forebrain postsynaptic 5‐HT receptors. The effect of zimelidine on these receptors was compared to that of saline and chlorimipramine by assessing the responsiveness of hippocampal pyramidal cells to microiontophoretic applications of 5‐HT, norepinephrine (NE) and γ‐aminobutyric acid (GABA).

Reduced excitatory effect of kainic acid on rat CA3 hippocampal pyramidal neurons following destruction of the mossy projection with colchicine

SummaryRats were injected unilaterally with colchicine in the dentate gyrus of the dorsal hippocampus. Two weeks later, under urethane anesthesia, extracellular recordings were obtained on both sides from pyramidal neurons of the CA1 and of the CA3 regions of the dorsal hippocampus. Microiontophoresis was used to assess the responsiveness of these neurons to kainate, glutamate and ibotenate. The colchicine injection produced a nearly complete destruction of the granule cells of the ipsilateral dentate gyrus and of their mossy fiber projections to CA3 without apparently affecting other hippocampal neurons. On the lesioned side, the potency of kainate in activating CA3 pyramidal neurons was reduced by 94% compared to the same neurons on the intact side. However, the excitatory effect of glutamate was unchanged and that of ibotenate only slightly reduced. Kainate was 80 times more potent in activating CA3 than CA1 pyramidal neurons on the intact side, whereas this ratio had dropped to 2.6 on the lesioned side. The selective decrease of the effectiveness of kainate in activating CA3 pyramidal neurons following the colchicine lesion suggests that this amino acid, but not glutamate and ibotenate, produces most of its excitatory effect in the intact CA3 region by releasing (an) excitatory neurotransmitter(s) from mossy fibers terminals, the nature of which remains to be identified.

Effects of quipazine on pre- and postsynaptic serotonin receptors: single cell studies in the rat CNS.

Many behavioural and biochemical studies have pointed to an agonistic activity of quipazine on serotonin (5-HT) receptors. In the present electrophysiological study, the effect of quipazine on pre- and postsynaptic 5-HT receptors in the rat was studied. Quipazine, administered intravenously, depressed the firing rate of 5-HT-containing dorsal raphe neurones (ED50 = 0.82 mg/kg). Microiontophoretic applications of quipazine on 5-HT-containing neurones in the dorsal raphe and on neurones of two forebrain regions receiving a 5-HT input (the ventral lateral geniculate nucleus and the dorsal hippocampus) consistently depressed neuronal firing rate as did 5-HT and D-lysergic acid diethylamide (LSD). Quipazine was more potent on 5-HT neurones than on the ventral lateral geniculate nucleus and hippocampal neurones: the post/presynaptic efficacy ratio for quipazine was similar to that of LSD. Following a selective denervation of 5-HT neurones with intraventricular injection of 5,7-di-hydroxy-tryptamine in desipramine-pretreated rats, the responsiveness of neurones in the ventral lateral geniculate nucleus to quipazine, applied microiontophoretically, was increased as was that to 5-HT and to LSD. These results provide direct evidence for the agonistic activity of quipazine on both pre- and postsynaptic 5-HT receptors.

Differential excitatory effects of kainic acid on CA3 and CA1 hippocampal pyramidal neurons: Further evidence for the excitotoxic hypothesis and for a receptor-mediated action

Abstract CA3 hippocampal pyramidal neurons are known to be extremely susceptible to the neurotoxic action of kainic acid (KA). The excitotoxic hypothesis claims that cytotoxic amino acids exert this effect via neuroexcitation. To put this hypothesis to the test, the responsiveness of CA3 neurons to KA was assessed by means of microiontophoresis and compared to that of CA1 and cortical neurons. CA3 pyramidal neurons showed an extreme sensitivity to KA, much greater than that of CA1 and cortical neurons. There was no such differential responsiveness to neither acetylcholine nor glutamate (GLU). The exquisite sensitivity of CA3 neurons to both neurotoxic and neuroexcitatory actions of KA supports the excitotoxic hypothesis. The clear dissociation between the effects of KA and GLU on hippocampal pyramidal cells indicates that KA-induced activation is not mediated by GLU receptors and favors the notion that KA might act on specific receptors.

Antidepressant Monoamine Oxidase Inhibitors Enhance Serotonin but not Norepinephrine Neurotransmission

Monoamine oxidase inhibitors (MAOIs) were the first effective drugs in the treatment of major depression (Klein et al. 1980). Given their inhibiting action on the catabolism of monoaminergic neurotransmitters, they constitute unique tools for investigating the neurobiological basis of the antidepressant response.

Pipequaline acts as a partial agonist of benzodiazepine receptors: An electrophysiological study in the hippocampus of the rat

Pipequaline (PK 8165), a quinoline derivative and a ligand of the benzodiazepine binding site, is a clinically-effective anxiolytic, which is devoid of sedative and anticonvulsant properties. Several biochemical and behavioral studies have indicated that this molecule shares some properties with both agonists and antagonists of benzodiazepine receptors. The present in vivo electrophysiological studies were undertaken to determine the effects of microiontophoretic applications and of intravenous injections of pipequaline on hippocampal pyramidal neurons, activated by kainate, glutamate or acetylcholine and to characterize the effects of pipequaline on the action of benzodiazepines. Intravenously administered pipequaline exerted a partial suppression of activations by kainate, glutamate and acetylcholine. Microiontophoretic applications of pipequaline reduced the neuronal activation by kainate. This effect was blocked by RO 15-1788. In small intravenous doses, pipequaline potentiated the effect of microiontophoretically-applied flurazepam whereas, in larger doses, it suppressed the effects of microiontophoretically-applied flurazepam and of intravenously administered lorazepam on kainate-induced activation. Similarly, microiontophoretic applications of pipequaline blocked the suppressant effect of microiontophoretically-applied flurazepam on kainate-induced activation. These results constitute further evidence that the selective anxiolytic activity of pipequaline might be ascribed to its partial agonistic action on benzodiazepine receptors.