Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

Abstract

Systemic lupus erythematosus is frequently accompanied by psychiatric manifestations of unknown origin. Although damage of central neurons had been documented, little is known about neurotransmitter systems affected by the autoimmune/inflammatory process. Recent studies on lupus-prone MRL-lpr mice point to imbalanced dopamine function and neurodegeneration in dopamine-rich brain regions. We follow up on anecdotal observations of singly housed mice developing chest wounds. Compulsive grooming and/or skin biting accounted for open lesions, lending itself to the operational term 'self-injurious behavior' (SIB). Low incidence of spontaneous SIB increased significantly after repeated injections of dopamine-2/ 3 receptor (D2/D3R) agonist quinpirole (QNP). To further probe the dopaminergic circuitry and examine whether SIB is associated with development of lupus-like disease, we compared behavioral responses among cohorts that differed in the immune status. Two-week treatment with QNP (intraperitoneal, 0.5 mg kg À1 body weight per day) induced SIB in 60% of diseased MRL-lpr mice, and exacerbated their splenomegaly. Although increased grooming and stereotypy were observed in less symptomatic MRL þ / þ controls, only one mouse (10%) developed SIB. Similarly, SIB was not seen in young, asymptomatic groups despite dissimilar ambulatory responses to QNP. In situ hybridization revealed treatment-independent upregulation of D2R mRNA in substantia nigra of diseased MRL-lpr mice. The above results suggest that development of systemic autoimmunity alters sensitivity of the dopaminergic system and renders MRL-lpr mice prone to SIB. Although pathogenic factors were not examined, we hypothesize that immune and endocrine mechanisms jointly contribute to early neuronal damage, which underlies behavioral deficiency in the adulthood.

Effects of prolonged treatment with memantine in the MRL model of central nervous system lupus

“…We previously established that the two MRL substrains differ in responsiveness to neurotransmitter modulators, such as quinpirole, amphetamine, sertraline, and risperidone (42;44;54). In the present study, we observed discrepancies in responsiveness to MEM when nocturnal activity and climbing behavior were considered.…”

“…Moreover, several lines of evidence suggest aberrant dopaminergic neurotransmission in autoimmune MRL/lpr mice (42-45). We further examine this notion and the effects of MEM by employing a brief climbing test.…”

Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model

“…dopamine, serotonin, norepinephrine, glutamate) catabolism could also be involved in the pathogenesis of CNS damage in lupus. This hypothesis was studied in MRL-lpr strain by evaluating the neurotransmitter/metabolite levels in several brain regions [104,105,165]. MRL-lpr brains showed increased dopamine levels in the paraventricular nucleus (PVN) and the median eminence, decreased serotonin concentrations in the PVN and enhanced levels in the hippocampus, and decreased norepinephrine levels in the prefrontal cortex [83].…”

The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

“…These include altered responses to the dopaminergic drugs amphetamine and apomorphine [52, 109, 132] and higher levels of apoptosis in the dopaminergic neurons in the nucleus accumbens and substantia nigra (thought to be involved in response to reward and anhedonia) in MRL/lpr mice [52, 109]. There are also decreased levels of serotonin in brain regions such as the hypothalamus, which regulate stress and response to appetitive stimuli (among other things) [133], and increased levels in the hippocampus [58].…”