Altered neurotransmission in brains of autoimmune mice: pharmacological and neurochemical evidence

Depressive-like behavior is the most profound manifestation of autoimmunity-associated behavioral syndrome in lupus-prone MRL-1pr mice. This led to the hypothesis that chronic autoimmunity and inflammation alter the activity of central serotonergic and dopaminergic systems. Three drugs with a selective mode of action were used to probe the functional status of these two systems in vivo. The behavioral effects of single and repeated intraperitoneal (i.p.) injections of sertraline, quinpirole (QNP) and risperidone were insured in the forced swim and brief sucrose preference tests. In comparison to MRL +/+ controls, autoimmune MRL-1pr mice did not show a reduction in sucrose intake after the administration of sertraline. Acute injection of quinpirole increased floating more in the MRI-1pr than in the control group, while intermittent administration induced self-injurious behavior in both group. Acute injection of risperidone significantly increased floating in MRL-1pr mice, while repeated administration abolished the difference between tire substrains in sucrose intake. These discrepancies in responsiveness implied that the central neurotransmitter activity is dissimilar in the two MRL substrains. This notion was confirmed in a cohort of untreated MRL-1pr and MRL +/+ mice by comparing their neurotransmitter metabolite lever in several brain regions. In particular, MRL-1pr brains showed increased dopamine (DA) levels in the paraventricular nucleus (PVN) and median eminence (ME), decreased concentrations of serotonin in the PVN and enhanced levels in the hippocampus, as well as decreased norepinephrine (NE) levels in the prefrontal cortex. Behavioral deficits correlated with the changes in PVN and median eminence. These results arc consistent with the hypothesis that unbalanced neurotransmitter regulation of the hypothalamus-pituitary,iris plays an important role in the etiology of behavioral dysfunction induced by systemic autoimmune disease. (C) 2002 Elsevier Science B.V. All rights reserved.