Chronic d-amphetamine depresses an imaging marker of arachidonic acid metabolism in rat brain.
Acute d-amphetamine (d-Amph) administration to rats leads to the release of arachidonic acid (AA, 20:4n-6) as a second messenger following indirect agonism at dopamine D2-like receptors in the brain. We hypothesized that chronically administered d-Amph in rats also would alter brain AA metabolism and signalling. To test this, adult male rats were injected i.p. daily for 2 wk with saline or 2.5 mg/kg d-Amph. After a 1-d washout, the unanaesthetized rats were injected acutely with i.v. saline, 1 mg/kg quinpirole (a D2-like receptor agonist) or 5.0 mg/kg SKF-38393 (a D1-like receptor agonist), followed by i.v. [1-14C]AA. The AA incorporation coefficient k* (brain radioactivity/integrated plasma radioactivity), a marker of AA signalling and metabolism, was quantified using autoradiography in each of 62 brain regions. Compared with chronic saline, chronic d-Amph widely decreased baseline values of k* in brain regions having D2-like receptors. On the other hand, chronic amphetamine did not alter the k* responses to quinpirole seen in chronic saline-treated rats. SKF-38393 had minimal effects on k* in both chronic saline-treated and amphetamine-treated rats, consistent with D1-like receptors not being coupled to AA signalling. The ability of chronic d-Amph after 1-d washout to down-regulate baseline values of k* probably reflects neuroplastic changes in brain AA signalling, and may correspond to depressive behaviours noted following withdrawal from chronic amphetamine in humans and in rats.
Bhattacharjee
Abesh K
AK
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. abeshb@mail.nih.gov
Chang
Lisa
L
Chen
Mei
M
White
Laura
L
Bell
Jane M
JM
Bazinet
Richard P
RP
Rapoport
Stanley I
SI
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism* / Q000493:pharmacokinetics; D001345:Autoradiography; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D003864:Depression, Chemical; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006207:Half-Life; D007091:Image Processing, Computer-Assisted; D007274:Injections, Intraperitoneal; D008297:Male; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017448:Receptors, Dopamine D2 / Q000819:agonists; D054507:Receptors, Phospholipase A2 / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D015415:Biomarkers; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D005230:Fatty Acids, Nonesterified; D017448:Receptors, Dopamine D2; D054507:Receptors, Phospholipase A2; D019257:Quinpirole; D016718:Arachidonic Acid; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D003913:Dextroamphetamine