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. 2012 Sep;223(1):75-88.
doi: 10.1007/s00213-012-2691-3. Epub 2012 Mar 31.

The effect of intermittent alcohol vapor or pulsatile heroin on somatic and negative affective indices during spontaneous withdrawal in Wistar rats

Angela M Williams  1 , Daniel J Reis, Alexa S Powell, Louis J Neira, Kathryn A Nealey, Cole E Ziegler, Nina D Kloss, Jessica L Bilimoria, Chelsea E Smith, Brendan M Walker
Affiliations

The effect of intermittent alcohol vapor or pulsatile heroin on somatic and negative affective indices during spontaneous withdrawal in Wistar rats

Angela M Williams et al. Psychopharmacology (Berl). 2012 Sep.

Abstract

Rationale: Once dependent on alcohol or opioids, negative affect may accompany withdrawal. Dependent individuals are hypothesized to "self-medicate" in order to cope with withdrawal, which promotes escalated alcohol and drug use.

Objectives: The current study aimed to develop a reliable animal model to assess symptoms that occur during spontaneous alcohol and opioid withdrawal.

Methods: Dependence was induced using intermittent alcohol exposure or pulsatile heroin delivery and assessed for the presence of withdrawal symptoms during acute withdrawal by measuring somatic signs, behavior in the forced swim test (FST), and air-puff-induced 22-kHz ultrasonic vocalizations (USVs). Additional animals subjected to 8 weeks of alcohol vapor exposure were evaluated for altered somatic signs, operant alcohol self-administration, and 22-kHz USV production, as well as performance in the elevated plus maze (EPM).

Results: During spontaneous withdrawal from pulsatile heroin or intermittent alcohol vapor, animals displayed increased somatic withdrawal signs, FST immobility, and 22-kHz USV production but did not show any behavioral change in the EPM unless the duration of alcohol exposure was extended to 4 weeks. Following 8 weeks of alcohol vapor exposure, animals displayed somatic withdrawal signs, escalated alcohol self-administration, and increased 22-kHz USVs.

Conclusions: These paradigms provide consistent methods to evaluate the behavioral ramifications, and neurobiological substrates, of alcohol and opioid dependence during spontaneous withdrawal. As immobility in the FST and percent open-arm time in the EPM were dissociable, with 22-kHz USVs paralleling immobility in the FST, assessment of air-puff-induced 22-kHz USVs could provide an ethologically valid alternative to the FST.

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Figures

Fig. 1
Fig. 1
Modified osmotic minipump that allows for pulsatile heroin delivery according to the desired experimental schedule. Preparation of the thermoformable polyethylene tubing so that it will remain tightly wrapped and untangled occurs via the Lynch coil method (Lynch et al. 1980). 50 ul of food coloring distinguished the drug solution and can be seen in this figure as the darker portions in the tubing.
Fig. 2
Fig. 2
Mean (+S.E.M.) somatic withdrawal scores (panel A, n=4–6), immobility time (panel B, n=4–6) and 22-kHz USV number (panel C, n=4–6) and duration (panel D, n=4–6) were dose-dependently increased during acute withdrawal using pulsatile exposure to induce heroin dependence (* = p<0.05, **p<0.01 and ***p<0.001 compared to the vehicle-treated condition).
Fig. 3
Fig. 3
Mean (+/−S.E.M.) somatic scores during spontaneous acute withdrawal (6–10 hrs) from pulsatile heroin. Following the second week of spontaneous withdrawal, the 1.5 and 3.0 mg/14hr doses produced a significant increase in somatic withdrawal scores that stabilized by day 23 (* = p<0.05 when compared to vehicle-treated controls and † = p<0.05 when compared to baseline data collected on Experimental Day 5).
Fig. 4
Fig. 4
Mean (+S.E.M.) somatic withdrawal scores (panel A, n=10/grp), forced swim test behavior (panel B, n=6/grp) and 22-kHz USVs (panels C and D, n=6/grp) following two weeks of air or intermittent alcohol vapor exposure (*=p<0.05 and ***=p<0.001/ when comparing air and vapor exposure conditions), LAT = Latency to immobility, IMM = immobility, SWM = swim time and CLM = climbing time.
Fig. 5
Fig. 5
Mean (+S.E.M.) percent time in the open-arms of the elevated plus-maze (EPM) following 2-weeks (n=9/grp) or 4-weeks (n=9/grp) of intermittent alcohol vapor exposure. Open-arm time in the EPM during acute withdrawal was not impacted by 2-weeks, but significantly decreased by 4-weeks of vapor exposure (‡ = p<0.05 when compared to the 4- week air-exposed group and † = p<0.05 when compared to the 2-week vapor-exposed group.
Fig. 6
Fig. 6
Mean (+S.E.M.) somatic withdrawal scores (panel A, n=6/grp), operant alcohol self-administration (panel B, n=10/grp) and 22-kHz USVs (panels C and D, n=10/grp) after 8-weeks of air or intermittent alcohol vapor exposure (**=p<0.01 and ***=p<0.001, when comparing air and vapor exposure conditions). In vapor-exposed animals, alcohol self-administration and 22-kHz USVs were shown to be predictive of each other (panels E and F;* =p<0.05 and ** =p<0.01).
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