Repeated blockade of 5-HT7 receptors depresses glutamatergic transmission in the rat frontal cortex.

The effects of the intraperitoneal administration of the 5-HT7 receptor antagonist SB 269970 were studied in the rat frontal cortex. In ex vivo slices prepared from rats receiving 14 daily doses of the drug (1.25 mg/kg) the mean frequency and the mean amplitude of glutamate-mediated, spontaneous excitatory postsynaptic currents (sEPSCs) recorded from layer II/III pyramidal neurons, were decreased. In contrast, single administration of SB 269970 affected neither the frequency nor the amplitude of sEPSCs. Treatment with SB 269970 did not affect membrane excitability of pyramidal cells. These data indicate that repeated, but not single, treatment with SB 269970 results in an attenuation of glutamatergic transmission in the frontal cortex, most likely due to a combination of pre- and postsynaptic mechanisms.

The GABA B receptor agonist CGP44532 and the positive modulator GS39783 reverse some behavioural changes related to positive syndromes of psychosis in mice.

BACKGROUND AND PURPOSE: An important role of GABAergic neurotransmission in schizophrenia was proposed a long time ago, but there is limited data to support this hypothesis. In the present study we decided to investigate GABA(B) receptor ligands in animal models predictive for the antipsychotic activity of drugs. The GABA(B) receptor antagonists CGP51176 and CGP36742, agonist CGP44532 and positive allosteric modulator GS39783 were studied. EXPERIMENTAL APPROACH: The effects of all ligands were investigated in MK-801- and amphetamine-induced hyperactivity tests. The anti-hallucinogenic-like effect of the compounds was screened in the model of head twitches induced by (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Furthermore, the effect of GS39783 and CGP44532 on DOI-induced frequency of spontaneous excitatory postsynaptic currents (EPSCs) in slices from mouse brain frontal cortices was investigated. The anti-cataleptic properties of the compounds were also assessed. KEY RESULTS: The GABA(B) receptor activators CGP44532 and GS39783 exhibited antipsychotic-like effects both in the MK-801- and amphetamine-induced hyperactivity tests, as well as in the head-twitch model in mice. Such effects were not observed for the GABA(B) receptor antagonists. DOI-induced increased frequency of spontaneous EPSCs was also decreased by the compounds. Moreover, CGP44532 and GS39783 inhibited haloperidol-induced catalepsy and EPSCs. CONCLUSION AND IMPLICATIONS: These data suggest that selective GABA(B) receptor activators may be useful in the treatment of psychosis.

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.

The role of alpha-1 adrenergic receptors in the stimulating effect of neuropeptide Y (NPY) on rat behavioural activity.

The role of noradrenergic alpha-1 receptors in increasing the behavioural activity after neuropeptide Y (NPY) injection into the frontal cortex was examined in rats. NPY (1 micrograms/1 microliter) injected into the frontal cortex of rats with chronically implanted cannulae, increased their locomotor and exploratory activity in the open field test. Similar effects were observed after injection of the alpha-1-adrenergic agonist phenylephrine (PH) (3-19 micrograms/1 microliter). Behavioural stimulation after NPY or PH was totally abolished by pretreatment with benextramine (1.73-173 micrograms/1 microliter), a compound blocking NPY and alpha-adrenergic receptors. The NPY-induced activation of behaviour was also abolished by i.p. injection of prazosine (3 mg/kg), a specific alpha-1-adrenergic receptor antagonist. It is concluded that: 1) NPY injected into the rat frontal cortex induces an increase in the locomotor and exploratory activity of the animals; and 2) indirect activation of alpha-1-adrenergic receptor seems to play a crucial role in the observed behavioural effects.