Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors.
Neurotransmitter transporters can affect neuronal excitability indirectly via modulation of neurotransmitter concentrations or directly via transporter currents. A physiological or pathophysiological role for transporter currents has not been described. We found that GABA transporter 1 (GAT-1) cation currents directly increased GABAergic neuronal excitability and synaptic GABA release in the periaqueductal gray (PAG) during opioid withdrawal in rodents. In contrast, GAT-1 did not indirectly alter GABA receptor responses via modulation of extracellular GABA concentrations. Notably, we found that GAT-1-induced increases in GABAergic activity contributed to many PAG-mediated signs of opioid withdrawal. Together, these data support the hypothesis that GAT-1 activity directly produces opioid withdrawal signs through direct hyperexcitation of GABAergic PAG neurons and nerve terminals, which presumably enhances GABAergic inhibition of PAG output neurons. These data provide, to the best of our knowledge, the first evidence that dysregulation of a neurotransmitter transporter current is important for the maladaptive plasticity that underlies opiate withdrawal.
Discipline of Pharmacology, University of Sydney, Sydney, Australia.
Elena E
EE
Bagley
Jennifer
J
Hacker
Vladimir I
VI
Chefer
Christophe
C
Mallet
Gavan P
GP
McNally
Billy C H
BC
Chieng
Julie
J
Perroud
Toni S
TS
Shippenberg
MacDonald J
MJ
Christie
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D018756:GABA Antagonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017551:Microdialysis / Q000379:methods; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D010487:Periaqueductal Gray / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D009292:Narcotic Antagonists; D009557:Nipecotic Acids; D010091:Oximes; C078793:NNC 711; D049452:Green Fluorescent Proteins; D009270:Naloxone; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1