The Rewarding and Anxiolytic Properties of Ethanol within the Central Nucleus of the Amygdala: Mediated by Genetic Background and Nociceptin

Abstract

In humans, alcohol is consumed for its rewarding and anxiolytic effects. The central nucleus of the amygdala (CeA) is considered a neuronal nexus that regulates fear, anxiety, and drug self-administration. Manipulations of the CeA alter ethanol (EtOH) consumption under numerous EtOH self-administration models. The experiments determined whether EtOH is reinforcing/anxiolytic within the CeA, whether selective breeding for high alcohol consumption alters the rewarding properties of EtOH in the CeA, and whether the reinforcing/anxiolytic effects of EtOH in the CeA are mediated by the neuropeptides corticotropin-releasing factor (CRF) and nociceptin. The reinforcing properties of EtOH were determined by having male Wistar and Taconic alcohol-preferring (tP) rats self-administer EtOH directly into the CeA. The expression of anxiety-like behaviors was assessed through multiple behavioral models (social interaction, acoustic startle, and open field). Coadministration of EtOH and a CRF1 antagonist (NBI35965) or nociceptin on self-administration into the CeA and anxiety-like behaviors was determined. EtOH was self-administered directly into the lateral CeA, and tP rats self-administered a lower concentration of EtOH than Wistar rats. EtOH microinjected into the lateral CeA reduced the expression of anxiety-like behaviors, indicating an anxiolytic effect. Coadministration of NBI35965 failed to alter the rewarding/anxiolytic properties of EtOH in the CeA. In contrast, coadministration of the nociceptin enhanced both EtOH reward and anxiolysis in the CeA. Overall, the data indicate that the lateral CeA is a key anatomic location that mediates the rewarding and anxiolytic effects of EtOH, and local nociceptin receptors, but not local CRF1 receptors, are involved in these behaviors. SIGNIFICANCE STATEMENT: Alcohol is consumed for the stimulatory, rewarding, and anxiolytic properties of the drug of abuse. The current data are the first to establish that alcohol is reinforcing and anxiolytic within the lateral central nucleus of the amygdala (CeA) and that the nociceptin system regulates these effects of alcohol within the CeA.

Graphical abstract

Fig. 1.

Depicts the mean (±S.E.M.) average number of infusions self-administered directly into the CeA during sessions 1–4 in Wistar and tP male rats. +Indicates significantly higher self-administration than aCSF and tP males > Wistar males. *Indicates significantly higher self-administration than aCSF controls.

Fig. 2.

Depicts the mean (±S.E.M.) number of lever responses in Wistar and tP male rats self-administering aCSF, 150 mg% EtOH, or 200 mg% EtOH. +Indicates significantly higher self-administration than aCSF and tP males > Wistar males. *Indicates significantly higher self-administration than aCSF controls.

Fig. 3.

Depicts the mean (±S.E.M.) number of lever responses in Wistar male rats self-administering 200 mg% EtOH and the CRF1 antagonist NBI35965 (top) or nociceptin (bottom). *Indicates that rats coadministering 200 mg% EtOH + 100 nM nociceptin, 500 nM nociceptin, or 5 µM nociceptin self-infused more than when only 200 mg% EtOH alone (sessions 1–4).

Fig. 4.

Depicts the mean (±S.E.M.) number of lever responses in Wistar male rats self-administering 200 mg% EtOH into the left (top panel) and right (bottom panel) CeA and 1 µM nociceptin (sessions 5 to 6). *Indicates that rats coadministering 200 mg% EtOH and 1 µM nociceptin self-infused more than rats self-administering 200 mg% EtOH alone.

Fig. 5.

Depicts the mean (±S.E.M.) percent change from aCSF controls for social interaction in Wistar male rats microinjected with EtOH into the posterior VTA (top panel), nucleus accumbens shell (middle panel), or the central amygdala (bottom panel). *Indicates significantly higher than aCSF. +Indicates significantly higher than all other comparison groups.

Fig. 6.

Depicts the mean (±S.E.M.) startle amplitude (right panel) and open field–dependent measures (center time and center crosses) in Wistar male rats microinjected with EtOH bilaterally into the CeA. *Indicates that all three EtOH concentrations are significantly different from each other. +Indicates that the 150 and 200 mg% EtOH groups are significantly different from the aCSF control group.

Fig. 7.

Depicts the mean (±S.E.M.) social interaction time in Wistar male rats microinjected with 200 mg% EtOH and the CRF1 antagonist NBI35965 (right panel) or nociceptin (left panel) directly into the CeA. *Indicates significantly higher than aCSF controls. +Indicates significantly higher than aCSF controls and 200 mg% EtOH group.