Table 1.
Neural adaptations beyond 24-h withdrawal from extended access Meth self-administration
| Brain region | SA procedure (dose) | Withdrawal day | Technique | Specific molecular targets | Major findings | Citation |
|---|---|---|---|---|---|---|
| Forced abstinence | ||||||
| SNC/VTA | 9 h/d × 10 d (0.1 mg/kg/inf) | WD 30 | ISH | DAT | ─/─ | Shepard et al., 2006 |
| TH | ─/─ | |||||
| WB | TH | ─/─ | ||||
| CPu | WB | TH | ─ | |||
| NAc | ─ | |||||
| SN | ─ | |||||
| Striatum | 8 h/d × 7 d (0.06 mg/ml/inf) | WD 30 | [3H]DA uptake assay | DAT | ▼ | McFadden et al., 2012 |
| VMAT2 | ─ | |||||
| 8 h/d × 7 d (0.12 mg/ml/inf) | DAT | ▼ | ||||
| 8 h/d × 7 d (0.24 mg/ml/inf) | WB | DAT | ▼ | |||
| DS | 1 h/d × 6 d, then 6 h/d × 22 d (0.05 mg/kg/0.1 ml inf) | WD 3 | WB | DAT | ▲ | D’Arcy et al., 2016 |
| TH | ─ | |||||
| D2R | ─ | |||||
| Striatum | 15 h/d × 8 d (0.1 mg/kg/inf) | WD 7/14 | HPLC analysis | DA | ▼/▼ | Krasnova et al., 2010 |
| DOPAC | ▼/─ | |||||
| HVA | ▼/─ | |||||
| NE | ─/─ | |||||
| 5-HT | ▲/─ | |||||
| 5-HIAA | ─/─ | |||||
| WD 7 | WB | GFAP | ▲ | |||
| WD 14 | WB | TH | ▼ | |||
| DAT | ▼ | |||||
| 5-HTT | ─ | |||||
| Cortex | WD 7/14 | HPLC analysis | DA | ─/▼ | ||
| DOPAC | ─/─ | |||||
| NE | ─/─ | |||||
| 5-HT | ─/─ | |||||
| 5-HIAA | ─/─ | |||||
| WD 7 | WB | GFAP | ▲ | |||
| WD 14 | WB | TH | ▼ | |||
| DAT | ▼ | |||||
| 5-HTT | ─ | |||||
| DS | 15 h/d × 8 d (0.1 mg/kg/inf) | ~WD 30 | HPLC analysis | DA | ▼ | Krasnova et al., 2013 |
| DOPAC | ─ | |||||
| qPCR/WB | Drd1/D1R | ─/─ | ||||
| Drd2/D2R | ─/▼ | |||||
| cfos /cFos | ─/▼ | |||||
| Fosb/FosB | ─/─ | |||||
| ΔFosb/ΔFosB | ─/▼ | |||||
| Bdnf/BDNF | ─/▼ | |||||
| Trkb/TrkB | ─/▼ | |||||
| WB | CREB | ▼ | ||||
| pCREB | ▼ | |||||
| ChIP | H3K4me3 | ─ | ||||
| DS | 9 h/d × 10 d (0.1 mg/kg/inf) | WD 2/35 (whole cell extracts) /WD30–50 (Fos-positive cells) | qPCR (whole cell extracts for WD2/35, compared with saline; Fos-positive cells for WD 30–50 relapse tests, compared with Fos-negative cells in Meth rats) | Bdnf | ─/─/▲ | Li et al., 2015d |
| TrkB | ─/─/▲ | |||||
| Gria1 | ─/─/▲ | |||||
| Gria2 | ─/─/▼ | |||||
| Gria3 | ─/─/▲ | |||||
| Grin1 | ─/─/─ | |||||
| Grin2a | ─/─/▲ | |||||
| Grin2b | ─/─/─ | |||||
| Grm1 | ─/─/▲ | |||||
| Grm5 | ─/─/─ | |||||
| Hdac1 | ─/─/─ | |||||
| Hdac2 | ─/─/─ | |||||
| Hdac3 | ─/─/▲ | |||||
| Hdac4 | ─/─/▲ | |||||
| Hdac5 | ─/─/▲ | |||||
| Sirt1 | ─/─/─ | |||||
| Sirt2 | ─/─/─ | |||||
| Crebbp | ─/─/─ | |||||
| Suv39h1 | ─/─/─ | |||||
| G9a | ─/─/─ | |||||
| GLP | ─/─/▲ | |||||
| Kdm1a | ─/─/▲ | |||||
| Mil1 | ─/▲/─ | |||||
| Dnmt3a | ─/─/▲ | |||||
| CeA | 9 h/d × 10 d (0.1 mg/kg/inf) | WD 2/35 | RNA-seq | DEGs | ─ (215) /▲ (2217) | Cates et al., 2018 |
| OFC | ▲ (118) / ─ (55) | |||||
| qPCR | Dcn | ▲/▼ | ||||
| Col3a1 | ▲/▼ | |||||
| Henmt1 | ─/─ | |||||
| NAc | 3 h/d × 20d (0.1 mg/kg/inf) | WD 30 | qPCR (male/female rats) | Pdyn | ▲/─ | Daiwile et al., 2019 |
| Hcrtr1 | ─/─ | |||||
| Hcrtr2 | ▼/▼ | |||||
| Crh | ▼/▼ | |||||
| Crhr1 | ─/─ | |||||
| Crhr2 | ▲/─ | |||||
| Avp | ▼/─ | |||||
| Avpr1a | ▼/▼ | |||||
| Avpr1b | ▼/▼ | |||||
| DMS/AIT | 6 h/d × 10 d (0.1 mg/kg/inf) | WD 30 (after the 2-h relapse test) | qPCR (Fos-positive cells, different from Fos-negative cells) | Bdnf | ─/─ | Li et al., 2019 |
| TrkB | ▲/▲ | |||||
| Gria1 | ─/─ | |||||
| Gria2 | ─/─ | |||||
| Gria3 | ▲/─ | |||||
| Grin1 | ▲/▲ | |||||
| Grin2a | ─/─ | |||||
| Grin2b | ▲/─ | |||||
| Grm1 | ▲/─ | |||||
| Grm5 | ─/─ | |||||
| Hdac1 | ─/─ | |||||
| Hdac2 | ─/─ | |||||
| Hdac3 | ▲/─ | |||||
| Hdac4 | ─/─ | |||||
| Hdac5 | ▲/▲ | |||||
| Sirt1 | ─/─ | |||||
| Sirt2 | ─/─ | |||||
| Crebbp | ▲/─ | |||||
| Suv39h1 | ─/─ | |||||
| G9a | ─/─ | |||||
| GLP | ─/─ | |||||
| Kdm1a | ─/─ | |||||
| Mll1 | ─/─ | |||||
| Dnmt3a | ─/─ | |||||
| PRh | 1 h/d × 7 d, then 6 h/d × 14 d (20 μg/50 μl/inf) | WD 8/14 | WB | mGlu2/3 | ─/─ | Reichel et al., 2011 |
| mGlu5 | ─/▼ | |||||
| HPC | mGlu2/3 | ─/─ | ||||
| mGlu5 | ─/─ | |||||
| PFC | WD 8 | mGlu2/3 | ─ | |||
| mGlu5 | ─ | |||||
| PFC | 1 h/d × 7 d, then 6 h/d × 14 d (20 μg/50 μl/inf) | WD 14 | WB (* surface, # total) | mGlu2/3 | ▼* | Schwendt, et al., 2012 |
| mGlu7 | ▼* | |||||
| NAc | mGlu2/3 | ▼*# | ||||
| mGlu7 | ─ | |||||
| DS | mGlu2/3 | ▼*# | ||||
| mGlu7 | ─ | |||||
| PRh/HPC/PFC | 1 h/d × 7 d, then 6 h/d × 14 d (20 μg/50 μl/inf) | WD 7 | WB | GluN1 | ─/─/─ | Reichel et al., 2014 |
| GluN2a | ─/─/─ | |||||
| GluN2b | ▼/─/─ | |||||
| PRh | 1 h/d × 7 d, then 6 h/d × 14 d (20 μg/50 μl/inf) | WD 7 | Capillary electrophoresis | GluN1 (surface) | ─ | Scofield et al., 2015 |
| GluN1 (intracellular) | ─ | |||||
| GluN2b (surface) | ▼ | |||||
| GluN1 (intracellular) | ─ | |||||
| mPFC/HPC/PRh | 1 h/d × 7 d, then 6 h/d × 14 d (20 μg/50 μl/inf) | WD 7 | WB | 5HT2A | ▲/─/▲ | Hamor et al., 2019 |
| mGlu2 | ─/─/─ | |||||
| Gq | ▲/─/▲ | |||||
| Gi | ─/─/─ | |||||
| Go | ─/─/─ | |||||
| NAc | 6 h/d × 10 d (0.1 mg/kg/inf) | WD 3/21/48 | WB | GluA1 (surface) | ─/─/─ | Murray et al., 2019 |
| GluA1 (total) | ─/─/─ | |||||
| GluA2 (surface) | ─/─/─ | |||||
| GluA2 (total) | ─/─/─ | |||||
| GluA3 (surface) | ─/─/─ | |||||
| GluA3 (total) | ─/─/─ | |||||
| mGlu1 (surface) | ─/─/─ | |||||
| mGlu1 (total) | ─/─/─ | |||||
| Homer1b/c | ─/─/─ | |||||
| Homer2 | ─/─/─ | |||||
| WD 30 | Puromycin IP | GluA1 | ▲ | |||
| GluA2 | ─ | |||||
| mPFC | 1 h/d × 7 d, then 6 h/d × 14 d (20 μg/50 μl/inf) | WD 8 | Electrophysiology (sEPSCs) | AMPA/NMDA | ▼ | Mishra et al., 2017 |
| PPR | ─ | |||||
| Avg. frequency | ─ | |||||
| Avg. amplitude | ─ | |||||
| NMDA (current amplitude) | ▲ | |||||
| AMPA (current amplitude) | ─ | |||||
| Capillary electrophoresis | GluN2b | ▲ | ||||
| NAc | Electroph7ysiology (sEPSCs) | PPR | ▼ | |||
| Avg. frequency | ▲ | |||||
| Avg. amplitude | ─ | |||||
| PL | 6 h/d × 14 d (0.05 mg/kg/inf) | WD 9–14 | Electrophysiology (sEPSCs, males/females) | Amplitude | ─/─ | Pena-Bravo et al., 2019 |
| Frequency | ─/─ | |||||
| Rise | ─/─ | |||||
| Decay | ─/─ | |||||
| Electrophysiology (eEPSCs, males/females) | Amplitude | ─/▲ | ||||
| Decay | ▼/─ | |||||
| NMDA current | ─/▲ | |||||
| HPC | 1 h/d × 8–10 d, then 6 h/d × 22d (0.05 mg/kg/inf) | WD 29 | IHC | BrdU | ─ | Recinto et al., 2012 |
| Ki-67 | ▲ | |||||
| Fos | ─ | |||||
| mPFC/NAc | Fos | ─/─ | ||||
| Punishment-induced abstinence | ||||||
| NAc/Striatum | 9 h/d × 20 d (0.1 mg/kg/inf) | WD 35 (5 d punishment, 30 d forced abstinence) | qPCR (SR) (*relative to yoked-SR shock saline control, # relative to no-shock saline control) | Oxt | ▲*#/─ | Krasnova et al., 2017 |
| OxtR | ▲#/─ | |||||
| CARTpt | ─/▲*# | |||||
| FMO2 | ─/▼* | |||||
| PDK4 | ▼*▲#/▼*# | |||||
| PTPRO | ▼*/▼* | |||||
| qPCR (SS) (*relative to yoked-SS shock saline control, # relative to no-shock saline control) | Oxt | ─/─ | ||||
| OxtR | ▲#/─ | |||||
| CARTpt | ─/─ | |||||
| FMO2 | ─/─ | |||||
| PDK4 | ▲#/─ | |||||
| PTPRO | ▲#/─ | |||||
| DS | 9 h/d × 22 d (0.1 mg/kg/inf) | WD 43 (13 d punishment, 30 d forced abstinence) | PCR array (SS relative to SR) | Bdnf | ▲ | Torres et al., 2018 |
| Gdnf | ─ | |||||
| Ngf | ▲ | |||||
| Vgf | ▲ | |||||
| Ntf3 | ▲ | |||||
| Trka | ─ | |||||
| Trkb | ─ | |||||
| Gfra1 | ▲ | |||||
| Gfra2 | ▲ | |||||
| Ngfr | ─ | |||||
| Crh | ▲ | |||||
| Crhr1 | ▲ | |||||
| Crhr2 | ─ | |||||
| Crhpb | ▲ | |||||
| Ucn | ─ | |||||
| qPCR (SR/SS) (relative to saline control) | Bdnf | ─/▲ | ||||
| Ngf | ─/─ | |||||
| TrkA | ─/▼ | |||||
| TrkB | ─/─ | |||||
| Gfra2 | ─/▲ | |||||
| Crh | ─/─ | |||||
| Crhr1 | ─/▲ | |||||
| Crhr2 | ─/─ | |||||
| Crhbp | ─/▲ | |||||
| Ucn2 | ─/▲ | |||||
| Cfos | ▲/▲ | |||||
| Fosb | ─/─ | |||||
| Egr1 | ▲/─ | |||||
| Egr2 | ▲/─ | |||||
| Egr3 | ─/─ | |||||
| WB (SR/SS) (relative to saline control) | proBDNF | ▼/▼ | ||||
| mature BDNF | ▲/▲ | |||||
| TrkB | ─/─ | |||||
| pTrkB | ─/─ | |||||
| proNGF | ─/─ | |||||
| mature NGF | ▲/▲ | |||||
| TrkA | ─/─ | |||||
| pTrkA | ─/▲ | |||||
| p75NTR | ─/▲ | |||||
| Sortilin | ─/─ | |||||
| pc-Raf | ─/─ | |||||
| pMek1/2 | ▲/▲ | |||||
| pErk1/2 | ─/─ | |||||
| pMSK1 | ─/▲ | |||||
| pCREB | ─/▲ | |||||
| pmTOR | ─/▲ | |||||
| H3ac | ─/▲ | |||||
| pMeCP2 | ─/▲ | |||||
| OFC→DMS | 9 h/d × 20 d (0.1 mg/kg/inf) | WD 35 (5 d punishment, 30 d forced abstinence) | fMRI (SR/SS) (compared to saline control) | Resting state functional connectivity | ─/─ | Hu et al., 2019 |
| PL→VLS | ─/─ | |||||
Comparisons are made in reference to saline controls unless otherwise stated in the table.
Abbreviations: 5-HIAA: 5-hydroxyindoleacetic acid; 5-HT: 5-hydroxytryptamine; CeA: central amygdala; CPu: caudate putamen; DA: dopamine; DAT: dopamine transporter; DMS: dorsomedial striatum; DOPAC: 3,4-dihydroxyphenylacetic acid; DS: dorsal striatum; HPC: hippocampus; HVA: homovanillic acid; GFAP: glial fibrillary acidic protein; mPFC: medial prefrontal cortex; NAc: nucleus accumbens; NE: norepinephrine; OFC: orbitofrontal cortex; PFC: prefrontal cortex; PL: prelimbic cortex; PRh: perirhinal cortex; SN: substantia nigra; SNC: substantia nigra pars compacta; SR: shock resistant; SS: shock sensitive; TH: tyrosine hydroxylase; VLS: ventrolateral striatum; VTA: ventral tegmental area; IHC: immunohistochemistry; DEG: differentially expressed genes; ISH: in situ hybridization; ChIP: chromatin immunoprecipitation; HPLC: high performance liquid chromatography; EPSC: excitatory postsynaptic currents; eEPSC: evoked EPSC; sEPSC; spontaneous EPSC; IP; immunoprecipitation; PPR: paired-pulse ratio; WB: western blot; WD: withdrawal day. Symbols: (▲): increase; (▼): decrease; (─): no change