Clozapine downregulates 5-hydroxytryptamine6 (5-HT6) and upregulates 5-HT7 receptors in HeLa cells

Clozapine is an atypical antipsychotic with high affinity for several serotonin receptors. This drug causes paradoxical downregulation of 5-hydroxytryptamine(2A) (5-HT)(2A) receptors, but its modulation of other serotonin receptors has not been studied. We examined the effects of clozapine and several other drugs on the regulation of rat 5-HT(6) and 5-HT(7) receptors individually expressed in transfected HeLa cells. Both 5-HT(6) and 5-HT(7) receptor densities (B(max)) were reduced by 5-carboxamidotryptamine, an agonist, and methiothepin, an inverse agonist. Clozapine reduced 5-HT(6) B(max). This suggests that 5-HT(6) receptors are also paradoxically downregulated by the antagonist clozapine. 5-Hydroxytryptamine(7) receptor B(max), on the other hand, was increased by clozapine. Clozapine's modulation of the 5-HT(6) and 5-HT(7) receptor levels may be important in the action of this atypical antipsychotic.     

DNA replication arrest and tolerance to DNA methylation damage

Inhibition of DNA replication by different DNA damaging agentshas been investigated in HeLaMR cells and amethylation damage-tolerantvariant HeLa5Al. In synchronous HeLaMR and HeLa5A1 cells exposedto N-ethyl-N-nitrosourea or ionizing radiation in mid-G₁ phase,DNA synthesis was inhibited in the following S phase. N-methyl-N-nitrosourea-inducedreplication inhibition in HeLaMR cells was delayed until thesecond S phase after treatment In contrast, N-methyl-N-nitrosoureatreatment of HeLa5Al cells affected neither the timing nor theextent of the first or second S phases. Both radiation and chemicaltreatment inhibited replication of an episomal plasmid and ofgenomic DNA in unison. Inhibition was observed at levels ofDNA damage that did not directly damage the plasmid molecules.Thus, DNA replication inhibition occurs immediately after ionizingradiation or ethylation damage, but methylation damage requiresprocessing through one cell cycle to generate an inhibitorysignal. The inhibitory signal appears to act in trans on undamagedDNA. Although methylationtolerantcells are responsive to inhibitionafter