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. 2019 Jul 29;176(17):3085–3109. doi: 10.1111/bph.14780

Table 3.

Repeated ethanol and withdrawal effects on the EC system

Measure Ethanol exposure Duration System Genus Genetic background Method of analysis Brain region Effect Duration of abstinence Withdrawal or abstinence effects Reference
AEA 50–150 mM of ethanol 24–72 hr In vitro Human Neuroblastoma SK‐N‐SH cells Cell and medium extract — ↑ — — Basavarajappa & Hungund, 1999a
100–150 mM of ethanol 72 hr In vitro Rat Wistar Cell and medium extract Cereb ↑ — — Basavarajappa et al., 2003
7.2% v/v ethanol in liquid diet, 24‐hr access 10–15 days Ex vivo Rat Sprague–Dawley Tissue content AMY — 3 hr ↓ Gonzalez et al., 2002; Rubio et al., 2008
CPu — 3 hr ↓
HyTh — 3 hr None
Cereb None — —
HP None — —
Limbic forebrain ↓ — —
Midbrain ↓ — —
Striatum None — —
Forced vapour inhalation 72 hr Ex vivo Mouse Swiss‐Wistar Tissue content Cortex ↑ 24 hr None Vinod, Yalamanchili, Xie, Cooper, & Hungund, 2006
Oral chronic intermittent 5–6 g·kg−1 alternate days 120 days Ex vivo Mouse Swiss‐Wistar Tissue content HP None 40 days ↑ Mitrirattanakul et al., 2007
Forced chronic ethanol consumption 7 days In vivo Rat Wistar Microdialysis NAc None 7–14 days None Ceccarini et al., 2013
Alcohol‐dependent patients Lifetime — Human — Plasma content Plasma ↑ 28 days — Garcia‐Marchena et al., 2017
Chronic intermittent ethanol vapour 21 days every day In vivo Rat Male Wistar AEA dialysate CeA None 12 hr ↓ Serrano et al., 2018
7 days None
Chronic intermittent ethanol vapour 10 days every day Ex vivo Rat Male Sprague–Dawley AEA BLA ↑ — — Robinson et al., 2016
NAPE‐PLD protein BLA None — —
FAAH protein BLA None — —
Chronic intermittent ethanol vapour 48 days every day Ex vivo Rat Male Wistar AEA BLA ↓ 3 days ↓ Henricks et al., 2017
Female Wistar AEA vmPFC — 3 days —
Male Wistar Napeld mRNA BLA — 3 days —
Female Wistar Napeld mRNA vmPFC ↓ 3 days ↓
Male Wistar Faah mRNA BLA — 3 days —
Female Wistar Faah mRNA vmPFC — 3 days —
2‐AG 100–150 mM of ethanol 48–72 hr In vitro Rat Sprague–Dawley Cell and medium extract Cereb ↑ — — Basavarajappa et al., 2000
Oral chronic intermittent 5–6 g·kg−1 alternate days 120 days + 2 days of withdrawal Ex vivo Mouse Swiss‐Wistar Tissue content HP ↑ 40 days ↑ Mitrirattanakul et al., 2007
7.2% v/v ethanol in liquid diet 10–15 days Ex vivo Rat Wistar Tissue content AMY — 3 hr None Rubio et al., 2007
CPu — 3 hr None
HyTh — 3 hr
Cereb None — —
Cortex None — —
HP None —
Limbic forebrain None — —
Midbrain ↓ — —
Striatum None — —
Chronic intermittent ethanol vapour 48 days every day Ex vivo Rat Male Wistar Mgll mRNA BLA ↓ 3 days ↓ Henricks et al., 2017
Female Wistar Mgll mRNA vmPFC — 3 days —
Male Wistar Dagla mRNA BLA ↓ 3 days ↓
Female Wistar Dagla mRNA vmPFC — 3 days —
Male Wistar 2‐AG BLA — 3 days —
Female Wistar 2‐AG vmPFC ↓ 3 days ↓
10 days every day 10 days every day Ex vivo Rat Male Sprague–Dawley 2‐AG BLA None — — Robinson et al., 2016
DAGL‐α protein BLA None — —
MAGL protein BLA None — —
Chronic intermittent ethanol vapour 21 days every day In vivo Rat Male Wistar Mgll mRNA CeA — 12 hr ↑ Serrano et al., 2018
Dagl mRNA CeA — 12 hr ↑
2‐AG dialysate CeA ↓ 12 hr ↓
7 days ↓
FAAH Chronic ethanol treatment (100–150 mM) 72 hr In vitro Rat Sprague–Dawley Activity and EC transport Cereb ↓ — — Basavarajappa et al., 2003
Forced vapour inhalation 72 hr Ex vivo Mouse Swiss‐Webster Activity Cortex ↓ — — Vinod et al., 2006
Alcohol dependent (patients/control) Lifetime Post‐mortem Human — Protein and activity NAc ↓ — — Vinod et al., 2010
CB1 Continuous forced vapour inhalation 72–96 hr Ex vivo Mouse Swiss‐Webster Binding and GTPγS binding Whole brain ↓ 24 hr None Basavarajappa, Cooper, & Hungund, 1998a; Basavarajappa & Hungund, 1999b
Cortex ↓ 24 hr None Vinod et al., 2006
HP ↓
Striatum ↓
Whole brain ↓
Chronic forced vapour inhalation (intermittent) 49 days Ex vivo Rat Wistar mRNA Cortex — 3 weeks ↑ Rimondini et al., 2002
7.2% v/v ethanol in liquid diet 10–15 days Ex vivo Rat Wistar mRNA and binding AMY — 3 hr None Gonzalez et al., 2002; Rubio et al., 2008
None — —
CPu — 3 hr None
None — —
HyTh None — —
Cereb None — —
Cortex — 3 hr None
None — —
HP None — —
NAc None — —
GP — 3 hr ↓
SN — 3 hr ↓
Forced consumption of ethanol (10%, v/v) 52 days Ex vivo Rat Wistar mRNA CPu ↓ — — Ortiz et al., 2004
Cortex None
HP Region dependent
HyTh ↓ — —
Operant ethanol self‐administration 10 days Ex vivo Rat msP mRNA AMY None — — Cippitelli et al., 2005
CPu ↓
Cortex None
HP None
Alcohol dependent (patients/control) Lifetime Post‐mortem Human — Protein and GTPγS NAc ↓ — — Vinod et al., 2010
Chronic, 5–6 g·kg−1 every other day (intermittent) 120 days Ex vivo Rat Sprague–Dawley Protein and mRNA HP ↓ 40 days ↑ Mitrirattanakul et al., 2007
Twice daily 4 g·kg−1 i.p. 10 days Ex vivo Mouse C57BL/6J Protein Cereb None — — Pava et al., 2012
Cortex None — —
HP None — —
HyTh ↓ — —
NAc None — —
Striatum None — —
VTA ↓ — —
Forced chronic ethanol consumption 7 days In vivo Rat Wistar PET imaging HP ↓ binding 7–14 days ↑ binding Ceccarini et al., 2013
CPu ↓ binding ↑ binding
OFC — ↓ binding
Chronic intermittent ethanol vapour 10 days every day Ex vivo Rat Male Sprague–Dawley Protein BLA ↓ — — Robinson et al., 2016

Abbreviations: 2‐AG, 2‐arachidonyl glycerol; AEA, anandamide; AMY, amygdala; BLA, basolateral amygdala; CB1, cannabinoid receptor 1; CeA, central amygdala; Cereb, cerebellum; CPu, caudate putamen; DAGL, DAG lipase; FAAH, fatty acid amide hydrolase; GP, globus pallidus; HP, hippocampus; HyTh, hypothalamus; MAGL, monoacylglycerol lipase; msP, marchigian Sardinian alcohol‐preferring; NAc, nucleus accumbens; NAPE‐PLD, N‐acylphosphatidylethanolamine‐specific PLD; OFC, orbitofrontal cortex; PFC, prefrontal cortex; SN, substantia nigra; vmPFC, ventromedial prefrontal cortex; VTA, ventral tegmental area.