Differential lipopolysaccharide-induced immune alterations in the hippocampus of two mouse strains: effects of stress.

Immunological activation may result in the development of depressive-like symptoms in a large percentage of patients treated with cytokine-based therapies. The mechanisms underlying susceptibility to cytokine-induced depression are currently unknown; however activation of the tryptophan catabolising enzyme indoleamine 2,3-dioxygenase (IDO) is associated with the induction of cytokine-induced depression. Peripheral administration of lipopolysaccharide (LPS) is one of the most commonly used immunological challenges in animal models of cytokine-induced depression. Inbred mouse strains are useful tools in the investigation of the neurobiology of psychiatric illnesses. In this study we hypothesised that two strains which differ in stress susceptibility, namely the BALB/c and C57BL/6J mice, would respond differentially to LPS and swim-stress in cytokine profile, corticosterone concentrations and mRNA expression of genes coding for the tryptophan metabolising enzymes, IDO1, IDO2, Tph1 and Tph2. The stress-sensitive BALB/c strain exhibited increased depressive-like behaviour and enhanced corticosterone concentrations in response to LPS. Furthermore, swim-stress attenuated the LPS-induced corticosterone response in BALB/c mice only. LPS significantly increased plasma interleukin (IL)-1ß and tumour necrosis factor α (TNFα) concentrations to a greater extent in BALB/c mice. The LPS-induced increase in IL-1ß mRNA expression was significantly attenuated by swim-stress in the hippocampus of C57BL/6J but not in BALB/c mice. TNFα mRNA expression was significantly increased in BALB/c mice only; this increase was attenuated by swim-stress. Tph1 mRNA expression was upregulated in the brainstem of C57BL/6J mice post-LPS and following the combination of swim-stress and LPS in BALB/c mice. In the hippocampus Tph1 and Tph2 mRNA expression was increased in C57BL/6J but not BALB/c mice in response to LPS challenge and swim-stress. Conversely, IDO2 but not IDO1 mRNA expression was significantly altered following swim-stress and LPS, particularly in the hippocampus of BALB/c mice. These data indicate altered central mRNA expression of tryptophan metabolising enzymes and immune activation in BALB/c mice compared to the normo-sensitive C57BL/6J strain.

Inhibition of P-glycoprotein enhances transport of imipramine across the blood-brain barrier: microdialysis studies in conscious freely moving rats.

BACKGROUND AND PURPOSE: Recent studies indicate that efflux of antidepressants by the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) may contribute to treatment-resistant depression (TRD) by limiting intracerebral antidepressant concentrations. In addition, clinical experience shows that adjunctive treatment with the P-gp inhibitor verapamil may improve the clinical outcome in TRD. Therefore, the present study aimed to investigate the effect of P-gp inhibition on the transport of the tricyclic antidepressant imipramine and its active metabolite desipramine across the BBB. EXPERIMENTAL APPROACH: Intracerebral microdialysis in rats was used to monitor brain levels of imipramine and desipramine following i.v. imipramine administration, with or without pretreatment with one of the P-gp inhibitors verapamil or cyclosporin A (CsA). Plasma drug levels were also determined at regular intervals. KEY RESULTS: Pretreatment with either verapamil or CsA resulted in significant increases in imipramine concentrations in the microdialysis samples, without altering imipramine plasma pharmacokinetics. Furthermore, pretreatment with verapamil, but not CsA, led to a significant elevation in plasma and brain levels of desipramine. CONCLUSIONS AND IMPLICATIONS: The present study demonstrated that P-gp inhibition enhanced the intracerebral concentration of imipramine , thus supporting the hypothesis that P-gp activity restricts brain levels of certain antidepressants, including imipramine. These findings may help to explain reports of a beneficial response to adjunctive therapy with verapamil in TRD.

The effects of iontophoretic clonidine on neurones in the rat superficial dorsal horn.

Clonidine and glutamate were applied by iontophoresis to cells in the superficial 3 laminae of the spinal cord in the anaesthetised rat. Only cells that were excited by glutamate (up to 150 nA) were studied. Some spontaneously active cells could be excited by clonidine (up to 100 nA). However, when applied to non-spontaneous cells, clonidine had no effect at any dose level. When ejected in a cyclic pattern alternating with glutamate ejection, clonidine powerfully amplified the response of many cells to the glutamate stimulus. This effect was seen only on cells with small-amplitude spikes and low-threshold (LT) receptive fields. The amplification was often sustained and could outlast the clonidine ejection by several minutes. Clonidine had a long-lasting inhibitory effect on the responses to glutamate of cells with high-threshold (HT) or wide-dynamic-range (WDR) receptive fields. Clonidine appeared to selectively decrease the responsiveness of WDR cells to noxious stimulation. It is suggested that an amplification of the response of LT cells to other excitatory inputs could contribute to the analgesic action of clonidine.