Table 2.

Preclinical studies examining the antidepressant-like effects of SSRIs (2A), effect of chronic SSRI treatment on SERT expression (2B), and age-dependent shifts in SERT expression (2C) in juvenile and adolescent rodents, compared to adults.

A: Behavioral outcomes from studies of antidepressant-like activity
Age	Species	Strain	Sex	Drug	Dose/duration	Assay	Outcome	Reference
Behavioral studies – acute administration
P21 compared with adult (age not specified)	Rat	Sprague-Dawley	Male	Escitalopram (ESC) Desipramine (DMI) Fluoxetine (FLX) Imipramine (IMI)	1–20 mg/kg 1–20 mg/kg 0.1–10 mg/kg 0.1–10 mg/kg Drugs given ip 23 h, 5 h, and 1 h prior to FST	FST	FLX and ESC produced similar, dose-dependent antidepressant-like effects in P21 and adults rats, however, DMI and IMI were without effect in both ages. Both ESC and DMI produced antidepressant-like effects in adult rats (FLX and IMI were not tested in adults).	Reed et al., 2008
P21 and P28 compared with P90	Mouse	C57BL/6J	Male and Female	Escitalopram (ESC) Desipramine (DMI)	10 mg/kg, sc 32 mg/kg, ip Drugs given 30 min prior to test	TST	Antidepressant-like effects were observed in all ages. However, ESC was less effective in P21 mice compared to P28 and P90 mice. No sex differences.	Mitchell et al., 2013
P21 and P28 compared with P90	Mouse	C57BL/6J SERT+/+ SERT+/- SERT-/-	Male and Female	Escitalopram (ESC)	0.32–10 mg/kg, sc, given 30 min prior to test	TST	Antidepressant-like effects were observed in all ages. Maximal effects were less in P21 mice than in P90 mice, and more so in SERT+/- mice. The potency for ESC to produce antidepressant-like effects in SERT+/+ and SERT+/- mice was greater in P21 and P28 mice than in adults. No effect of ESC in SERT-/- mice. No sex differences.	Mitchell et al., 2016
P28 compared with P84, P168, and P280	Mouse	Swiss	Male	Citalopram (CIT) Paroxetine (PRX) Imipramine (IMI) Desipramine (DMI) Bupropion (BUP) Moclobemide (MOC)	2–32 mg/kg 1–8 mg/kg 4–32 mg/kg 2–16 mg/kg 4–64 mg/kg 8–128 m/kg Drugs given ip 30 min prior to test	FST	At low doses, CIT and PRX reduced immobility time in P280 mice, but not younger mice. At higher doses, CIT and PRX were inactive in P280 mice, but active in younger mice. IMI, DMI and BUP reduced immobility in all age groups. MOC reduced immobility only at the highest dose, and only in P84 mice.	Bourin et al., 1998
P28 compared with P280	Mouse	Swiss	Male	Fluvoxamine (FLV) Sertraline (SER) Venlafaxine (VEN) Imipramine (IMI) Maprotiline (MAP)	4–16 mg/kg 8–32 mg/kg 4–16 mg/kg 8–32 mg/kg 8–32 mg/kg Drugs given ip 30 min prior to test	FST	At higher doses, all antidepressants were effective in both ages, with the exception of FLV in P280 mice. Reduction in time spent immobile was greater in P28 mice than P280 mice following SER, IMI and MAP.	David et al., 2001
P35 compared with P84–91	Mouse	C57BL/6J F2 BALB/cJ	Male	Fluoxetine (FLX) Imipramine (IMI)	10 and 20 mg/kg 10 and 30 mg/kg Drugs given ip 30 min prior to TST, and 24 h, 18 h, and 1 h prior to FST.	TST and FST	FLX produced an antidepressant-like effect in F2 and C57 P35 and adult mice but not BALB/cJ P35 and adult mice in the TST. In the FST, FLX produced an antidepressant-like effect in adult mice of all strains, however, only in F2 juvenile mice. IMI produced an antidepressant-like effect across all strains and ages of mice in both tests.	Mason et al., 2009
Behavioral studies – chronic administration
P21 and P28 compared with adult (age not specified)	Rat	Sprague-Dawley	Male	Escitalopram (ESC) Desipramine (DMI)	10 mg/kg 3–15 mg/kg All drugs administered ip twice per day for 7 days	Inescapable shock and shuttle box test	ESC produced an antidepressant-like effect in all ages. DMI did not produce an effect in P21 rats, but did in P28 and adult rats.	Reed et al., 2009
P25 compared with P65	Rat	Wistar	Male	Fluoxetine (FLX)	5 mg/kg, ip for 3 weeks with a 1 week washout	FST	No antidepressant-like effect in either age.	Bouet et al., 2012
P25–49 compared with P67–88 at start of treatment	Rat	Wistar	Male	Fluoxetine (FLX)	12 mg/kg, oral gavage for 21 days	FST, 10 days after last dose.	FLX increased immobility time in adolescents, and had no effect in adults.	Homberg et al., 2011
P28–49 compared with P70–91	Rat	Wistar	Male	Paroxetine (PRX)	5 and 10 mg/kg, drinking water for 18 days	FST	PRX did not produce an antidepressant-like effect in adolescent rats, however, it did in adult rats.	Karanges et al., 2011
B: SERT expression after chronic SSRI treatment
Age	Species	Strain	Sex	Drug	Dose and Duration	Assay	Outcome	Reference
P25 compared with P50	Rat	Wistar	Male	Fluoxetine (FLX)	5 mg/kg, drinking water for 2 weeks	[3H]paroxetine binding assay	Increase in SERT expression in the frontal cortex in rats treated with FLX starting at P25, however, not in rats treated with FLX starting at P50.	Wegerer et al., 1999
P25 compared with P65	Rat	Wistar	Male	Fluoxetine (FLX)	5 mg/kg, ip for 3 weeks with a 1 week washout	Ex vivo binding assay with [123I]β-citalopram and in vivo pharmacological MRI (phMRI)	In P25 rats, there was an increase in binding after FLX treatment in the prefrontal cortex and hippocampus. In P65 rats, there was a decrease in binding in the occipital and cingulate cortex after treatment with FLX. phMRI did not indicate changes in level of activation of brain areas after treatment with FLX in either P25 or P65 rats.	Bouet et al., 2012
P28–49 compared with P70–91	Rat	Wistar	Male	Paroxetine (PRX)	5 and 10 mg/kg, drinking water for 18 days	Autoradiography with [125I]RTI-55	SERT density in the basolateral amygdala was increased in adolescent rats treated with PRX compared to control, but not in adults. There were no differences in SERT density in the CA3 of the hippocampus between rats treated with PRX and control in adolescent and adult rats.	Karanges et al., 2011
Two-year old∗	Monkey	Rhesus	Male	Fluoxetine (FLX)	3 mg/kg/day for 1 year in mashed banana, with a 1.5 year washout	Positron emission tomography (PET) with [11C]DASB	SERT expression was increased in neocortex, hippocampus, lateral temporal and cingulate cortices.	Shrestha et al., 2014
C: Post-natal ontogeny of SERT
Age	Species	Strain	Sex			Assay	Outcome	Reference
P0, P7, P14, P21, P28, P70	Rat	Wistar	Male			Quantitative autoradiography with [3H]N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (MADAM)	In terminal regions such as amygdala and hypothalamus, expression peaked around P21, decreased at P28 and plateaued through P70.	Galineau et al., 2004
P21 and P28 compared with P90	Mouse	C57BL/6J	Male and female			[3H]Citalopram saturation binding in hippocampal homogenates	There was no difference in [3H]citalopram maximal binding or affinity across ages. However, there was significantly greater variability in affinity for [3H]citalopram binding in P21 mice compared to P28 and P90 mice.	Mitchell et al., 2013
P21 and P28 compared with P90	Mouse	C57BL/6J	Male and female			Quantitative autoradiography with [3H]citalopram	SERT expression increased with age in terminal regions and decreased with age in cell body regions.	Mitchell et al., 2016
P24–32 and P40–41 compared with 3–5 months and 12–14 months	Rat	Wistar	Male			Immunofluorescence	Prepubertal (P24–32) and pubertal (P40–41) rats exhibited lower SERT immunoreactivity in the lateral septum and dorsal raphe compared to young adult (3–5 months) rats with no difference in SERT immunoreactivity compared to middle age rats.	Ulloa et al., 2014
P25 compared with P65	Rat	Wistar	Male			Ex vivo binding assay with [123I]β-citalopram and phMRI	[123I]β-citalopram binding in the prefrontal cortex and cingulate cortex was lower in P25 rats compared to P65 rats, however, it was higher in the raphe nuclei of P25 rats compared to P65 rats.	Bouet et al., 2012
P28–49 compared with P70–91	Rat	Wistar	Male			Autoradiography with [125I]RTI-55	There were no significant differences between adolescents and adults in [125I]RTI-55 binding in either BLA or CA3 region of hippocampus.	Karanges et al., 2011

^∗Note that puberty occurs in Rhesus macaques between 2.5 and 4.5 years (Colman et al., 2009).