Hippocampal protein expression is differentially affected by chronic paroxetine treatment in adolescent and adult rats: a possible mechanism of "paradoxical" antidepressant responses in young persons

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are commonly recognized as the pharmacological treatment of choice for patients with depressive disorders, yet their use in adolescent populations has come under scrutiny following reports of minimal efficacy and an increased risk of suicidal ideation and behavior in this age group. The biological mechanisms underlying these effects are largely unknown. Accordingly, the current study examined changes in hippocampal protein expression following chronic administration of paroxetine in drinking water (target dose = 10 mg/kg for 22 days) to adult and adolescent rats. Results indicated age-specific changes in protein expression, with paroxetine significantly altering expression of 8 proteins in adolescents only and 10 proteins solely in adults. A further 12 proteins were significantly altered in both adolescents and adults. In adults, protein changes were generally suggestive of a neurotrophic and neuroprotective effect of paroxetine, with significant downregulation of apoptotic proteins Galectin 7 and Cathepsin B, and upregulation of the neurotrophic factor Neurogenin 1 and the antioxidant proteins Aldose reductase and Carbonyl reductase 3. Phosphodiesterase 10A, a signaling protein associated with major depressive disorder, was also downregulated (-6.5-fold) in adult rats. Adolescent rats failed to show the neurotrophic and neuroprotective effects observed in adults, instead displaying upregulation of the proapoptotic protein BH3-interacting domain death agonist (4.3-fold). Adolescent protein expression profiles also suggested impaired phosphoinositide signaling (Protein kinase C: -3.1-fold) and altered neurotransmitter transport and release (Syntaxin 7: 5.7-fold; Dynamin 1: -6.9-fold). The results of the present study provide clues as to possible mechanisms underlying the atypical response of human adolescents to paroxetine treatment.

Keywords: adolescent; antidepressant; hippocampus; paroxetine; proteomics; rat.

Figure 1

Results of proteomics conducted on the hippocampus of adult and adolescent rats chronically treated with paroxetine (10 mg/kg). (A) A representative 2-DE gel image of a hippocampal protein sample from an Adolescent/Control rat. Approximately 400 μg of protein was loaded onto an IPG strip (pH 4–7) followed by 2-dimensional electrophoresis. Experimental masses are located on the Y-axis and pI's on the X-axis. Spot numbers are given in Table 1. (B) Cropped 2-DE gel images of 3 hippocampal protein spots from each of the 4 experimental groups: Adult/PRX, Adult/Control, Adolescent/PRX and Adolescent/Control. PRX downregulated Protein kinase C (PKC; spot 23124; top panel) and upregulated BH3-interacting domain death agonist (BID; spot 23204; bottom panel) in adolescents only. Tryptophan-5-hydroxylase 1 (TPH1; spot 23664; middle panel) was upregulated in 4.3-fold adult rats, but only 1.6-fold in adolescents. (C) Normalized volumes of Protein kinase C, Tryptophan-5-hydroxylase and BH3-interacting domain death agonist. ^*p < 0.05.

Figure 2

Schematic representation of protein expression changes induced by paroxetine in adult (top panel) and adolescent rats (bottom panel) showing interactions between proteins and their involvement in key cellular activities. Interaction between G protein-coupled receptors and their corresponding ligands leads to activation of downstream signaling pathways. Within these pathways, protein kinases such as PKA, PKC and CaMKII phosphorylate and regulate proteins impacting on cell growth and death, neurotransmission, syntaptic plasticity and receptor function. Arrows represent positive feedback or activation between protein units, while capped lines represent negative feedback or inhibition. The magnitude of the protein expression change induced by is represented by the size and color of the boxes: larger boxes represent larger fold changes, and downregulation is indicated with gray shading. Boxes with dashed outlines represent non-significant protein changes. 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine; 5HT3B, Serotonin 3B receptor; AR, Aldose reductase; BDNF, Brain-derived neurotrophic factor; BID, BH3-interacting domain death agonist; CaMKII, Calcium/calmodulin-dependent protein kinase; CBR3, Carbonyl reductase 3; CREB, cAMP response element binding protein; CTSB, Cathepsin B; CYP1B1: Cytochrome P450 1B1; DA, Dopamine; DAT, Dopamine transporter; DYN1, Dynamin 1; GAL7, Galectin 7; GILT, Interferon γ inducible protein 30; GMPR2, Guanosine monophosphate reductase 2; GNAI1, Guanine nucleotide-binding protein Gi, α1 subunit; NA, Noradrenaline; NG1, Neurogenin 1; PDE10A, Phosphodiesterase 10A; PDE4A, Phosphodiesterase 4A; PKA, Protein kinase A; PKC, Protein kinase C; PLC, Phospholipase C; PNMT, Phenylethanolamine-N-methyltransferase; PP6c, Protein phosphatase 6, catalytic subunit; SERT, Serotonin transporter; STX7, Syntaxin 7; TAT, Tyrosine aminotransferase; TM4, Tropomyosin 4; TPH1, Tryptophan hydroxylase 1.