Omega-3 fatty acid deficiency augments amphetamine-induced behavioral sensitization in adult mice: prevention by chronic lithium treatment.
OBJECTIVE
Emerging data suggests that omega-3 fatty acid deficiency may be a risk factor for bipolar disorder. In the present study, we determined the effects of chronic dietary-induced omega-3 fatty acid deficiency and/or concomitant chronic lithium chloride (LiCl) treatment on amphetamine (AMPH)-induced behavioral sensitization, a phenomenon that may recruit neuroplastic mechanisms relevant to the pathophysiology of bipolar disorder.


METHODS
Adult male C57BL/6J mice were randomly assigned to one four diets: Control (alpha-linolenic-fortified), Control+LiCl (0.255%), alpha-linolenic-Deficient, or Deficient+LiCl (0.255%), and behavioral testing initiated 65 days later. Locomotor activity was determined following 3 intermittent (separated by 7d) injections of amphetamine (AMPH) (1mg/kg). After behavioral testing, red blood cell (RBC) and regional brain (prefrontal cortex, hippocampus, ventral striatum) fatty acid composition was determined by gas chromatography.


RESULTS
Each diet group exhibited comparable locomotor activity following acute AMPH treatment. However, the development of sensitization following repeated AMPH treatment was significantly augmented in Deficient mice relative to controls, and this augmented response was prevented by chronic LiCl treatment. Relative to controls, Deficient mice exhibited deficits in RBC and regional brain docosahexaenoic acid (DHA, 22:6n-3) composition, reciprocal elevations in vaccenic acid (18:1n-7), arachidonic acid (AA, 20:4n-6), and docosapentaenoic acid (DPA, 22:5n-6) compositions, and elevations in AA:DHA, oleic acid:DHA, and DPA:DHA ratios. The fatty acid abnormalities in Deficient mice were not altered by concurrent chronic lithium treatment. Mice fed the Control+LiCl diet exhibited a significant increase in AA composition in RBC and all brain regions, and an elevated AA:DHA ratio in the prefrontal cortex and hippocampus, relative to Controls. Fatty acid composition in RBC and different brain regions were predominantly positively correlated. Within the ventral striatum, DHA composition was inversely correlated, and AA:DHA and oleic acid:DHA ratios positively correlated, with total distance traveled following the final AMPH treatment.


CONCLUSIONS
These data indicate that alterations in fatty acid composition resulting from dietary-induced omega-3 fatty acid deficiency augment the development of AMPH-induced behavioral sensitization in a manner that is prevented by chronic lithium treatment. The implications of these findings for understanding the contribution of omega-3 fatty acid deficiency to the pathophysiology and progression of bipolar disorder are discussed.
McNamara
Robert K
RK
Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States. robert.mcnamara@psychiatry.uc.edu
Sullivan
Juliana
J
Richtand
Neil M
NM
D000661:Amphetamine / Q000009:adverse effects*; D000818:Animals; D018692:Antimanic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004342:Drug Hypersensitivity / Q000209:etiology* / Q000517:prevention & control*; D044943:Fatty Acid Desaturases / Q000172:deficiency*; D006624:Hippocampus / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D018021:Lithium Chloride / Q000008:administration & dosage / Q000627:therapeutic use*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation
D018692:Antimanic Agents; D000697:Central Nervous System Stimulants; D000661:Amphetamine; D044943:Fatty Acid Desaturases; C078565:omega-3 fatty acid desaturase; D018021:Lithium Chloride