The Central Amygdala and Alcohol: Role of  -Aminobutyric Acid, Glutamate, and Neuropeptides

Abstract

Alcohol dependence is a chronically relapsing disorder characterized by compulsive drug seeking and drug taking, loss of control in limiting intake, and the emergence of a withdrawal syndrome in the absence of the drug. Accumulating evidence suggests an important role for synaptic transmission in the central amygdala (CeA) in mediating alcohol-related behaviors and neuroadaptative mechanisms associated with alcohol dependence. Acute alcohol facilitates g-aminobutyric acid-ergic (GABAergic) transmission in CeA via both pre-and postsynaptic mechanisms, and chronic alcohol increases baseline GABAergic transmission. Acute alcohol inhibits glutamatergic transmission via effects at N-methyl-D-aspartate (NMDA) and AMPA receptors in CeA, whereas chronic alcohol up-regulates N-methyl-D-aspartate receptor (NMDAR)-mediated transmission. Pro-(e.g., corticotropin-releasing factor [CRF]) and anti-stress (e.g., NPY, nociceptin) neuropeptides affect alcohol-and anxiety-related behaviors, and also alter the alcohol-induced effects on CeA neurotransmission. Alcohol dependence produces plasticity in these neuropeptide systems, reflecting a recruitment of those systems during the transition to alcohol dependence.

Glutamate Signaling in Alcohol Abuse and Dependence

“…Because mGlu2/3 receptors act as autoreceptors on glutamate terminals (see previous discussion), this indicator of increased mGlu2/3-receptor function does not easily explain the results of in vivo microdialysis and electrophysiological studies indicating greater glutamate sensitivity within the CeA during alcohol withdrawal in dependent animals (cf. Roberto et al, 2012). Moreover, although several reports indicate an elevation in basal and/or alcohol-stimulated glutamate release within forebrain structures, including the NAC (see earlier discussion), Kufahl et al (2011) reported no changes in G protein coupling to mGlu2/3 receptors within either the prefrontal cortex or NAC during alcohol withdrawal in dependent animals.…”

“…When assayed by in vivo microdialysis, the effects of intraperitoneal (IP) injections of alcohol upon mesocorticolimbic glutamate levels are biphasic with respect to dose; lower doses tend to elevate, whereas higher doses either do not affect or reduce glutamate levels (e.g., Ding, Engleman, Rodd, & McBride, 2012;cf. De Witte, Pinto, Ansseau & Verbanck, 2003;Olive and Becker, 2008;Roberto et al, 2012). Repeated administration of alcohol IP elicits a progressive increase in the capacity of alcohol to stimulate glutamate release, and this alcohol-induced sensitization is well characterized for striatal structures (e.g., Carrara-Nascimento, Griffin, Pastrello, Olive, & Camarini, 2011;Chandler et al, 2006;Melendez, Hicks, Cagle, & Kalivas, 2005;.…”

“…Koob, 2003;Roberto, Gilpin, & Siggins, 2012). As discussed in great detail ahead, alcohol directly targets several glutamate receptor subtypes and can elicit pronounced changes in the expression and function of glutamate receptors.…”

Nociceptin/Orphanin FQ Decreases Glutamate Transmission and Blocks Ethanol-Induced Effects in the Central Amygdala of Naive and Ethanol-Dependent Rats

“…Specifically, the central nucleus of the amygdala (CeA) is considered critical in mediating the behavioral effects of ethanol (Eckardt et al, 1998;Pich et al, 1995;Rassnick et al, 1993;Roberts et al, 1996). In particular, alcohol dependence is defined by the emergence of a negative emotional state mediated in part by the recruitment of pro-and antistress peptides in the amygdala (Koob, 2008;Koob and Le Moal, 2008;Roberto et al, 2012).…”

Biological Mechanisms Underlying Addiction

“…Permanent changes in the brain may induce relapses to drug abuse long after detoxification. Gamma-aminobutyric acid (GABA)-ergic system and the glutamatergic system play important role in alcohol withdrawal 13 . Increased glutamatergic NMDA function is involved in seizures and cell death.…”