Cyclooxygenase-2 deficiency modifies the neurochemical effects, motor impairment and co-morbid anxiety provoked by paraquat administration in mice.
Parkinson's disease and other motor disorders of midbrain basal ganglia dopaminergic functioning are often characterized by alterations of brainstem and limbic systems with accompanying co-morbid anxiety and depressive symptoms. Accumulating evidence suggests that inflammatory processes may play an important role in such neurodegenerative and psychiatric pathology. In this regard, inhibition of the inflammatory enzyme cyclooxygenase-2 (COX-2) was reported to limit the impact of stressors as well as the neurodegenerative effects of dopaminergic toxins. The present investigation assessed the impact of the putative dopamine toxin paraquat (a widely used herbicide) upon motor functioning, behavioural indices of anxiety-like states and central monoamine levels and whether these effects were altered in mice lacking COX-2. Indeed, paraquat did induce motor impairment and altered dopamine utilization within the striatum, and COX-2 deletion moderately attenuated these effects. Conversely, COX-2 deficiency enhanced the impact of paraquat upon indices of anxiety (open field exploration) and on serotonergic, noradrenergic and dopaminergic alterations within two brain regions implicated in stressor-related pathologies, namely the dorsal hippocampus and medial prefrontal cortex. These results suggest that COX-2 might differentially influence the motor and psychiatric symptoms associated with environmental toxin exposure. Furthermore, these data indicate that the neurochemical impact of paraquat is not restricted to the nigrostriatal dopamine pathway but also involves stressor-sensitive limbic regions. It is possible that COX-2 may play a dual role by contributing to the motor impairment induced by paraquat, but acting to moderate the effects of paraquat upon processes aligned with anxiety and depression.
Litteljohn
Darcy
D
Institute of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
Mangano
Emily N
EN
Hayley
Shawn
S
D000818:Animals; D001007:Anxiety / Q000139:chemically induced*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D015897:Comorbidity; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000235:genetics; D003863:Depression / Q000139:chemically induced; D004298:Dopamine / Q000737:chemistry / Q000378:metabolism; D006540:Herbicides / Q000494:pharmacology*; D007249:Inflammation / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D010269:Paraquat / Q000494:pharmacology*
D006540:Herbicides; D051546:Cyclooxygenase 2; D010269:Paraquat; D004298:Dopamine