Effects of NMDA receptor antagonists and antipsychotics on high frequency oscillations recorded in the nucleus accumbens of freely moving mice.

RATIONALE: Abnormal oscillatory activity associated with N-methyl-D-aspartate (NMDA) receptor hypofunction is widely considered to contribute to the symptoms of schizophrenia. OBJECTIVE: This study aims to characterise the changes produced by NMDA receptor antagonists and antipsychotics on accumbal high-frequency oscillations (HFO; 130-180 Hz) in mice. METHODS: Local field potentials were recorded from the nucleus accumbens of freely moving mice. RESULTS: Systemic injection of ketamine and MK801 both dose-dependently increased the power of HFO and produced small increases in HFO frequency. The atypical antipsychotic drug, clozapine, produced a robust dose-dependent reduction in the frequency of MK801-enhanced HFO, whilst haloperidol, a typical antipsychotic drug, had little effect. Stimulation of NMDA receptors (directly or through the glycine site) as well as activation of 5-HT1A receptors, reduced the frequency of MK801-enhanced HFO, but other receptors known to be targets for clozapine, namely 5-HT2A, 5-HT7 and histamine H3 receptors had no effect. CONCLUSIONS: NMDA receptor antagonists and antipsychotics produce broadly similar fundamental effects on HFO, as reported previously for rats, but we did observe several notable differences. In mice, HFO at baseline were weak or not detectable unlike rats. Post-injection of NMDA receptor antagonists HFO was also weaker but significantly faster. Additionally, we found that atypical antipsychotic drugs may reduce the frequency of HFO by interacting with NMDA and/or 5-HT1A receptors.

Aberrant high frequency oscillations recorded in the rat nucleus accumbens in the methylazoxymethanol acetate neurodevelopmental model of schizophrenia.

BACKGROUND: Altered activity of the nucleus accumbens (NAc) is thought to be a core feature of schizophrenia and animal models of the disease. Abnormal high frequency oscillations (HFO) in the rat NAc have been associated with pharmacological models of schizophrenia, in particular the N-methyl-d-aspartate receptor (NMDAR) hypofunction model. Here, we tested the hypothesis that abnormal HFO are also associated with a neurodevelopmental rat model. METHODS: Using prenatal administration of the mitotoxin methylazoxymethanol acetate (MAM) we obtained the offspring MAM rats. Adult MAM and Sham rats were implanted with electrodes, for local field potential recordings, in the NAc. RESULTS: Spontaneous HFO (spHFO) in MAM rats were characterized by increased power and frequency relative to Sham rats. MK801 dose-dependently increased the power of HFO in both groups. However, the dose-dependent increase in HFO frequency found in Sham rats was occluded in MAM rats. The antipsychotic compound, clozapine reduced the frequency of HFO which was similar in both MAM and Sham rats. Further, HFO were modulated in a similar manner by delta oscillations in both MAM and Sham rats. CONCLUSION: Together these findings suggest that increased HFO frequency represents an important feature in certain animal models of schizophrenia. These findings support the hypothesis that altered functioning of the NAc is a core feature in animal models of schizophrenia.

Biochanin A affects steroidogenesis and estrogen receptor-ß expression in porcine granulosa cells.

Biochanin A, similar to other isoflavones, is present in soy and soy-based food, but predominantly in red clover. Red clover extract and biochanin A were reported to affect reproductive processes as well as to demonstrate menopause relief and anticancerogenic properties. Because porcine granulosa cells provide a suitable in vitro model for studying the intracellular mechanism of phytoestrogen action in the ovary, the objective of the study was to evaluate the in vitro effects of biochanin A on the following: (1) progesterone (P4) and estradiol (E2) secretion by granulosa cells, (2) viability of the granulosa cells, and (3) mRNA and protein expression of estrogen receptors α (ERα) and ß (ERß) in the granulosa cells harvested from both medium (3-6 mm) and large (≥8 mm) porcine ovarian follicles. RIA, alamarBlue assay, reverse transcriptase-polymerase chain reaction, and immunocytochemistry were used in the study to address the objectives. Biochanin A significantly inhibited P4 and did not affect E2 secretion by porcine granulosa cells regardless of the size of follicles that served as the source of the cells. Cell viability was not affected by the treatment. Biochanin A did not alter ERα and ERß mRNA levels in the cultured porcine granulosa cells. In contrast, this isoflavone increased (P < 0.05) the immunoexpression of ERß in the cells from both follicle types. In summary, biochanin A, similar to genistein and daidzein, affects follicular steroidogenesis and ER expression. Its effect on ERß protein was more intense compared with other previously examined phytoestrogens.

Serotonergic hallucinogens differentially modify gamma and high frequency oscillations in the rat nucleus accumbens.

RATIONALE: The nucleus accumbens (NAc) is a site critical for the actions of many drugs of abuse. Psychoactive compounds, such as N-methyl-D-aspartate receptor (NMDAR) antagonists, modify gamma (40-90) and high frequency oscillations (HFO, 130-180 Hz) in local field potentials (LFPs) recorded in the NAc. Lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-iodoamphetamine (DOI) are serotonergic hallucinogens and activation of 5HT2A receptors likely underlies their hallucinogenic effects. Whether these compounds can also modulate LFP oscillations in the NAc is unclear. OBJECTIVE: This study aims to examine the effect of serotonergic hallucinogens on gamma and HFO recorded in the NAc and to test whether 5HT2A receptors mediate the effects observed. METHODS: LFPs were recorded from the NAc of freely moving rats. Drugs were administered intraperitoneally. RESULTS: LSD (0.03-0.3 mg/kg) and DOI (0.5-2.0 mg/kg) increased the power and reduced the frequency of HFO. In contrast, the hallucinogens produced a robust reduction in the power of low (40-60 Hz), but not high gamma oscillations (70-90 Hz). MDL 11939 (1.0 mg/kg), a 5HT2A receptor antagonist, fully reversed the changes induced by DOI on HFO but only partially for the low gamma band. Equivalent increases in HFO power were observed after TCB-2 (5HT2A receptor agonist, 0.1-1.5 mg/kg), but not CP 809101 (5H2C receptor agonist, 0.1-3 mg/kg). Notably, hallucinogen-induced increases in HFO power were smaller than those produced by ketamine (25 mg/kg). CONCLUSIONS: Serotonergic hallucinogen-induced changes in HFO and gamma are mediated, at least in part, by stimulation of 5HT2A receptors. Comparison of the oscillatory changes produced by serotonergic hallucinogens and NMDAR antagonists are also discussed.

Antipsychotic compounds differentially modulate high-frequency oscillations in the rat nucleus accumbens: a comparison of first- and second-generation drugs.

Improved understanding of the actions of antipsychotic compounds is critical for a better treatment of schizophrenia. Abnormal oscillatory activity has been found in schizophrenia and in rat models of the disease. N-Methyl-D-aspartic acid receptor (NMDAR) antagonists, used to model certain features of schizophrenia, increase the frequency and power of high-frequency oscillations (HFO, 130-180 Hz) in the rat nucleus accumbens, a brain region implicated in schizophrenia pathology. Antipsychotics can be classified as first- and second-generation drugs, the latter often reported to have wider benefit in humans and experimental models. This prompted the authors to examine the pre- and post-treatment effects of clozapine, risperidone (second-generation drugs) and sulpiride and haloperidol (first-generation drugs) on ketamine and MK801-enhanced accumbal HFO. Both NMDAR antagonists increased HFO frequency. In contrast, clozapine and risperidone markedly and dose-dependently reduced the frequency of spontaneous and NMDAR-antagonist-enhanced HFO, whilst a moderate effect was found for sulpiride and a much weaker effect for haloperidol. Unexpectedly, we found reductions in HFO frequency were associated with an increase in its power. These findings indicate that modulation of accumbal HFO frequency may be a fundamental effect produced by antipsychotic compounds. Of the drugs investigated, first- and second-generation compounds could be dissociated by their potency on this measure. This effect may partially explain the differences in the clinical profile of these drugs.

The aryl hydrocarbon receptor agonist 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) alters early embryonic development in a rat IVF exposure model.

Aryl hydrocarbon receptor (AHR) ligands, including 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), accelerate reproductive senescence and one proposed target is the early embryo. To discriminate between direct effects on the oocyte and early embryo and those mediated by complex ovarian interactions with TCDD, IVF was carried out in the presence of TCDD (10, 100 nM) and the aryl hydrocarbon antagonist CH-223191 (1 µM) combined factorially. TCDD-induced Cyp1a1 mRNA expression was absent in 2-cell embryos; however morulae exhibit dose-dependent Cyp1a1 expression. TCDD induced accumulation of sperm in the perivitelline space and displacement of blastomere nuclei. At 100 nM TCDD, aberrations in cytokinesis and nuclear positioning were observed 2-cell embryos and morula and these effects were reversed in the presence of CH-223191. Our data suggest that acute exposure to TCDD has direct effects on early development in the rat that permit discrimination of AHR-mediated and AHR-independent mechanisms through which environmental toxicants impair mammalian reproduction.

The expression of the aryl hydrocarbon receptor in reproductive and neuroendocrine tissues during the estrous cycle in the pig.

The aryl hydrocarbon receptor (AhR) has been recognized as a mediator of xenobiotic-induced toxicity. In addition, it was demonstrated that the AhR is able to influence the regulation of reproductive processes in females. The aim of this study was to examine AhR mRNA (real-time PCR) and protein (Western-blot) expression in ovarian follicles and stroma, corpora lutea (CL), oviducts, endometrium, myometrium as well as in medial basal hypothalami (MBH), and anterior (AP) and posterior (PP) pituitaries harvested during the follicular (days 17-19) and luteal (days 8-10) phase of the porcine estrous cycle. The AhR transcript and protein were found in all structures collected during both phases. AhR mRNA expression tended (p=0.06) to be higher in the CL than in follicles. The AhR protein expression in ovarian stroma was higher (p≤0.01) during the follicular than in the luteal phase. Endometrial expression of AhR mRNA was higher (p≤0.01), while AhR protein was lower (p≤0.01) during the follicular phase in comparison to the luteal phase. Within neuroendocrine tissues, AhR mRNA and protein content in hypothalamus were relatively low and did not differ (p>0.05) between phases. In contrast, higher AhR mRNA expression in AP (p≤0.001) and protein expression in PP (p≤0.01) were found during the luteal phase compared to the follicular phase. Differences in AhR expression observed in reproductive and neuroendocrine tissues during the follicular and luteal phase of the estrous cycle indicate the involvement of AhR in the regulation of reproductive function in pigs.