Animal models of olfactory dysfunction in neurodegenerative diseases.

Olfactory dysfunction seems to occur earlier than classic motor and cognitive symptoms in many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD). Thus, the use of the olfactory system as a clinical marker for neurodegenerative diseases is helpful in the characterization of prodromal stages of these diseases, early diagnostic strategies, differential diagnosis, and, potentially, prediction of treatment success. The use of genetic and neurotoxin animal models has contributed to the understanding of the mechanisms underlying olfactory dysfunction in a number of neurodegenerative diseases. In this chapter, we provide an overview of behavioral and neurochemical alterations observed in animal models of different neurodegenerative diseases (such as genetic and Aß infusion models for AD and neurotoxins and genetic models of PD), in which olfactory dysfunction has been described.

Treadmill Exercise Attenuates L-DOPA-Induced Dyskinesia and Increases Striatal Levels of Glial Cell-Derived Neurotrophic Factor (GDNF) in Hemiparkinsonian Mice.

Exercise can act as a disease-modifying agent in Parkinson's disease (PD), and we have previously demonstrated that voluntary exercise in running wheels during 2 weeks normalizes striatopallidal dopaminergic signaling and prevents the development of L-DOPA-induced dyskinesia (LID) in C57BL/6 mice. We now tested whether LID in Swiss albino mice could be attenuated by treadmill-controlled exercise alone or in combination with the reference antidyskinetic drug amantadine. The daily intraperitoneal (i.p.) treatment with three different doses of L-DOPA/benserazide (30/12.5, 50/25, or 70/35 mg/kg) during 3 weeks induced increasing levels of LID scores in hemiparkinsonian Swiss albino mice previously lesioned with a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA, 10 µg). Then, we addressed the antidyskinetic effects of treadmill-controlled exercise by comparing LID, induced by L-DOPA/benserazide (50/25 mg/kg, i.p.) during 4 weeks, in sedentary and daily exercised mice. Exercise reduced LID and improved motor skills of dyskinetic mice, as indicated by decreased contralateral bias, increase in maximal load test, and latency to fall in rotarod. The antidyskinetic effect of amantadine (60 mg/kg, i.p.) was only observed in sedentary mice, indicating the absence of synergistic antidyskinetic effect of the combination of treadmill exercise plus amantadine. Finally, Western blot analysis unraveled an ability of exercise to increase the striatal immunocontent of glial cell-derived neurotrophic factor (GDNF), apart from normalizing striatal levels of tyrosine hydroxylase. These findings show that controlled treadmill exercise attenuates LID and provide the first indication that the antidyskinetic effects of treadmill exercise may involve increased striatal GDNF levels.

Repeated cycles of binge-like ethanol exposure induce immediate and delayed neurobehavioral changes and hippocampal dysfunction in adolescent female rats.

Binge-like ethanol intake (BEI) is a socioeconomical problem among adolescents and increasingly affects women. BEI can leave a long-term imprint in the brain, but it is unknown if its effect on cognition and anxiety is cumulative on repeated binge-ethanol episodes. We now submitted female Wistar rats to repeated cycles of binge-like ethanol treatment by intragastrically administering ethanol (3.0 g/kg/day, 20% w/v ethanol; 3 days on/4 days off) starting at postnatal day 35 (PND35). To investigate the short-term effects of BEI during adolescence, rats underwent 1 or 4 cycles of BEI, being evaluated at PND37 and PND58, respectively: both groups displayed anxiety-like behavior in the open field and elevated plus-maze tests, as well as short-term memory deficits in the object recognition task; this was associated with transient decreases of BDNF levels and increases of GFAP levels in the hippocampus. To evaluate the short- and long-lasting effects of BEI in adulthood, rats were subjected to 8 cycles of BEI and evaluated after 7.5 h (PND86) or after 14 days of ethanol withdrawal (PND100). This caused a persistent anxiogenic profile whereas recognition memory was impaired on the short-term, but not 14 days post-administration. The reduced BDNF level observed shortly after BEI recovered upon withdrawal, whereas increased GFAP immunoreactivity was persistent up to 14 days post-administration in adulthood. These findings show that repeated binge-like ethanol episodes from adolescence to adulthood in female rats cause consistent and long-term alterations of anxiety and hippocampal astrogliosis, whereas they trigger a recognition memory deficit paralleled by lower hippocampal BDNF levels, both recovering upon ethanol withdrawal.