Krzysztof Tokarski

Group II mGlu receptor agonists inhibit behavioural and electrophysiological effects of DOI in mice

It has been suggested that metabotropic glutamate (mGlu) receptor agonists selective for Group II mGlu receptors may have antipsychotic action. Therefore, we studied whether the effects, which could be related to psychotomimetic action of hallucinogenic drugs, are inhibited by Group II mGlu receptor agonists. The selective mGlu2/3 agonists LY354740 and LY379268 inhibited (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitches in mice in a dose-dependent manner. Furthermore, LY379268 suppressed an increase in the frequency of spontaneous excitatory synaptic potentials induced by bath-applied DOI in layer V pyramidal cells recorded in the murine medial frontal cortex. The data indicate that Group II mGlu receptor agonists may counteract the effects of hallucinogenic drugs.

5-HT7 receptors increase the excitability of rat hippocampal CA1 pyramidal neurons

In the CA1 area of rat hippocampal slices, a combined application of 5-CT, a potent 5-HT(1A) and 5-HT(7) receptor agonist, and WAY 100635, a selective 5-HT(1A) receptor antagonist, resulted in a reversible increase of the CA1 extracellular population spike amplitude. In whole-cell recording from identified pyramidal neurons, the effects of 5-CT applied in the presence of WAY 100635 involved a reduction of the slow afterhyperpolarization (sAHP) and the frequency adaptation of action potential firing, which could be blocked by a specific 5-HT(7) receptor antagonist SB 269970. The results indicate that the activation of 5-HT(7) receptors increases the excitability of hippocampal CA1 pyramidal cells.

Repeated administration of imipramine attenuates glutamatergic transmission in rat frontal cortex.

The effects of repeated administration of a tricyclic antidepressant, imipramine, lasting 14 days (10 mg/kg p.o., twice daily), were studied ex vivo in rat frontal cortex slices prepared 48 h after last dose of the drug. In slices prepared from imipramine-treated animals the mean frequency, and to a lesser degree the mean amplitude, of spontaneous excitatory postsynaptic currents recorded from layer II/III pyramidal neurons, were decreased. These effects were accompanied by a reduction of the initial slope ratio of pharmacologically isolated N-methyl-D-aspartate to AMPA/kainate receptor-mediated stimulation-evoked excitatory postsynaptic currents. Imipramine treatment also resulted in a decrease of extracellular field potentials evoked in layer II/III by stimulation of underlying sites in layer V. These results indicate that chronic treatment with imipramine results in an attenuation of the release of glutamate and an alteration in the postsynaptic reactivity of ionotropic glutamate receptors in rat cerebral cortex.

Repeated administration of antidepressants decreases field potentials in rat frontal cortex.

The effects of repeated administration of a tricyclic antidepressant, imipramine, and a selective serotonin reuptake blocker, citalopram, for 14 days (10 mg/kg p.o., twice daily), were studied ex vivo in rat frontal cortex slices prepared 48 h after last dose of the drug. Treatment with both antidepressants resulted in a decrease in the amplitude of field potentials evoked in layer II/III by stimulation of underlying sites in layer V. The amplitude ratio of pharmacologically isolated N-methyl-D-aspartic acid (NMDA) to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor-mediated components of the field potential was reduced. These results indicate that chronic treatment with imipramine or citalopram results in an attenuation of glutamatergic synaptic transmission in the cerebral cortex.

Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents

Several lines of evidence implicate dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. Previous behavioral studies have indicated that metabotropic glutamate (mGlu) receptors may be useful targets for the treatment of psychosis. It has been shown that agonists and positive allosteric modulators of group II mGlu receptors produce potential antipsychotic effects in behavioral models of schizophrenia in rodents. Group III mGlu receptors seem to be also promising targets for a variety of neuropsychiatric and neurodegenerative disorders. However, despite encouraging data in animal models, most ligands of group III mGlu receptors still suffer from weak affinities, incapacity to cross the blood-brain barrier or absence of full pharmacological characterization. These limitations slow down the validation process of group III mGlu receptors as therapeutic targets. In this work, we choose to study an agonist of group III mGlu receptors (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) using intraperitoneal administration in three animal behavioral models predictive of psychosis or hallucinations. The results of the present study show that ACPT-I, given at doses of 10 or 30mg/kg, decreased MK-801-induced hyperlocomotion and at a dose of 100mg/kg decreased amphetamine-induced hyperlocomotion in rats. Furthermore, ACPT-I dose-dependently decreased DOI-induced head twitches in mice and suppresses DOI-induced frequency and amplitude of spontaneous EPSPs in slices from mouse brain frontal cortices. These data demonstrate that ACPT-I is a brain-penetrating compound and illustrates its promising therapeutic role for the treatment of schizophrenia.

Repeated treatment with antidepressant drugs induces subsensitivity to the excitatory effect of 5-HT4 receptor activation in the rat hippocampus

Abstract The effect of repeated treatment with various antidepressant drugs on the reactivity of CA1 neurons to the 5-HT4 receptor agonist zacopride was examined. Zacopride decreased the calcium-activated afterhyperpolarization and adaptation, it also elicited a slow membrane depolarization associated with an increase in input resistance. All those effects may have contributed to the zacopride-induced increase in the amplitude of population spikes, evoked in the CA1 cell layer by stimulation of the Schaffer collateral/commissural pathway. The later effect of zacopride was concentration-dependent and was antagonized by the 5-HT4 receptor antagonist DAU 62805.Repeated (14 days, twice daily), but not single, administration of the antidepressant drugs imipramine, citalopram, fluvoxamine and paroxetine (10 mg/kg) attenuated the effect of zacopride on population spikes. Because inhibitory 5-HT1A and excitatory 5-HT4 receptors are colocalized on pyramidal neurons, and our previous data demonstrated an increase in the 5-HT1A receptor-mediated inhibition after repeated treatment with antidepressants, we conclude that treatment with antidepressant drugs may enhance the inhibitory effect of 5-HT directly, by increasing the 5-HT1A receptor responsiveness, and indirectly, by inducing subsensitivity to the 5-HT4 receptor activation.

Antidepressant treatment influences group I of glutamate metabotropic receptors in slices from hippocampal CA1 region.

We investigated the effects of repeated electroconvulsive shock or imipramine treatment on inositol phosphate accumulation and on the reactivity of neurons to metabotropic glutamate (mGlu) receptor agonists in rat hippocampal slices. (1S,3R)-1-carboxycyclopentane-3-acetic acid (1S,3R-ACPD), a nonselective mGlu receptor agonist, caused a concentration-dependent increase in inositol phosphate in slices from the CA1 region of the hippocampus, an effect that was not modified by imipramine or electroconvulsive shock treatment. 1S,3R-ACPD or the selective agonist of the I group of mGlu receptor, (R,S)-3,5-dihydroxyphenylglycine ((R,S)-3,5-DHPG), produced a concentration-dependent increase of the population spike recorded in the CA1 cell layer. This effect of 1S,3R-ACPD was markedly attenuated by both repeated imipramine and electroconvulsive shock treatment, and the action of (R,S)-3,5-DHPG was markedly attenuated by prolonged imipramine treatment (electroconvulsive shock was not tested). Our results indicate that antidepressant treatment may induce a subsensitivity of group I mGlu receptors when assessed by electrophysiological but not biochemical measures.

Sensory learning-induced enhancement of inhibitory synaptic transmission in the barrel cortex of the mouse

In adult mice, repetitive pairing of stimulation of mystacial vibrissae with an electrical shock to the tail induces expansion of the cortical representation of stimulated vibrissae accompanied by elevation of the GABAergic markers. Here, we show that this associative learning paradigm results in a selective increase in the frequency of spontaneous inhibitory postsynaptic currents in layer IV excitatory neurons located within the barrel representing stimulated vibrissae, evident 24 h after the end of training. The mean amplitude of spontaneous inhibitory postsynaptic potentials recorded from excitatory neurons was unchanged. Recordings from layer IV excitatory and fast spiking neurons showed that the training induced changes neither in the mean frequency nor it the mean amplitude of spontaneous excitatory postsynaptic currents. On the other hand, the mean amplitude of field potentials evoked by the stimulation of layer VI and recorded in layer IV was significantly reduced. These data indicate that aversive training results in a selective and long‐lasting enhancement of GABAergic transmission within the cortical representation of stimulated vibrissae, which may result in a decrease in layer VI‐evoked field responses.

Imipramine increases the 5-HT1A receptor-mediated inhibition of hippocampal neurons without changing the 5-HT1A receptor binding

The effect of repeated treatment with imipramine on the 5-HT1A receptor-mediated inhibition of a population spike was studied in the rat CA1 hippocampal region ex vivo. Serotonin (5-hydroxytryptamine, 5-HT) and the selective 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) decreased dose-dependently the amplitude of population spikes; this effect was blocked by the selective 5-HT1A receptor antagonist (S)-N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylpro panamide dihydrochloride [(S)-WAY 100135]. Repeated (14 days, twice daily), but not single, administration of imipramine (10 mg/kg) shifted the dose-response curves for serotonin and 8-OH-DPAT to the left. Repeated treatment with imipramine did not change the density of 5-HT1A receptors in the hippocampus as measured by autoradiography using [3H]8-OH-DPAT as a ligand. The latter findings indicate that the imipramine-induced increase in the responsiveness of hippocampal neurons to stimulation of 5-HT1A receptors may not involve an increase in the density of this receptor subtype. To find out whether the efficacy of the postreceptor transduction mechanism is changed by repeated treatment with imipramine, we examined the effect of baclofen. The baclofen-induced inhibition of the population spike was not changed by imipramine. Our results suggest that repeated treatment with imipramine induces sensitization to the inhibitory effects of 5-HT1A receptor agonists in the hippocampus.

Comparison of the effects of 5-HT1A and 5-HT4 receptor activation on field potentials and epileptiform activity in rat hippocampus

Abstract. The effects of serotonin (5-HT) as well as 5-HT1A and 5-HT4 receptor agonists, (±)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) and zacopride, respectively, on population spikes evoked by electrical stimulation and on spontaneous epileptiform activity were investigated in CA1 area of hippocampal slices. Spontaneous epileptiform activity was recorded from slice in a nominally Mg2+-free medium. While 5-HT application resulted in a decrease of population spikes evoked in standard incubation conditions, in accordance with earlier studies, it exerted two opposite effects on epileptiform activity. The early inhibitory effect was mimicked by 8-OH-DPAT while the later, excitatory, by zacopride. The application of 8-OH-DPAT decreased, and that of zacopride increased, the amplitude of population spikes. A comparison of the dose-dependence of the excitatory and inhibitory effects of serotonergic agonists on the amplitude of the population spike and on the frequency of epileptiform discharges indicated that the latter is a more sensitive measure of the activation of 5-HT1A and 5-HT4 receptors than the former. Thus, spontaneous epileptiform activity recorded in a nominally Mg2+-free slice medium represents a convenient model for investigation of hippocampal neuronal reactivity to the activation of various 5-HT receptor subtypes.