Impaired response to amphetamine and neuronal degeneration in the nucleus accumbens of autoimmune MRL-lpr mice

Abstract

Spontaneous development of lupus-like disease in MRL-lpr mice is accompanied by a constellation of behavioral deficits, including blunted responsiveness to sucrose. Although autoimmunity-induced damage of limbic areas is proposed to underlie this deficit, the systemic nature of the disease precludes inference of a causal relationship between CNS damage and functional loss. Based on the stimulatory effects of d-amphetamine sulfate (AMPH) on sucrose intake, the present study pharmacologically probes the functional status of central dopaminergic circuits involved in control of behavioral reward. The response rates were compared between diseased MRL-lpr mice and congenic MRL +/+ controls tested in the sucrose preference paradigm. Neuronal loss was assessed by Fluoro Jade B (FJB) staining of nucleus accumbens and the CA2/CA3 region. While control mice significantly increased intake of sucrose solutions 60 min after administration of AMPH (i.p., 0.5 mg/kg), the intake in drugged MRL-lpr mice was comparable to those given saline injection. Increased FJB staining was detected in the nucleus accumbens and hippocampus of diseased mice, and AMPH treatment neither altered this nor other measures of organ pathology. The results obtained are consistent with previously observed changes in the mesolimbic dopamine system of MRL-lpr mice and suggest that the lesion in the nucleus accumbens and deficits in dopamine release underlie impaired responsiveness to palatable stimulation during the progress of systemic autoimmune disease. As such, they point to a neurotransmitter-specific regional brain damage which may account for depressive behaviors in neuropsychiatric lupus erythematosus.

Fig. 1

Consumption of sucrose in the brief sucrose preference test 60 min after i.p. injections. (A) Diseased MRL-lpr females injected with saline (Sal) showed a lower intake of sucrose in comparison to age-matched MRL +/+ controls. (B) This substrain difference was exacerbated when the same group of animals was injected with d-amphetamine (AMPH, 0.5 mg/kg b.w.), as MRL +/+ mice significantly increased their performance and MRL-lpr mice showed intake comparable to performance after Sal injections.

Fig. 2

Sucrose intake in diseased MRL-lpr and age-matched MRL +/+ males. As expected, Sal-treated MRL +/+ controls had higher consumption than diseased, Sal-treated MRL-lpr mice. Although administration of AMPH further increased the intake in the MRL +/+ substrain, it had no effects in the AMPH-treated MRL-lpr group tested at different sucrose concentrations.

Fig. 3

Substrain-related differences in spleen and brain weights. (A) Increased spleen weight and (B) lower brain weight confirmed autoimmune status and brain atrophy in diseased MRL-lpr mice.

Fig. 4

Significant increase in the density of FJB+ neurons was observed in the hippocampus CA2/CA3 region and nucleus accumbens of the MRL-lpr group, suggesting an enhanced neurodegenerative process in limbic structures during a more severe development of lupus-like disease.

Fig. 5

Representative images (obtained by a confocal microscope) of the horizontal sections of the nucleus accumbens (NAc) in autoimmune mice (A) and control mice (B). Numerous brightly stained FJB-positive neurons confirmed a degenerative process in MRL-lpr brains in comparison to asymptomatic MRL +/+ controls.