Voluntary induction and maintenance of alcohol dependence in rats using alcohol vapor self-administration - PubMed (original) (raw)

Voluntary induction and maintenance of alcohol dependence in rats using alcohol vapor self-administration

Giordano de Guglielmo et al. Psychopharmacology (Berl). 2017 Jul.

Abstract

Rationale: A major issue in the addiction field is the limited number of animal models of the voluntary induction and maintenance of alcohol dependence in outbred rats.

Objectives: To address this issue, we developed a novel apparatus that vaporizes alcohol for 2-10 min after an active nosepoke response.

Methods: Male Wistar rats were allowed to self-administer alcohol vapor for 8 h/day every other day for 24 sessions (escalated) or eight sessions (non-escalated). Escalated and non-escalated rats were then tested for progressive ratio responding. Anxiety-like behavior, somatic signs of withdrawal, and hyperalgesia were assessed during acute withdrawal.

Results: The results showed that rats exhibited excellent discrimination between the active and inactive operanda (>85%), and the escalated rats quickly increased their blood alcohol levels from ~50 to >200 mg% in ~6 weeks. Compared with non-escalated rats, escalated rats exhibited severe addiction-like behavior, including somatic signs of withdrawal, anxiety-like behavior, hyperalgesia, and higher responding on a progressive ratio schedule of reinforcement.

Conclusions: These results demonstrate that outbred rats will voluntarily self-administer alcohol vapor to the point of dependence without the use of forced alcohol administration, sweeteners, food/water restriction, operant pretraining, or behavioral/genetic selection. This novel animal model may be particularly useful for medication development to help unveil the neuronal circuitry that underlies the voluntary induction of alcohol addiction and identify novel molecular targets that are specifically recruited after the voluntary induction and maintenance of alcohol dependence.

Keywords: Addiction; Alcohol; Anxiety; Dependence; Vapor; Withdrawal.

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Conflict of interest statement

Disclosure The other authors declare no conflict of interest.

Figures

Fig. 1

Fig. 1

Schematic of the apparatus

Fig. 2

Fig. 2

a Air alcohol levels after one nosepoke (2 min of vapor). b Air alcohol levels after two consecutive nosepokes (2 + 2 min of vapor). Blood alcohol levels (c) during 1 h of consecutive vapor pulses (1 pulse = 2 min) and d) in the successive 3 h after discontinuing alcohol vapor. The data are expressed as mean ± SEM

Fig. 3

Fig. 3

a Left discrimination between active and inactive nosepokes throughout the self-administration paradigm in non-escalated rats. Right mean ± SEM minutes of vapor during the self-administration paradigm in non-escalated rats. b Left discrimination between active and inactive nosepokes throughout the self-administration paradigm in escalated rats. Right mean ± SEM minutes of vapor during the self-administration paradigm in escalated rats. The animals presented escalation of intake starting from session 13 (*p < 0.05, vs. last day of 2 min) and continued increasing their intake (***p < 0.001, vs. last day of 2 min) until stabilization from sessions 21 to 24. c Progressive ratio responding for alcohol vapor self-administration. ***p < 0.001, vs. non-escalated group. The data are expressed the mean ± SEM of rewards (left y axis) or breakpoint (right y axis). d Increase in BALs in the different phases of the self-administration paradigm. ***p < 0.001, vs. naive; ##p < 0.01, ###p < 0.001, vs. 2 min phase. e Somatic withdrawal signs measured 8 h after the last session. Inset overall withdrawal severity (sum of somatic withdrawal scores across the five behavioral signs of alcohol withdrawal). *p < 0.05, **p < 0.01, ***p < 0.001, vs. naive. VLR ventromedial limb retraction, AG abnormal gait, VOC vocalization, TR tail rigidity, BT body tremors

Fig. 4

Fig. 4

Elevated plus maze test during withdrawal in alcohol vapor-escalated vs. non-escalated and naive rats. a Percent time spent on the open arms. b Number of open arms entries. c Number of total arm entries. The data indicate higher anxiety-like behavior in rats that escalated alcohol vapor self-administration. d Development of mechanical hypersensitivity after 24 sessions of alcohol vapor self-administration. The data are expressed as mean ± SEM. **p < 0.01, vs. naive rats; #p < 0.05, ##p < 0.01, vs. non-escalated rats

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