Drug-induced GABA transporter currents enhance GABA release to induce opioid withdrawal behaviors

• Published in: Nature neuroscience Vol. 14; no. 12; pp. 1548 - 1554
• Main Authors: Bagley, Elena E, Hacker, Jennifer, Chefer, Vladimir I, Mallet, Christophe, McNally, Gavan P, Chieng, Billy C H, Perroud, Julie, Shippenberg, Toni S, Christie, MacDonald J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-12-2011; Nature Publishing Group
• Subjects: 631/378/1689/5; 631/378/2587; 631/378/548; Analysis of Variance; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Disease Models, Animal; GABA; GABA Antagonists - pharmacology; GABA Plasma Membrane Transport Proteins - metabolism; gamma-Aminobutyric Acid - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Glutamate Decarboxylase - genetics; Green Fluorescent Proteins - genetics; Health aspects; In Vitro Techniques; Inhibitory Postsynaptic Potentials - drug effects; Inhibitory Postsynaptic Potentials - genetics; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microdialysis - methods; Morphine - adverse effects; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Neural transmission; Neurobiology; Neurosciences; Nipecotic Acids - pharmacology; Opioids; Oximes - pharmacology; Periaqueductal Gray - drug effects; Periaqueductal Gray - physiology; Physiological aspects; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome - pathology; Substance Withdrawal Syndrome - physiopathology; Time Factors; Australia
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.2940

The authors report that GABA transporter 1 (GAT-1) cation currents directly increase GABAergic neuronal excitability and synaptic GABA release in the periaqueductal gray (PAG), and that these GAT-1 changes contribute to PAG-mediated signs of opioid withdrawal.
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.