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. Author manuscript; available in PMC: 2022 Jun 1.
Published in final edited form as: Neurosci Biobehav Rev. 2022 Apr 20;137:104674. doi: 10.1016/j.neubiorev.2022.104674

Table 2.

Overview of animal models of METH self-administration and sex differences.

Source Experimental Paradigm Result Ref.
Wistar Rats METH SA: Automated priming, 1 hr/day for 6 days, followed by 6 hr/day
of METH SA until rats showed stable METH infusion for 4 consecutive days under FR1 schedule. Rats were then shifted to PR schedule until rats reached breaking point.
METH dose: 0.02 mg/kg/Inf.		 Female rats were more vulnerable and had increased METH intake. Roth andCarroll,(2004)
Long Evans Rats METH SA: 1 hr/day for a total of 7 days (FR1 schedule); then, LgA: 6 hr/day and ShA: 1 hr/day for a total of 14 days (FR1 schedule).
METH dose: 0.0175 mg/kg/Inf for females and 0.02 mg/kg/Inf for males.
Abstinence: 14 days; object recognition and object in place test: days 7 and 14.		 Increased METH intake and seeking in female rats.
Both sexes showed decreased object recognition memory in LgA group.		 Reichel et. al. (2012)
Long Evans Rats METH SA: 2 hr/day until rats reaching criterion of > 10 Inf for 5 days (FR1 schedule). A progressive ratio (PR) schedule was started: FR3 for 3 days and FR5 for the remaining days for a total of 14 days.
The animals were also treated with oxytocin (1 mg/kg, i.p).
METH dose: 0.0175 mg/kg/Inf for female & 0.02 mg/kg/Inf for male.
Extinction session: 2 hr/day for total of 9 days.
Reinstatement Tests: Oxytocin (0, 0.3, or 1 mg/kg, i.p) followed by re-instatement test; 1. Cue-induced: 2 hr on 1 day; 2. METH-primed (1 mg/kg, i.p): 2 hr on 1 day; 3. Yohimbine-induced (2.5 mg/kg, i.p): 2 hr on 1 day.		 Oxytocin decreased motivation for METH SA in females only. Cox et. al. (2013)
Sprague Dawley Rats METH SA: 90 min/day for a total of 14 days (FR1 schedule).
METH dose: 0.08 mg/kg/Inf.
Abstinence: 14 days; Cue-induced reinstatement: 90 min on day 15.		 Increased METH intake in males. Ruda- Kucerova et. al. (2015)
Sprague Dawley Rats METH SA: 2 hr/day for 5 day at FR1, day 6 at FR3, day 7 – 9 at FR10, day 10 – 12 at FR32 & day 13 at FR100.
METH Dose: 0.0175 mg/kg/Inf for female & 0.02 mg/kg/Inf for male.
BE stabilization: 2 hr/day from day 14 – 18. BE testing: 2 h/day from day 19 – 32, counterbalanced manner.
1. Oxytocin effect (Microinfusions of 0.6 μg/side, bilateral in NAc; unilateral intracerebroventricular infusion).
2. Systemic oxytocin (1 mg/kg, i.p) + oxytocin antagonist (microinfused 1 μg/side bilateral in NAc and unilateral intraventricular infusion).
Extinction sessions: 2 hr/day for total of 7 days; Cue induced reinstatement: 2 hr/day for 10 days + oxytocin (1 mg/kg, i.p).		 Increased METH demand in females.
Effects of oxytocin were Similar on both sexes.		 Cox et. al. (2017)
Sprague Dawley rats METH SA: 2 hr/day for 5 day at FR1, 3 days at FR3 & 5 days for FR5.
METH Dose: 0.0175 mg/kg/Inf for female & 0.02 mg/kg/Inf for male.
Extinction sessions: 2 hr/day for total of 8 days; Cue-induced reinstatement: 2 hr/day on test day (1. Systemic administration of LY341395 (1 mg/kg) + oxytocin (1 mg/kg, i.p); 2. Microinfusions of oxytocin (0.6 nmol/0.25 μl/side) + LY341395 (1.3 nmol/0.25 μ/side) in NAc).		 No sex differences in METH intake.
Oxytocin decreased METH seeking in both sexes, with mGluR2/3 agonist reversing the effects.		 Bernheim et. al. (2017)
Sprague Dawley rats Food SA: 14 hr/day for total of 4 days before surgery.
METH SA: 8 hr/day for total of 7 days (FR1 schedule).
METH Dose: 0.09 mg/kg/inf for female & 0.12 mg/kg/inf for male.		 No sex differences in METH intake.
METH increased BDNF in Male HIP.		 JohansenandMcFadden, (2017)
Sprague Dawley rats Food SA: 6 hr/day for a total of 6 days.
METH SA: 6 hr/day for a total of 12 days (FR1 schedule).
METH dose: 0.1 mg/kg/inf.
Extinction sessions: Days 1 (30 min) & day 21 (2 hr).		 Steeper escalation of METH in males.
No differences in METH seeking.		 Venniro et. al. (2017)
Baboon monkey METH SA: 60 min/day for a total of 5 months (8–10 aerosol deliveries/day) (FR1 schedule). Availability of next puff 2 min for males, 1 min for females.
METH dose: Vaporized 0.3 mg/kg/puff.		 Male baboons had higher METH puffing. Foltin, (2018)
Sprague Dawley rats METH SA: Operant chamber exploration, 90 min on day 1. METH SA on next day 2, 2 hr/day for a total of 15 days (7 days at FR1, 4 days at FR3 & 4 days at FR5).
METH dose: 0.02, 0.05, or 0.08 mg/kg/inf.
Progressive ratio testing (PR): 0.08 mg/kg/inf used in trained rats tested in PR test on 0.02, 0.05, 0.08 and 0.1 mg/kg/inf for 5 hr/day session until breaking point.		 Female acquired more METH at 0.08 mg/kg dose. Hankosky et. al. (2018a)
Sprague Dawley rats METH SA: Operant chamber exploration, 90 min on day 1. Next day SA, 2 hr/day for total of 15 days (7 days at FR1, 4 days at FR3 & 4 days at FR5).
METH dose: 0.02, 0.05, or 0.08 mg/kg/inf.
Strategy Shifting: 23 days.		 Female required more trial & committed more errors during discrimination & reversal learning behavior.
Male had ↑ 5-HT2-CR within PV-INs & in OFC.		 Hankoskyet al. (2018b)
Sprague Dawley rats Food SA: 14 hr/day for total of 4 days before surgery.
METH SA: 8 hr/day for total of 7 days (FR1 schedule). After that DOI test.
METH Dose: 0.09 mg/kg/Inf females and 0.12 mg/kg/Inf for male.
DOI testing: On day 8 rats were injected with serotonin 2 A/2 C agonist (2 mg/kg, i.p.) to measure head twitched behavior.
Extinction sessions: 2 hr/day for total of 10 days. DOI testing on day 11.		 No differences in METH intake & seeking behavior.
Females had increased DOI-induced head twitches after METH SA & extinction.
METH decreased 5-HTT in male ILC.		 McFaddenet al.(2018)
Long Evans rats METH SA: 6 hr/day for total of 14 days (FR1 schedule).
METH dose: 0.05 mg/kg/inf.
Progressive Ratio: 6 hr/day for total of 20 days with increasing PR ratio
till breaking point.
Extinction session: 1 hr for total of 6 days; Cue-induced reinstatement: 1 hr on day 7.		 Female had higher METH intake & GluN2A/2B ratio in the DG.
Male showed increased METH seeking & CaMKII, choline acetyltransferase in the DG.		 Takashima et. al. (2018)
Sprague Dawley rats Food SA: 14 hr/day for total of 5 days before surgery.
METH SA: 8 hr/day for total of 7 days (FR1 schedule).
METH Dose: 0.09 mg/kg/Inf female & 0.12 mg/kg/Inf for male.
Extinction sessions: 2 hr/day from day 6–17; METH-primed reinstatement (1 mg/kg, ip): 2 hr on day 18 (optogenetic inhibition); Extinction: 2 hr/day from day 19–23; METH-primed reinstatement (1 mg/kg, i.p): 2 hr on day 24 (optogenetic inhibition).		 No differences in METH intake & in extinction behavior. Females increased METH seeking behavior during METH primed reinstatement in laser off condition. Cordie and McFadden, (2019)
Long Evans rats METH SA: 6 hr/day (30 min break after 3 hr) for total of 20 day (FR1 schedule).
METH dose: 0.1 mg/kg/Inf.
METH seeking test: 3 hr/day on withdrawal 3 & 30.		 Increased METH intake in males. No differences in seeking behavior.
Female rats had higher basal mRNA levels of Pdyn & Hcrtr1 in NAc, PFC & HIP; also higher basal mRNA levels of Hcrtr2 and Avpr1a in NAc & Crhr1, Crhr2, Hcrtr2 and Oprk1 in the PFC.
Males has higher Avp mRNA in NAc & Crh and Crhr1 in HIP.		 Daiwile et. al. (2019) and (2021)
Sprague Dawley rats METH SA: 6 hr/day for total of 14 days (FR1 schedule). METH dose: 0.05 mg/kg/Inf.
Abstinence: 9–14 day.		 No differences in METH intake. METH SA increased the amplitude of eEPSCs only in female rats. Pena- Bravo et. al. (2019)
Sprague Dawley rats METH SA: 2 hr/day for total of 12 days (FR1 schedule). After that LgA: 6 hr/day & ShA: 2 hr/day for total of 10 days (FR1 schedule).
METH dose: 0.1 mg/kg/Inf.
Abstinence: 30 days. Cue-induced: 1 hr /day on day 2 and days 6–20 with oxytocin treatment (1 mg/kg, i.p); EMP/SIT testing 1 hr from days 25–28; Cue-induced: 1 hr/day on day 30; METH-primed (0.3 or 1.0 mg/kg, i.p) or yohimbine (0.625 or 1.25 mg/kg, i.p) for 1 hr on day 31.		 No differences in METH intake.
ShA female showed increased METH seeking behavior.
Female showed increased locomotor hyperactivity.		 Everettet al. (2020)
Long Evans rats METH SA: 6 hr/day (30 min break after 3 hr) for total of 20 day (FR1 schedule).
METH dose: 0.1 mg/kg/Inf.
CNO testing (chemogenetic inhibition of D1R in dSTR): CNO (1 mg/kg, i.p, 30 min) + 6 hr/day METH SA total of 4 days (FR1 schedule) in counterbalance method.		 Males acquire METH at faster rate than females. Inhibition of Drd1 in the dorsal striatum had no effect on METH intake in both sexes. Job et. al. (2020)
Sprague Dawley rats METH SA: Operant chamber exploration, 90 min on day 1. Next day SA, 2 hr/day for total of 7 days (FR1 schedule), followed by LgA: 6 hr/day for total of 14 days (FR1 schedule).
METH dose: 0.1 mg/kg/Inf.
Extinction session: 4 days of 30 min/day extinction with Ro256981 (6 mg/kg, i.p.); 4 days of 2 hr/day extinction without Ro256981; followed by METH-primed reinstatement (1 mg/kg, i.p): 2 hr on day 9.		 No differences in METH intake.
Female showed increased METH seeking behavior.
Effect of GluN2B antagonist on drug seeking behavior was similar in both sexes.		 Westbrook and Gulley, (2020)
Sprague Dawley rats METH SA: Operant chamber exploration, 90 min on day 1. Next day SA, 2 hr/day for total of 7 days (FR1 schedule), followed by LgA: 6 hr/day for total of 14 days (FR1 schedule).
METH dose: 0.1 mg/kg/Inf.
Abstinence: 21 days; cognitive testing on day 7 & 14 days.		 Females begin to increase METH intake earlier.
No differences in the protein level of Drd1, GluN1, GluN2B in PFC and NAc of rats.		 Westbrook et. al. (2020)
C57/Bl6 mice Voluntary oral METH SA: 0.25 mg/kg, 1 dose/day for 3 days; followed by 4 doses/day for 3 days; followed by 16 doses/day for 2 days; followed by 16 doses/day at 0.5 mg/kg for 2 days. Which is followed by 16 doses/day at 1 mg/kg from day 11–28.
METH dose: 0.25 mg/kg, 0.5 mg/kg and 1 mg/kg.		 No differences in METH intake.
Females showed increased locomotor hyperactivity.
Increased Oprk1 & decreased PKMζ level in HIP.		 Avila et al. (2021)
Sprague Dawley rats Sucrose training: 60–80 min (till 60 sucrose deliveries) for total of 3 days before surgery. After that,
METH SA: 2 hr/day for total of 21 days (FR1 schedule).
METH dose: 0.05 mg/kg/inf.
Extinction session: 2 hr/day for total of 12 days; after that METH-primed reinstatement (0.3 mg/kg, i.p): 70 min/day.		 No differences in METH intake. Females had increased seeking Behavior in METH-primed reinstatement.
Greater increases in c-Fos expression in cortex, amygdala, dorsal & ventral striatum of females.		 Pittenger et al. (2021)
Wistar rats METH SA: 6 hr/day (40 inf/day) for total of 5 days, followed by SA 2 hr/day for total of 5 days (FR1 schedule).
METH dose: 0.05 mg/kg/inf.
Extinction session: 2 hr per day for a total of 10 days; Cue-induced reinstatement and METH-primed reinstatement (1 mg/kg, i.p): 2 hr on each test day with or without Hcrtr1 antagonist (SB-334867, 20 mg/kg) and Hcrtr2 antagonist (TCS-OX2–29, 20 mg/kg, i.p).		 Male showed increased METH intake. Females showed more active lever responses on WD2.
Males showed active lever responses on WD4 and WD6.
Both sexes adolescent presence of SB-334867 and adult in presence of TCS-OX2–29 had decreased METH primed reinstatement.		 Zlebnik et al. (2021)

Abbreviation: METH, Methamphetamine; SA, Self-administration; BE, Behavioral economic; LgA, Long access; ShA, Short-Access; WD, Withdrawal day; PR, progressive ratio; FR, Fixed ratio; mg/kg/inf, milligram per kilogram per infusion; μg, Microgram; μl, Microliter; nmol, nanomole; hr, Hours; min, Minutes; i.p., Intraperitoneal; PFC, Prefrontal cortex; OFC, Orbitofrontal cortex; ILC, Infralimbic cortex; NAc, Nucleus accumbens; HIP, Hippocampus; DG, Dentate gyrus; PV-INs, Parvalbumin interneurons; mRNA, Messenger RNA; mGluR2/3, Metabotropic glutamate receptor 2/3; BDNF, Brain-derived neurotrophic factor; 5-HT2-CR, Serotonin 2 C receptors; 5-HTT, Serotonin transporter; GluN1, Glutamate receptor subunit zeta-1; GluN2A/2B, Glutamate receptor subunit epsilon-1/2; CaMKII, Calcium/calmodulin-dependent protein kinase II; Pdyn, Prodynorphin; Oprk1, Opioid receptor kappa 1; Hcrtr1, Hypocretin Receptor 1 and 2; Hcrtr2, Hypocretin Receptor 2; Avp, Arginine vasopressin; Avpr1a, Arginine vasopressin receptor 1 A; Crh, Corticotropin releasing hormone; Crhr1, Corticotropin releasing hormone receptor 1; Crhr2, Corticotropin releasing hormone receptor 2; Drd1, Dopamine receptor D1; PKMζ, protein kinase M zeta; LY341395, Group II mGlu receptor antagonist; Ro256981, NMDA receptors GluN2B antagonist; DOI, Dimethoxy-4-iodoamphetamine; eEPSCs, Evoked excitatory postsynaptic currents.