Katarzyna Fijał

WAY 100135, an Antagonist of 5-HT1A Serotonin Receptors, Attenuates Psychotomimetic Effects of MK-801

In the present study, we investigated whether the antagonist of 5-HT1A receptors, WAY 100135, was capable of modifying the psychostimulant and psychotomimetic effects of MK-801, a non-competitive antagonist of NMDA receptors. It was found that: 1) WAY 100135 (10 and 20 mg/kg, but not 1.25, 2.5, and 5 mg/kg) transiently, in a dose dependent manner, attenuated the locomotor stimulant effects of MK-801 (0.4 mg/kg). Given alone, WAY 100135 had no effect on the locomotor activity of rats; 2) WAY 100135 (1.25 and 2.5 mg/kg, but not 10 or 20 mg/kg), attenuated or abolished the disruptive effects of MK-801 on the sensorimotor gating measured in a prepulse-induced inhibition of the acoustic startle response paradigm. WAY 100135 in all tested doses had no effect on the sensorimotor gating or amplitude of the acoustic startle response; 3) WAY 100135 (1.25, 2.5 mg/kg, but not 5 mg/kg) attenuated the detrimental effects of MK-801 on working memory and selective attention, measured in a delayed alternation task. Again, given alone, WAY 100135 did not influence the behavior of rats in that experimental paradigm; and 4) MK-801 (0.4 mg/kg) had no effect on the 5-HT1A receptor mRNA level in rat hippocampus, measured 2 and 24 hours after MK-801 administration. These data indicate that 5-HT1A receptors might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists. In addition, 5-HT1A serotonin receptor antagonists and partial agonists may have potential antipsychotic properties.

Evidence that conditioned stress enhances outflow of dopamine in rat prefrontal cortex: A search for the influence of diazepam and 5-HT1A agonists

We evaluated the impact of conditioned stress on outflow of dopamine in the rat prefrontal cortex. Exposure of rats to an environment associated with aversive stimuli‐foot shock enhanced outflow of dopamine in a similar way as seen during the conditioning session when foot shocks were applied. Diazepam (2.5 and 10 mg/kg) dose‐dependently decreased outflow of dopamine and, when given in a dose of 10 mg/kg, but not 2.5 mg/kg, decreased enhanced dopamine outflow evoked by conditioned stress. On the other hand, ipsapirone (10 mg/kg, but not 2.5 mg/kg) and buspirone (2.5 mg/kg) enhanced basal outflow of dopamine. When ipsapirone (10 mg/kg) and buspirone (2.5 mg/kg) were given to rats exposed to conditioned stress, the stress‐evoked elevation in dopamine outflow was abolished. Ipsapirone in a dose of 2.5 mg/kg was ineffective in the stress paradigm tested. It is concluded that conditioned stress in vivo enhances dopaminergic neurotransmission in the rat prefrontal cortex, this effect being attenuated by diazepam, a classic anxiolytic drug, and by such novel anxiolytics as ipsapirone and buspirone, which operate via serotonergic 5‐HT1A receptors. Although ipsapirone and buspirone blocked stress‐induced enhancement of dopamine outflow, this effect seems to result from their influence on the basal outflow of dopamine. Differential effects of diazepam and 5‐HT1A agonists on basal and stress‐induced alterations in dopamine outflow are discussed in terms of their possible effectiveness in various types of general anxiety disorders.

Effects of the Selective 5-HT7 Receptor Antagonist SB-269970 and Amisulpride on Ketamine-Induced Schizophrenia-like Deficits in Rats

A wide body of evidence suggests that 5-HT7 receptors are implicated in a variety of central nervous system functions, including control of learning and memory processes. According to recent preclinical data, the selective blockade of these receptors may be a potential target for cognitive improvement in schizophrenia. The first aim of the present study was to evaluate the effects of the selective 5-HT7 receptor antagonist, SB-269970, and the antipsychotic drug with a high affinity for 5-HT7 receptors, amisulpride, on ketamine-induced deficits in attentional set-shifting and novel object recognition tasks in rats. Because the role of 5-HT7 receptor blockade in ameliorating positive and negative symptoms of schizophrenia remains equivocal, the second aim of these experiments was to examine the effectiveness of SB-269970 and amisulpride in reversing ketamine-induced deficits in prepulse inhibition of the startle reflex and in social interaction test in rats. The study revealed that acute administration of SB-269970 (1 mg/kg) or amisulpride (3 mg/kg) ameliorated ketamine-induced cognitive inflexibility and novel object recognition deficit in rats. Both compounds were also effective in attenuating ketamine-evoked disruption of social interactions. In contrast, neither SB-269970 nor amisulpride affected ketamine-disrupted prepulse inhibition or 50 kHz USVs accompanying social behaviour. In conclusion, antagonism of 5-HT7 receptors may represent a useful pharmacological approach in the treatment of cognitive deficits and some negative symptoms of schizophrenia.

Ipsapirone enhances the dopamine outflow via 5-HT1A receptors in the rat prefrontal cortex

In the present study, we investigated both the effect of ipsapirone on the dopamine outflow and its selectivity towards 5-HT1A receptors in the rat prefrontal cortex. Using a brain microdialysis method in freely moving animals, it was found that ipsapirone, 5 and 10 mg/kg dose-dependently enhanced the outflow of dopamine, while 2.5 mg/kg was ineffective. The above effects of ipsapirone were mimicked by buspirone (2.5 and 5 mg/kg), another 5-HT1A receptor agonist, but not 1-PP (1-pyrimidinylpiperazine, 5 mg/kg)-a centrally active metabolite of ipsapirone. The effect of ipsapirone (10 mg/kg) on the dopamine outflow in the rat prefrontal cortex was antagonized by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190, 1 mg/kg) and (N-tert-butyl-3-(4-(2-methoxyphenylpiperazin-1-yl)-2- phenylpropionamide (WAY 100135, 10 mg/k.g.), i.e. substances with agonistic/antagonistic and antagonistic properties in relation to 5-HT1A receptors, respectively. NAN-190 (1 mg/kg) enhanced the outflow of dopamine, while WAY 100135 (10 mg/kg) failed to alter it. It is concluded that 5-HT1A receptor agonists may be involved in the regulation of dopaminergic neurotransmission in the rat prefrontal cortex and may have therapeutic potential in the treatment of disorders associated with dysfunction of the mesocortical dopaminergic system.

Different pattern of brain c-Fos expression following re-exposure to ethanol or sucrose self-administration environment.

Exposure of alcohol addicts to alcohol-related environmental cues may elicit alcohol-seeking behavior and lead to relapse to heavy drinking. The aim of the present study was to identify brain regions activated by alcohol (ethanol)-related stimuli in Wistar rats trained to lever press for 8% ethanol solution in operant self-administration cages. Ethanol self-administration was stabilized in a maintenance phase, which lasted for 30xa0days. c-Fos protein expression was used as a marker of neuronal activation.Re-exposure to ethanol self-administration environment after 30-day but not after 24-h abstinence increased the number of Fos-positive nuclei in the thalamic paraventricular nucleus, granular insular cortex and medial prefrontal cortex. In general, no differences were found in c-Fos protein expression between the rats allowed to self-administer alcohol and the subjects exposed only to alcohol-related stimuli. In contrast, no increase in c-Fos immunoreactivity was observed in rats trained to lever press for sucrose solution and exposed to sucrose-related environmental stimuli after 30-day abstinence.Taken together, these results suggest that at least some thalamo-cortical circuits become more responsive to ethanol-paired stimuli after prolonged abstinence and that ethanol- and sucrose-seeking behavior may be regulated by partially different neural mechanism(s).

Acute and repeated administration of cocaine differentially regulates expression of PSA-NCAM-positive neurons in the rat hippocampus.

Recent data indicating that addictive substances are able to alter brain plasticity and its morphology inclined us to determine whether acute and chronic cocaine administration could modify the expression of a polysialylated form of the neuronal cell adhesion molecule (PSA-NCAM) in the dentate gyrus of the rat hippocampus. Alterations in the PSA-NCAM expression are known to effect a variety of neuroanatomical rearrangements in the brain structure. Cocaine was administered acutely (15 mg/kg, i.p.) or repeatedly (15 mg/kg, i.p. once a day for five consecutive days). The number of PSA-NCAM immunopositive cells was determined at six time points after cocaine treatment: 6 h and 1, 2, 4, 6, and 10 days (both in acute and repeated treatment). It was found that a single injection of cocaine induced a time-dependent decrease in the number of PSA-NCAM cells in the dentate gyrus. The decrease was observed on day 1 after cocaine treatment and lasted for at least 6 days. In contrast, an increase in the number of PSA-NCAM-positive cells in the dentate gyrus was observed 2 and 4 days after the last dose of repeated cocaine. It is concluded that cocaine can evoke long-lasting changes in the PSA-NCAM protein expression in the dentate gyrus and that the direction of cocaine-induced PSA-NCAM changes depends on the regimen of cocaine administration. It is postulated that cocaine may have impact on hippocampal plasticity and subsequent processes that are controlled by plastic changes in the hippocampal structure.

Single doses of MK-801, a non-competitive antagonist of NMDA receptors, increase the number of 5-HT1A serotonin receptors in the rat brain

In the present study, we investigated the impact of MK-801, a non-competitive NMDA receptor antagonist, on the density of serotonergic receptors of the 5-HT1A subtype and on the metabolism of serotonin in various regions of the rat brain containing terminals and cell bodies of serotonergic neurons. The binding of [3H]8-OH-DPAT to 5-HT1A serotonin receptors was increased after MK-801 (0.4 mg/kg) as was shown by autoradiographic studies in the frontal, cingulate and part of enthorinal cortex, subregions of the hippocampus and raphe nuclei. The above receptor changes were observed at 2 h and, in some brain regions, at 24 h after MK-801. In saturation binding studies, an increase in the Bmax value in the rat hippocampus was found after MK-801 (0.4 mg/kg) while no changes being noted in the Kd value. MK-801 (0.4 mg/kg) increased the concentration of the serotonin metabolite 5-HIAA in the prefrontal cortex and hippocampus, respectively, at 2 and 3 or 3 h after administration, being without effect on the level of serotonin. In the dorsal raphe nucleus, MK-801 (0.4 mg/kg) decreased the level of serotonin without affecting the level 5-HIAA (0.5 h after administration) or increased the level of 5-HIAA without altering the concentration of serotonin (3 h after administration). It is concluded that single administration of MK-801 may alter the density of serotonergic 5-HT1A receptors and in consequence influence the function of the central nervous system associated with activation of 5-HT1A receptors.

IMPACT OF POSTNATAL BLOCKADE OF N-METHYL-D-ASPARTATE RECEPTORS ON RAT BEHAVIOR : A SEARCH FOR A NEW DEVELOPMENTAL MODEL OF SCHIZOPHRENIA

The malfunction of glutamatergic neurotransmission in the neonatal or postnatal periods may be a risk factor for the appearance of neuroanatomical, neurochemical or functional changes that are characteristic of schizophrenia. Thus, the present study was undertaken to investigate whether blockade of N-methyl-d-aspartate (NMDA) receptors in the postnatal period influences rat behavior in tests characterizing schizophrenia-like deficits such as psychomotor agitation, impairments of sensorimotor gating, working memory, and intensity of social interactions. (E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), a competitive antagonist of NMDA receptors, was given postnatally (1.25 mg/kg on days 1, 3, 6, 9; 2.5 mg/kg on days 12, 15, 18; and finally 5 mg/kg on day 21, all injections s.c.), and rats were tested at 60 days old. We found that blockade of NMDA receptors in the postnatal period led to an enhancement of exploration, mimicking psychomotor agitation, impairments in sensorimotor gating as measured by a prepulse-evoked inhibition of acoustic startle response, and an impaired working memory, as measured by an increase in the latency to achieve accurate rate of response in the delayed alternation task. Decreases in non-aggressive social interactions and increases in aggressive interactions were also observed. In addition to cognitive deficits typical of schizophrenia, rats treated postnatally with NMDA receptor antagonists also showed higher level of fear exhibited in the elevated plus maze. Thus, the blockade of NMDA receptors in the postnatal period may model deficits that are characteristic of schizophrenia.

The corticosterone synthesis inhibitor metyrapone decreases dopamine D1 receptors in the rat brain

Experiments were performed to examine the effect of metyrapone, an inhibitor of corticosterone synthesis, on the level of dopamine D1 receptors and their transcripts in the caudate-putamen, nucleus accumbens and olfactory tubercle of the rat brain. The binding to dopamine D1 receptors was measured by receptor autoradiography using the specific D1 receptor antagonist [3H]SCH 23390. The level of dopamine D1 receptor messenger RNA was determined by in situ hybridization histochemistry. The results obtained have shown that metyrapone (two injections of 150 and 50 mg/kg, i.p., given 20 and 3 h before killing, respectively) induced a decrease in the D1 receptor-specific binding in the studied areas of the rat brain. In the caudate putamen, the decrease in [3H]SCH 23390 binding was stronger in the medial (31-39%) than in the lateral part (24-27%). Decreases similar to those in the caudate-putamen were observed in the nucleus accumbens (21%) and olfactory tubercle (32%). Furthermore, metyrapone decreased the level of dopamine D1 receptor messenger RNA in the caudate putamen (17-28%), nucleus accumbens (20%) and olfactory tubercle (18%). In conclusion, our study indicates that glucocorticoids might be involved in the regulation of dopamine D1 receptor level in the rat brain. since metyrapone (which inhibits the synthesis of these hormones) decreases the messenger RNA encoding D1 receptor synthesis, as well as the specific binding to this receptor.

Prolonged corticosterone treatment alters the responsiveness of 5-HT1A receptors to 8-OH-DPAT in rat CA1 hippocampal neurons

Abstract. Hippocampal 5-HT1A receptors have been shown to be suppressed by glucocorticoids in a variety of animal studies, however the molecular mechanism and the functional meaning of this effect are still not well understood.The present study was designed to investigate the impact of repeated administration of corticosterone (10xa0mg/kg s.c. twice daily for 7xa0days) on the functional consequences of 5-HT1A receptor stimulation measured electrophysiologically in hippocampal slices. Additionally, the effects of corticosterone on 5-HT1A receptor binding and on receptor mRNA levels in the hippocampus were studied. Prolonged, but not acute treatment with corticosterone attenuated (±)-8-hydroxy-2-di-N-propylamino)tetralin hydrobromide (8-OH-DPAT)-induced inhibition of population spikes, and 8-OH-DPAT-induced hyperpolarization in rat CA1 hippocampal neurons. Chronic, but not acute treatment with corticosterone also decreased 5-HT1A receptor binding in the CA1 region (in the ventral part only) and the dentate gyrus. A single dose of corticosterone increased [3H]8-OHDPAT binding in the dentate gyrus and in the CA3 and CA4 hippocampal regions. Only acute, but not prolonged treatment with corticosterone decreased the level of 5-HT1A receptor mRNA in the CA1 region and dentate gyrus of the hippocampus. 5-HT turnover in the hippocampus was not influenced by chronic corticosterone.It is concluded that a chronically elevated level of corticosterone can induce functional desensitization of 5-HT1A receptors in the CA1 area of the hippocampus, although this effect is not always followed consequently by decreases in 5-HT1A receptor synthesis in this or other areas of the hippocampus.