Table 1.

Sex differences in animal models of investigator-administered METH.

Source	Experimental Paradigm	Result	Ref.
Swiss Webster mice	METH dose: 4 injections of 10 mg/kg, s.c. separated by 2 hr intervals.	↓ striatal DA in males.	Wagner et al. (1993)
Heterozygous, homozygous SOD-transgenic & Wild type mice	METH dose: 4 injections of 2.5 or 5.0 mg/kg, i.p, at 2 hr intervals.	Greater ↓ in striatal DA uptake in males. Reversal of ↓ of DA uptake in METH exposed transgenic females.	Hirata et al. (1996)
Sprague-Dawley rats	METH dose: Escalating METH doses, 0.1, 0.3, 1 & 3.0 mg/kg, i.p. for 4 days separated by 2 days Locomotor activity: Habituation using 30 min/day for 10 days, with saline injection & locomotor activity in chamber. Then rats received escalating doses of METH and were tested for locomotor activity for 30 min for 4 days, separated by 2 days.	↑ locomotion activity in females.	Schindler et al. (2002)
Sprague-Dawley rats	METH dose: 1.0 and 3.0 mg/kg, s.c. Pharmacokinetic experiment: Pretreatment with a single injection of METH (1.0 mg/kg, s.c) day 1. On days 3 and 6, respectively, rats received METH (1.0 and 3.0 mg/kg. i.v) in a 15 s bolus.	↑ percentage of METH metabolite (amphetamine) in urine of females (1.0 mg/kg).	Milesi- Hallé et al. (2005)
Sprague-Dawley rats	METH dose: A single injection of METH (1.0 mg/kg, s.c.). Locomotor activity: Habituation using 6 hr/day for 4 days. On day 1, rats received saline. Then, rats received METH every 3 days for a total of 19 days.	↑ locomotion and stereotypic behavior in females.	Milesi-Hallé et al. (2007)
CD-1 mice	METH dose: One injection of 20 mg/kg, i.p. or Two injections of 20 mg/kg, i.p using a 2 hr interval.	↑ DA levels in female striatum (20 mg/kg dose). ↑ depletion in the levels of DAT, DA and its metabolites in male striatum. ↑ BLC2 in male striatum. ↑ VMAT2 in female striatum. ↓ DAT binding in substantia nigra & VMAT2 in striatum of male. ↓ expression of IGF-1R & GPER1 in female striatum. ↓ in AKT (40 mg/kg) & GSK3β (20 mg/kg) in male striatum.	Bourque et al. (2011)
CD-1 mice	METH dose: One injection of 40 mg/kg, i.p. Brain was isolated 30 min, 1 day and 3 days post METH injection.	Greater ↓ in male striatal DA levels than females at day 3. ↓ striatal DOPAC levels in male all days. Greater ↓ in male striatal DAT binding than females at day 3. ↓ VMAT2 binding in male substantia nigra at day 3. ↑ AKT phosphorylation in female striatum at day 1. ↑ phosphorylation of GSKβ in female striatum at day 1 & 3. ↑ ERK 1 and 2 in female striatum at 30 min	Bourque et al. (2012)
Long Evans rats	METH dose: A single injection of METH (1.0 or 3.0 mg/kg, s.c.) Locomotor activity: Habituation to room for 30 min, followed by habituation to activity chamber for 30 min. Then, a saline Injection was given to test baseline behavior for 30 min. Finally, rat received METH and tested for locomotor activity for 2 hr.	↑ locomotion activity in females.	Pritchard et al. (2012)
Long Evans rats	METH dose: A single injection of METH (1.0 mg/kg, s.c.) Early life stress: Pups separated from mother for 180 min/day from PND 2–8. CPP paradigm: Habituation for 30 min on each day before CPP. CPP testing 30 min for 10 days; chamber habituation day 1, days 2–9 conditioning, day 10 preference test. Saline injections on days 2, 4, 6, and 8, METH injections on days 3, 5, 7, and 9. On day 10, rats were tested for CPP without METH.	Both sexes responded similar in conditioned place preference. ↑ locomotion and stereotypic behavior in females. Early life stress ↑ METH-induced locomotor activity in male rats.	Hensleigh and Pritchard (2014)
C57BL/6 J mice	METH dose: 4 injections × 7.5 mg/kg, s.c on PDN 30 and 31, 2 hr intervals. Open field: 10 min on PDN 41 & 62. Novel object recognition: Habituation for 2 days (PND 42–43 & 63–64), followed by 2 trials over 2 days (PND 44–45 & 65–66) for 10 min (5 min interval between trials 1 & 2; 24 hr interval between trials 2 & 3). Social Interaction: 5 min on PND 46 & 67. Porsolt forced swim test: 5 min on PND 47 & 68. Morris water maze: 2 sessions/day: each session is for three 60 s trials with a 10–15 min interval.	↑ depression-like behavior in adolescent males. ↓ vasopressin in PVN in adolescent males.	Joca et al. (2014)
Wistar rats	METH dose: A single injection of 1 mg/kg or 5 mg/kg, s.c. Pharmacokinetic experiment: a single injection of METH (1 mg/kg or 5 mg/kg, s.c), followed by euthanization of rats at various time points post-injection.	↑ plasma (1 mg/kg & 5 mg/kg) & brain (1 mg/kg) level of METH in female rats.	Rambousek et al. (2014)
C57BL/6 J mice	METH dose: A single injection of 1 mg/kg, i.p. Blood collected after 30, 70, or 120 min after injection. Rats were perfused 2 hr after the injection.	↑ glucocorticoid receptor in the hippocampus in males. ↑ plasma corticosterone in females.	Zuloaga et. al. (2014)
Sprague-Dawley rats	METH dose: 4 injections × 7.5 mg/kg, i.p, 2 h intervals. Rats were euthanized 8 days after METH exposure.	↓ 5-HT content in olfactory bulb of female rats.	McFadden and Vieira-Brock (2016).
BALB/c mice	METH dose: A single injection of 1 mg/kg or 4 mg/kg, s.c. Locomotor activity: Habituation for 60 min/day for 3 days. Then, a saline injection followed by a test for basal locomotor activity for 30 min. Mice were then injected with METH and locomotor activity was measured for 90 min	↑ locomotion behavior in females.	Ohia-Nwoko et al. (2017)
C57BL/6 J mice.	METH dose: Repeated injections of 5 mg/kg, i.p for 10 consecutive days. Tissues were collected 21 days after the last injection. Open-field test: 5 min on day 12. Light/dark box test: 5 min on day 14. Elevated plus maze: 5 min on day 16.	↑ plasma corticosterone in females.	Jacobskind et. al. (2018)
Sprague-Dawley rats	METH dose: 4 injections of 4 mg/kg, s.c. Novel object recognition: Habituation, 10 min for 3 day (After 3 days of METH injections). After that, 5 min to explore the object (7 days after METH injection); one hour later, rats were again placed into the same chambers for object recognition for 5 min	↑ striatal DAT levels in males. ↑ FosB in dSTR and NAc of males. Impaired object recognition memory in males.	Klambatsen et al. (2019)
Prairie vole (Microtus ochrogaster)	METH dose: A single dose of 0.2 mg/kg or 2.0 mg/kg, s.c. Open field: Habituation to the test room for 10 min, followed by a METH injection and open field test for 10 min 2nd test 48 h after 1st test. 3rd test after 30 min of 2nd test. Alloparental behavior: 24 hr after 3rd open field test, Prairie voles were tested for alloparental behaviors (entry into pup chambers) for 10 min	↑ locomotor activity in males. Males took longer time to enter the pup chamber. Females attacked the pups.	Perry et al. (2019)
Sprague-Dawley rats	METH dose: Escalating doses of 0.1, 0.32, 1.0, 3.2 mg/kg, i.p., after 15 min interval, once weekly for 6 weeks. Locomotor activity: Habituation for 30 min. Rats then received a saline injection 15 min before injections of escalating doses of METH or SKF 82958 (vehicle, 0.01, 0.032, 0.1, 0.32, 1.0, 3.2 mg/kg) every 15 min intervals. Rats were tested once weekly for 6 weeks.	↑ locomotion activity in females. Female displayed ↑ locomotion activity even after for 4–5 weeks of METH abstinence.	Ramos et al. (2020)
Heterozygous Nrg1 III transgenic and control wild type-like mice.	METH dose: 1, 1.5, 2 or 3 mg/kg, s.c., four testing days using Latin-Square design. CPP paradigm: Habituation on day 1 for 30 min. Mice were given METH (2 mg/kg, s.c) and tested for CPP for 30 min for 2–4 days. Open field: Habituation for 30 min. Mice were then placed in field arena for 30 min. This was followed by METH injections (1, 1.5 or 2 mg/kg, s.c) in Latin-Square design to test open field behaviors for 60 min Prepulse inhibition: Habituation for 5–10 min/day for 3 days + background noise of 70 dB. On the test day, mice were injected with a single dose of METH (2 or 3 mg/kg) and tested for Prepulse inhibition for 30 min	↑ locomotion behavior in female. ↓ anxiety-like behavior in female. ↑ negative impact of METH on prepulse inhibition in NRG1 mutant male. Mutant female ↓ sensitive to METH-induced locomotion METH-induced disruption of sensorimotor gating in female.	Chesworth et al. (2021)
Swiss Mice	METH dose: A single dose (0.1 mg/kg, i.p.) CPP paradigm: Habituation on day 1 for 30 min. On days 2 and 5, mice were injected with saline in the morning followed by a CPP test. In the afternoon, mice were injected with METH (0.1 mg/kg, i.p.) or saline and tested for CPP for 30 min	↑ locomotion behavior in female.	Cullity et al. (2021)
Wildtype C57Bl/6 & BDNF heterozygous mice.	METH dose: 1 mg/kg for 1st week, 2 mg/kg for 2nd week & 4 mg/kg for 3rd week for 5 days/week.	↓ 5-HT1A receptor binding in dorsal raphe nucleus of male. ↑ 5-HT transporter binding in dorsal raphe nucleus of female. ↓ tryptophan hydroxylase 2 in dorsal raphe nucleus of male.	Sepulveda et al. (2021)
Sprague-Dawley rats	METH dose: A single injection (1.0 mg/kg, s.c.) CPP paradigm: Pretest for 15 min on 1st day of each CPP test. CPP test for 30 min for 8 days, with rats being injected with METH and saline on alternate days. Acquisition of METH CPP: Test on 9th day for 30 min after rats were given Ro 63–1908 (0, 1.0, or 3.0 mg/kg; s.c.). Expression METH CPP: Test on 9th day for 30 min after rats were given Ro 63–1908 (0, 1.0, 3.0 or 10.0 mg/kg; s.c.).	Female showed ↑ vulnerability to METH-induced CPP. Ro 631908 (3.0 mg/kg) blocked acquisition of METH CPP in male rats.	Yates et al. (2021)

Abbreviation: METH, Methamphetamine; PND, Postnatal day; CPP, Conditioned place preference; dB, decibels; s.c., Subcutaneous; i.p., Intraperitoneal; i.v., Intravenous; hr, Hours; min, Minutes; sec, Seconds; mg/kg, milligram per kilogram; ↑, significantly increased; ↓, significantly decreased; PVN, Paraventricular nucleus of the hypothalamus; dSTR, Dorsal striatum; NAc, Nucleus accumbens; SOD, Superoxide dismutase; Nrg1, Neuregulin 1; BDNF, Brain-derived neurotrophic factor; DA, Dopamine; DAT, Dopamine transporter; BCL2, B-cell lymphoma 2; VMAT2, Vesicular monoamine transporter 2; IGF-1R, Insulin-like growth factor type 1 receptor; GPER1, G protein-coupled estrogen receptor 1; 5-HT, Serotonin/5-hydroxytryptamine; FosB, FBJ murine osteosarcoma viral oncogene homolog B; 5-HT1A, Serotonin 1A receptor; SKF 82958, D1 receptor agonist; Ro 631908, N-methyl-D-aspartate (NMDA) antagonist, ERK; extracellular signal-regulated kinases.