18423
Effects of Acute N-Acetylcysteine Administration on Striatal Glutamate Concentrations and Behaviour in C57BL/6J Adult Mice
Objectives: To investigate the acute effects of NAC on striatal glutamate concentrations and its effects on behaviours known to depend upon excitatory transmission in striatal networks, namely open-field activity (a measure of anxiety) and prepulse inhibition of the startle response (PPI; an operational measure of sensorimotor gating).
Methods: Two cohorts of C57BL/6J adult mice received an intraperitoneal injection of either 150mg/kg NAC (injection volume approximately 100 μL) or vehicle (saline), 110 to 180 minutes before testing. In Cohort I, concentrations of glutamate in the left striatum were quantified using 7 Tesla in vivoproton magnetic resonance spectroscopy ([1H]MRS). In Cohort II, activity over a period of 10 minutes was measured in a standard open field apparatus. PPI was assessed in a startle chamber for mice where the startle response to auditory stimuli was recorded.
Results: As expected, NAC induced a decrease in creatine normalised striatal glutamate concentrations in both male and female animals (F(1)=5.54, p=0.026). This reduction in glutamate was time-dependent, as shown by a main effect of time post-dose (F(1)=7.90, p=0.009) (See figure). Time post-dose was negatively correlated with glutamate concentrations in the NAC-treated group (Pearson r=-0.657, p=0.008), but not in the control group. However, contrary to expectation, NAC treated females were significantly more anxious than controls, as indicated by less time spent in the central zone of the open field (F(1)=6.870, p=0.016), and less frequent entries in the centre (F(1)=6.630, p=0.018). NAC also impaired PPI in females (F(1)=5.290, p=0.032), but NAC treatment had no significant effect on anxiety and PPI in male animals.
Conclusions: The striatal glutamate decrease caused by NAC is analogous to our recent findings of lower striatal glutamate in adult men with ASD compared with healthy controls (Horder et. al. 2013). However, although the dose of NAC used was sufficient to lower glutamate concentrations in both sexes, only females were sensitive to its behavioural consequences. In female mice, NAC disrupted behaviours known to be impaired in neurodevelopmental disorders such as ASD or schizophrenia. Thus there is a paradox; NAC has been suggested to have clinical benefit in conditions like ASD, but we find that in this animal system, it causes biochemical and behavioural effects similar to the pathological condition.