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.
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. abeshb@mail.nih.gov
Abesh K
AK
Bhattacharjee
Lisa
L
Chang
Mei
M
Chen
Laura
L
White
Jane M
JM
Bell
Richard P
RP
Bazinet
Stanley I
SI
Rapoport
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