ABSTRACT
DBA mice are models of sudden unexpected death in epilepsy (SUDEP) that exhibit audiogenic generalized convulsive seizures (GCS), ending in death due to respiratory arrest (RA). Serotonin (5-HT) normally enhances respiration in response to elevated CO(2) levels, which occur during GCS in patients. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), blocks GCS-induced SUDEP in both DBA/2 and DBA/1 mice. This study examined the effects of a 5-HT(2B/2C) agonist (m-chlorophenylpiperazine, mCPP) to test the generality of serotonergic effects on DBA mice. In DBA/2 mice mCPP pre-treatment [5 or 10 (but not 2) mg/kg, i.p.] significantly reduced RA incidence without blocking seizure susceptibility. However, in DBA/1 mice mCPP in doses up to 40mg/kg was ineffective in blocking seizure-induced RA, and 60mg/kg was toxic. The cause of this strain difference was perplexing. Previous studies showed that brainstem 5-HT receptor protein expression was abnormal in DBA/2 mice. Therefore, expression of 5-HT receptor proteins in the medial-caudal brainstem of DBA/1 mice was evaluated using Western blots. In DBA1/mice 5-HT(2C) and 5-HT(3B) receptor expression levels were significantly reduced, as seen previously in DBA/2 mice. However, 5-HT(2B) receptor expression was also reduced in DBA/1 mice, contrasting with the 5-HT(2B) receptor elevation seen in DBA/2 mice. This difference may explain the differential effects of the 5-HT(2B/2C) agonist in these SUDEP models. mCPP blocked RA in DBA/2 mice and concomitantly reduced tonic seizures, which also occurs. Fluoxetine is the only agent tested that blocks RA selectively in these SUDEP models, which may be clinically relevant.
Subject(s)
Brain Stem/metabolism , Death, Sudden/prevention & control , Piperazines/therapeutic use , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/therapeutic use , Animals , Brain Stem/drug effects , Death, Sudden/etiology , Disease Models, Animal , Dose-Response Relationship, Drug , Fluoxetine/therapeutic use , Gene Expression Regulation/drug effects , Mice , Mice, Inbred C57BL , Mice, Inbred DBA/classification , Receptors, Serotonin/genetics , Seizures/complications , Seizures/etiology , Selective Serotonin Reuptake Inhibitors/therapeutic use , Species SpecificityABSTRACT
The effect of ethanol on the number of Fos-like immunoreactive (Fos-li) neurons was previously studied in the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains (Hitzemann and Hitzemann, 1997). Data obtained suggested that the locomotor activation response to ethanol found in the D2 but not the B6 strain was associated with an increase in the number of Fos-li neurons (a putative measure of synaptic activity) in the central nucleus of the amygdala (CeA), but not in other brain regions, including the basal ganglia. Supporting results were obtained in B6D2 F2 intercross animals (Demarest et al., 1998) those animals exhibiting a marked locomotor activation response to ethanol also showed a significant increase in the number of Fos-li neurons in the CeA. The current study extends this line of investigation to the FAST and SLOW selected lines of mice (Shen et al., 1995). Twenty-eight SLOW and FAST mice (taken evenly from both replicate lines) were randomly assigned to receive either saline or ethanol (1.5 g/kg). One hour later, the animals were sacrificed, and the number of Fos-li neurons were determined using standard immunocytochemical techniques. Both the FAST and SLOW lines showed a marked increase (>300%) in the number of Fos-li neurons in the lateral aspect of the CeA; however, in the capsular division, only the FAST line showed an increase (>500%). In several brain regions, the basal (saline) response was markedly higher in the SLOW line; these regions included the subthalamic nucleus, the entopeduncular nucleus, the substantia nigra compacta, and the ventral tegmental area. Furthermore, it was found that ethanol decreased the number of Fos-li neurons in the ventral tegmental area of the SLOW but not FAST mice. These data suggest a substantial involvement of the basal ganglia in the segregation of the FAST and SLOW lines.
Subject(s)
Amygdala/drug effects , Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Genes, fos/drug effects , Mice, Inbred C57BL/genetics , Mice, Inbred DBA/genetics , Motor Activity/drug effects , Amygdala/physiology , Animals , Female , Gene Expression/drug effects , Genes, fos/genetics , Mice , Mice, Inbred C57BL/classification , Mice, Inbred DBA/classification , Motor Activity/genetics , Species SpecificityABSTRACT
B10.BR, DBA/2, and BALB/c by J mice were infected with Trypanosoma brucei rhodesiense (Lou Tat clone 1). Subsequent infection with the D variant of encephalomyocarditis virus (EMC-D) resulted in no diabetes or encephalitis, even in the susceptible DBA/2 and BALB/c by J strains. Low levels of circulating interferon (IFN) were detected in trypanosome-infected mice at the time of EMC-D infection. All strains were severely immunosuppressed as a result of trypanosome infection, as evidenced by decreased virus-specific neutralizing antibody titers, compared to virus-infected controls. We attempted to simulate some aspects of T.b. rhodesiense infection in B10.BR mice by pretreating mice with cyclophosphamide and IFN prior to EMC-D infection. Immunosuppression by cyclophosphamide greatly enhanced the pathogenesis of EMC-D, while IFN protected against the diabetogenic effect of this virus. Our results indicate that: (i) T.b. rhodesiense infection inhibited EMC-D-induced diabetes, (ii) this inhibition was not due solely to the immunosuppression generated by the trypanosome infection, and (iii) IFN generated by the trypanosome infection could play some protective role in the inhibition of EMC-D-induced diabetes by trypanosome infection.
