Occupancy of dopamine D(1), D (2) and serotonin (2A) receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol.

RATIONALE: Flupentixol (FLX) has been used as a neuroleptic for nearly 4 decades. In vitro data show comparable affinity to dopamine D(2), D(1) and 5-HT(2A) receptors and recently, FLX showed to be not inferior to risperidone in schizophrenic patients with predominant negative symptomatology, which was implicated with flupentixol's interaction with 5-HT(2A) and/or D(1) receptors. OBJECTIVES: To assess in vivo receptor occupancy (RO) in patients clinically treated with FLX (n = 13, 5.7 +/- 1.4 mg/day) in comparison with risperidone (RIS, n = 11, 3.6 +/- 1.3 mg/day) and haloperidol (HAL, n = 11, 8.5 +/- 5.5 mg/day). MATERIALS AND METHODS: Each patient underwent two PET scans with 3-N-[(11)C]methylspiperone (target: frontal 5-HT(2A)), [(11)C]SCH23390 (striatal D(1)) or [(11)C]raclopride (striatal D(2)). RO was calculated as the percentage reduction of specific binding in comparison with healthy controls. RESULTS: D(2)-RO under FLX was between 50% and 70%, indicating an ED(50) of about 0.7 ng/ml serum. 5-HT(2A) and D(1)-RO was 20 +/- 10% and 20 +/- 5% (mean, SEM). Under HAL, D(1)-RO was 14 +/- 6% and under RIS not significantly different from zero. CONCLUSIONS: We were able to demonstrate a moderate 5-HT(2A) and D(1) occupancy under clinically relevant doses of flupentixol, albeit lower than expected from in vitro data and clearly below saturation. Therefore, if flupentixol's efficacy on negative symptoms is based on its interaction with 5-HT(2A) and/or D(1) receptors, it should be highly dependent on serum concentration and thus on dosage and metabolism. However, these data suggest that mechanisms other than D(1) or 5-HT(2A) antagonism may contribute to flupentixol's efficacy on negative symptoms.

Opposing actions of androgen and estrogen on in vitro firing frequency of neuronal oscillators in the electromotor system.

The South American knifefish (Apteronotus leptorhynchus), or brown ghost, produces a high-frequency (600-1000 Hz) sinusoidal electric organ discharge (EOD) with males discharging at higher frequencies than females. In addition, each fish has a unique EOD frequency within the frequency range of its gender. The electromotor circuit responsible for EOD production consists of a medullary pacemaker nucleus (PMN) and spinal electromotor neurons (EMNs). In vitro spinal slice recording showed that, similar to the PMN, EMNs fire spontaneously at rates near the EOD frequency of each fish. The persistence of firing 2 weeks after high spinal transaction demonstrated that spontaneous firing rate was intrinsic to the EMNs and was not dependent on presynaptic input. We confirmed that 11-ketotestosterone (11 kT) raised and 17-beta-estradiol (E2) lowered the EOD frequency of intact fish. Because electromotor cells fire spontaneously near EOD, frequency, we investigated whether these steroids affect endogenous firing rates. Steroid implants were made in normal or spinally transected fish. Two weeks later, PMNs of normal fish and EMNs of transected fish were recorded in vitro. 11 kT increased and E2 decreased the intrinsic firing rate of neurons in the PMN and the EMNS. Hormones shifted the intrinsic firing rates of EMNS, although they were synaptically isolated during the hormone exposure.

A Drosophila rRNA gene located in euchromatin is active in transcription and nucleolus formation.

P-element transformants of a single rRNA gene (rDNA) were used to investigate the relationship between the organization of the nucleolus organizer (NO) and rDNA function in Drosophila melanogaster. In situ hybridization to rRNA in polytene nuclei of salivary glands demonstrated that an rRNA gene can be transcribed at a high rate when inserted into chromosomal sites other than the NO. Structures that resemble morphologically the endogenous nucleoli ('mininucleoli') were associated with four different euchromatic sites of rDNA insertion. Molecular analyses revealed that these mininucleoli contained both rRNA and an antigen specific to nucleoli. Phenotypes resulting from rDNA deficiencies were rescued partially by the presence of the transformed rDNA, indicating that the transcripts and mininucleoli associated with the rDNA insertion sites were functional. Thus, two conserved features of rDNA organization in eukaryotes, namely tandem repetition and heterochromatic localization, are not required for rRNA gene function. We conclude that 'nucleolar organizing activity' is an intrinsic property of the rDNA or its RNA products.