Maria Bijak

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.

Neuropeptide Y suppresses epileptiform activity in rat frontal cortex and hippocampus in vitro via different NPY receptor subtypes

Neuropeptide Y (NPY) and different NPY receptor (Y) subtype-selective agonists were tested for their effects on spontaneous epileptiform discharges which developed in rat cortical and hippocampal slices in Mg(2+)-free medium. Epileptiform activity, recorded extracellularly, was attenuated by NPY (0.5-1 microM) in both the frontal cortex and hippocampal CA3/CA1 pyramidal cell layers. In the cortex the Y1/5 selective agonist [Leu31 Pro34] NPY was more effective than the Y2 preferring agonist NPY13-36 and the Y2/5 preferring agonist NPY3-36. The suppression of epileptiform discharges induced by NPY in cortical slices was blocked by the selective Y1 receptor antagonist (R)-N2-(diphenylacetyl)-N-((4-hydroxyphenyl)methyl] argininamide (BIBP 3226). In the hippocampus, NPY13-36 and NPY3-36 were more effective than [Leu31 Pro34] NPY. In conclusion, the antiepileptic activity of NPY is mediated predominantly by the Y1 receptor subtype in the frontal cortex and by Y2 and probably Y5 receptors in the hippocampal CA3/CA1 areas.

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.

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.

An antidepressant-induced decrease in the responsiveness of hippocampal neurons to group I metabotropic glutamate receptor activation

Imipramine, a serotonin and noradrenaline uptake inhibitor, is the prototypical tricyclic antidepressant. The effects of imipramine on neuronal responsiveness to the group I glutamate metabotropic (mGlu) receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) were studied ex vivo, in the CA1 area of rat hippocampus, using extracellular and intracellular recording. DHPG increased the population spike amplitude, depolarized CA1 cells and decreased the slow afterhyperpolarization. Imipramine (20 microM) administered acutely in vitro did not change the effect of DHPG on population spikes. Repeated treatment with imipramine (10 mg/kg, twice daily, for 14 days) significantly attenuated the enhancing effect of DHPG (2.5 and 5 microM) on population spikes, as well as the DHPG-induced depolarization and the decrease in the slow afterhyperpolarization. Repeated treatment with imipramine had no effect on passive or active membrane properties of CA1 pyramidal cells. The results of the time-course experiment demonstrated that the imipramine-induced decrease in the responsiveness of CA1 cells to DHPG was apparent after a 7-day treatment; there was a further decrease after 14 days of treatment to a level which was not changed by longer (21-day) administration of imipramine. The attenuation of neuronal responsiveness to DHPG induced by a 14-day treatment was still detectable 7 days after imipramine withdrawal. It is concluded that repeated treatment with imipramine induces a decrease in the responsiveness of rat CA1 hippocampal neurons to group I mGlu receptor activation with a time course which correlates with the delayed onset of the therapeutic effect of antidepressants in humans. This suggests that alterations in mGlu receptors may contribute to antidepressant efficacy.

Serotonin receptor blocking effect of SCH 23390

The effect of SCH 23390 administration on the serotonin system-dependent head twitch behavior was studied in the rat. A small dose of SCH 23390 (1.25 micrograms/kg), injected 20 min before the test, decreased the number of quipazine-induced head twitches. Repeated treatment with SCH 23390 (0.5 mg/kg, SC), once a day for 18 days, increased the number of spontaneously occurring and quipazine-induced head twitches. The enhancing effect of repeated administration of SCH 23390 was blocked by cyproheptadine (0.4 mg/kg). The results indicate that acute injection of SCH 23390 blocks central serotonin receptors, whereas repeated treatment induces their functional supersensitivity.

Antidepressant drugs potentiate the α1-adrenoceptor effect in hippocampal slices

Abstract The effect of prolonged treatment with antidepressant drugs on the phenylephrine- and norepinephrine (NE)-evoked reaction in hippocampal slices was examined by extracellular recording of the spontaneous activity of CA1 layer neurons. The α 1 -adrenoceptor agonists, phenylephrine and methoxamine, depressed the neuronal discharges of most of the units tested, while NE evoked both excitatory and inhibitory effects which were blocked by propranolol and phentolamine or prazosin, respectively. Imipramine, mianserin, (+)- and (-)-axaprotiline administered subchronically (10 mg/kg p.o., twice daily for 14 days, withdrawal 48 h), potentiated the inhibitory reaction to phenylephrine. Mianserin was the only drug tested in the acute dose to effectively augment the reaction to α 1 -adrenoceptor stimulation. Prolonged administration of mianserin and imipramine attenuated the excitatory effect to NE, which probably reflects β-receptor down-regulation; however, only mianserin, but not imipramine, enhanced the NE-induced inhibition. The observed potentiation of the α 1 -adrenoceptor-related inhibitory reaction to phenylephrine produced by antidepressant drugs may reflect the development of the α 1 -adrenergic system supersensitivity in the hippocampus.

Imipramine but not 5-HT1A receptor agonists or neuroleptics induces adaptive changes in hippocampal 5-HT1A and 5-HT4 receptors

It has been reported that the treatment with a tricyclic antidepressant imipramine induces an increase in the sensitivity of 5-HT(1A) receptors and a decrease in the sensitivity of 5-HT(4) receptors in the rat hippocampus. 5-HT(1A) receptor agonists and neuroleptics also affect 5-HT(1A) receptors in different brain areas; therefore, it was of interest to compare their effects on hippocampal 5-HT receptors with the influence of the well-established antidepressant imipramine. We studied the effects of repeated treatment with imipramine, the 5-HT(1A) receptor agonists 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, and the neuroleptics haloperidol and clozapine on the sensitivity of rat hippocampal CA1 neurons to 5-HT(1A)- and 5-HT(4) receptor activation. Imipramine was administered for 21 days (10 mg/kg p.o., twice daily), 8-OH-DPAT for 7 days (1 mg/kg s.c., twice daily) and buspirone for 21 days (5 mg/kg s.c., twice daily). The rats received haloperidol (1 mg/kg) and clozapine (30 mg/kg) for 6 weeks in drinking water. Hippocampal slices were prepared 2 days after the last treatment with imipramine, 8-OH-DPAT or buspirone, and 5 days after the last treatment with the neuroleptics. Using an extracellular in vitro recording, we studied changes in the amplitude of stimulation-evoked population spikes, induced by 5-HT, 8-OH-DPAT and the 5-HT(4) receptor agonist zacopride. Activation of 5-HT(1A) receptors decreased, while activation of 5-HT(4) receptors increased the amplitude of population spikes. Imipramine significantly enhanced the inhibitory effects of 5-HT and 8-OH-DPAT, and attenuated the excitatory effect of zacopride. No other treatment used in the present study changed the sensitivity of hippocampal CA1 neurons to 5-HT(1A) and 5-HT(4) receptors activation. These findings indicate that adaptive changes in the sensitivity of hippocampal neurons to 5-HT(1A) and 5-HT(4) receptors agonists are specific to imipramine and may thus-at least partly-mediate its effects.

Repeated imipramine treatment increases the responsivity of the rat hippocampus to dopamine. An in vitro study.

The sensitivity of hippocampal neurons to dopamine was studied in hippocampal slices obtained from rats treated acutely (10 mg/kg) or repeatedly (10 mg/kg, 14 days, twice a day) with imipramine. In non-treated rats dopamine induced a slight excitation or depression of the firing rate of CA 1 pyramidal neurons in slice preparations. Hippocampal slices prepared from the imipramine-treated rats displayed greater changes in the firing rate after dopamine application. Repeated imipramine administration also increased the number of slices sensitive to dopamine. it is concluded that repeated imipramine administration induces supersensitivity of hippocampal dopamine receptors.