GABA(A) receptors containing (alpha)5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry.
GABA receptors within the mesolimbic circuitry have been proposed to play a role in regulating alcohol-seeking behaviors in the alcohol-preferring (P) rat. However, the precise GABA(A) receptor subunit(s) mediating the reinforcing properties of EtOH remains unknown. We examined the capacity of intrahippocampal infusions of an alpha5 subunit-selective ( approximately 75-fold) benzodiazepine (BDZ) inverse agonist [i.e., RY 023 (RY) (tert-butyl 8-(trimethylsilyl) acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate)] to alter lever pressing maintained by concurrent presentation of EtOH (10% v/v) and a saccharin solution (0.05% w/v). Bilateral (1.5-20 microgram) and unilateral (0.01-40 microgram) RY dose-dependently reduced EtOH-maintained responding, with saccharin-maintained responding being reduced only with the highest doses (e.g., 20 and 40 microgram). The competitive BDZ antagonist ZK 93426 (ZK) (7 microgram) reversed the RY-induced suppression on EtOH-maintained responding, confirming that the effect was mediated via the BDZ site on the GABA(A) receptor complex. Intrahippocampal modulation of the EtOH-maintained responding was site-specific; no antagonism by RY after intra-accumbens [nucleus accumbens (NACC)] and intraventral tegmental [ventral tegmental area (VTA)] infusions was observed. Because the VTA and NACC contain very high densities of alpha1 and alpha2 subunits, respectively, we determined whether RY exhibited a "negative" or "neutral" pharmacological profile at recombinant alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors expressed in Xenopus oocytes. RY produced "classic" inverse agonism at all alpha receptor subtypes; thus, a neutral efficacy was not sufficient to explain the failure of RY to alter EtOH responding in the NACC or VTA. The results provide the first demonstration that the alpha5-containing GABA(A) receptors in the hippocampus play an important role in regulating EtOH-seeking behaviors.
Psychobiology Program, Department of Psychology, Indiana University-Purdue University, Indianapolis, Indiana 46202, USA. hjune@iupui.edu
H L
HL
June
S C
SC
Harvey
K L
KL
Foster
P F
PF
McKay
R
R
Cummings
M
M
Garcia
D
D
Mason
C
C
Grey
S
S
McCane
L S
LS
Williams
T B
TB
Johnson
X
X
He
S
S
Rock
J M
JM
Cook
D000818:Animals; D016739:Behavior, Addictive / Q000209:etiology / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D018755:GABA Agonists / Q000008:administration & dosage; D018756:GABA Antagonists / Q000008:administration & dosage; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D015870:Gene Expression / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008845:Microinjections; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D012313:RNA / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D012439:Saccharin / Q000008:administration & dosage; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism; D014981:Xenopus
D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D021122:Protein Subunits; D011963:Receptors, GABA-A; D000431:Ethanol; D012313:RNA; D012439:Saccharin