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. 2017 Mar;22(2):423-434.
doi: 10.1111/adb.12342. Epub 2015 Dec 21.

Chronic EtOH Effects on Putative Measures of Compulsive Behavior in Mice

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Free PMC article

Chronic EtOH Effects on Putative Measures of Compulsive Behavior in Mice

Anna K Radke et al. Addict Biol. .
Free PMC article

Abstract

Addictions, including alcohol use disorders, are characterized by the loss of control over drug seeking and consumption, but the neural circuits and signaling mechanisms responsible for the transition from controlled use to uncontrolled abuse remain incompletely understood. Prior studies have shown that 'compulsive-like' behaviors in rodents, for example, persistent responding for ethanol (EtOH) despite punishment, are increased after chronic exposure to EtOH. The main goal of the current study was to assess the effects of chronic intermittent EtOH (CIE) exposure on multiple, putative measures of compulsive-like EtOH seeking in C57BL/6 J mice. Mice were exposed to two or four weekly cycles of CIE and then, post-withdrawal, tested for progressive ratio responding for EtOH, sustained responding during signaled EtOH unavailability and (footshock) punished suppression of responding for EtOH. Results showed that mice exposed to CIE exhibited attenuated suppression of EtOH seeking during punishment, as compared with air-exposed controls. By contrast, CIE exposure affected neither punished food reward-seeking behavior, nor other putative measures of compulsive-like EtOH seeking. Ex vivo reverse transcription polymerase chain reaction analysis of brain tissue found reduced sensitivity to punished EtOH seeking after CIE exposure was accompanied by a significant increase in gene expression of the GluN1 and GluN2A subunits of the N-methyl-d-aspartate receptor, specifically in the medial orbitofrontal cortex. Moreover, slice electrophysiological analysis revealed increased N-methyl-d-aspartate receptor-mediated currents in the orbitofrontal cortex after CIE exposure in test-naïve mice. Collectively, the current findings add to the growing body of evidence demonstrating that chronic exposure to EtOH fosters resistance to punished EtOH seeking in association with adaptations in cortical glutamatergic transmission.

Keywords: Addiction; CIE; NMDAR; alcohol; mouse; orbitofrontal cortex.

Figures

Figure 1
Figure 1. Behavioral procedures. (a)
Mice were trained to lever-press for a 14 mg food pellet or a 0.01 mL 10% EtOH reward, on a FR3 schedule of reinforcement, and then given CIE exposure or air for 2 or 4 weekly cycles. A series of three behavioral tests of compulsive behavior followed. (b) Mice were tested for rewarded lever-pressing during ‘reward-available’ (signaled by illumination of the reward magazine) and ‘reward-unavailable’ periods. (c) Motivation for reward was assayed from lever-pressing breakpoints on a progressive ratio (PR) schedule. (d) Punished-suppression of reward-seeking was tested with a 0.4 mA (food-reward) or 0.6 mA (EtOH-reward) footshock.
Figure 2
Figure 2. CIE attenuates punished-suppression of EtOH-seeking. (a)
Mice exposed to 2 cycles of CIE made more rewarded lever-presses during available than unavailable periods. (b) Progressive ratio breakpoints were unaffected by exposure to 2 CIE cycles. (c) Punishment suppressed rewarded lever-pressing in air controls, but not mice exposed to 2 CIE cycles. (d) Mice exposed to 4 cycles of CIE or air made more rewarded lever-presses during available than unavailable periods. (e) Exposure to 4 CIE cycles did not affect progressive ratio breakpoints. (f) Punishment suppressed rewarded lever-pressing in air controls, but not mice exposed to 4 CIE cycles. n=12-15 per group. *P<.05, **P<.01, ***P<.001
Figure 3
Figure 3. CIE does not decrease punished-suppression of food reward-seeking. (a)
Mice exposed to 2 cycles of CIE or air made more rewarded lever-presses during available than unavailable periods. (b) Progressive ratio breakpoints were unaffected by 2 cycles of CIE. (c) Punishment suppressed rewarded lever-pressing in air controls and mice exposed to 2 cycles of CIE. (d) Mice exposed to 4 cycles of CIE or air made more rewarded lever-presses during available than unavailable periods. (e) Exposure to 4 CIE cycles did not affect progressive ratio breakpoints. (f) Punishment suppressed rewarded lever-pressing in air controls and mice exposed to 4 cycles of CIE. n=6-10 per group. *P<.05, **P<.01, ***P<.001
Figure 4
Figure 4. CIE exposure increases NMDA receptor mRNA expression and NMDAR-mediated synaptic currents in the mOFC
Mice exposed to 4 cycles of CIE had higher GluN1 and GluN2A gene expression in the (a) medial orbitofrontal cortex (mOFC), not (b) ventromedial prefrontal cortex (vmPFC), (c) dorsolateral striatum (DLS) or (d) basolateral amygdala (BLA) (n=13-16). (e,f) Mice exposed to 4 cycles of CIE had higher evoked NMDAR-mediated currents in the mOFC. Neither sEPSC nor sIPSCs were affected by CIE exposure (n=13-16 neurons from n=8 mice). *P<.05, **P<.01 compared to air-exposed control.

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