Modulation of stress consequences by hippocampal monoaminergic, glutamatergic and nitrergic neurotransmitter systems

Figures & data

Table I.  Gene expression changes in the hippocampal formation induced by stress.

Hippocampal regions	Molecular approach	Stress procedure	Effect	References
All	ISH	Shaking stress	↑ GPDH	Nichols et al. (1990)
CA1	ISH	Restraint plus tail electrical shocks	↑ c-fos, ↑ zif/268	Schreiber et al. (1991)
DG	ISH	Acute restraint	↓ c-fos	Titze-de-Almeida et al. (1994a,b)
All	ISH	Acute and repeated restraint	↓ c-fos	Melia et al. (1994)
CA1, DG	ISH	Acute restraint	↓ MR hmRNA	Herman and Watson (1995)
CA1	ISH	Maternal deprivation	↓ MR, ↓ GR	Vazquez et al. (1996)
DG, CA1, CA3	ICC	Chronic social stress	↑ c-fos	Matsuda et al. (1996)
DG, CA1, CA3	ISH	Maternal deprivation	↑ GR	Liu et al. (1997)
DG	ISH, ICC	Acute restraint	↑ c-fos mRNA, ↔ Fos protein	Del Bel et al. (1998)
All	ISH;	Acute prolonged stress (restraint, 2 h; forced swim, 20 min and ether anaesthesia); CVUS	Acute: ↓ GR and ↓ MR; CVUS: ↔ GR and MR	Liberzon et al. (1999)
DG, CA1	ISH	Acute prolonged stress (restraint, 2 h; forced swim, 20 min and ether anaesthesia); CVUS	Acute: ↓ 5-HT1A, CVUS: ↔ 5-HT1A	Lopez et al. (1999)
All	ISH, Northern blot	Chronic stress	↓ GR	Kitraki et al. (1999)
CA1-3, DG	ISH	Acute restraint	↑ CRH	Givalois et al. (2000)
All	Quantitative RT-PCR	Repeated restraint	↑ GluR1, ↔ NMDA R1	Schwendt and Jezova (2000)
CA1-3, DG	ISH	Acute or repeated restraint	↔ nNOS	de Oliveira et al. (2000)
DG, CA1, CA3	ISH	Acute or repeated restraint	↓ Synaptophysin ↑ synaptotagmin	Thome et al. (2001)
DG, CA1, CA3	ISH	Repeated social stress	↓ GR, ↑ MR	Meyer et al. (2001)
All	ISH, RNAse protection assay	Maternal deprivation	↓ BDNF; ↓ NMDA (NR-2A and NR-2B)	Roceri et al. (2002)
All	RNAse protection assay	Acute restraint	↑ BDNF	Marmigere et al. (2003)
All	ICC	Acute restraint	↑ PPA2	Morinobu et al. (2003)
All	SAGE	Forced swimming test	53 Genes differently expressed	Drigues et al. (2003)
All	ICC	Repeated social stress	↓ NGF, ↓ M6a, ↓ CLK-1, ↓ GNAQ,	Alfonso et al. (2004)
CA1, CA2, CA3, DG	ICC	Acute restraint	↑ c-fos;	de Medeiros et al. (2005)
All	RT-PCR, microarray	Learned helplessness	Distinct gene expression profile compared to controls	Kohen et al. (2005)
All	real-time RT-PCR	Repeated restraint	↓ NGF, ↓ M6a, ↓ GNAQ, ↓ CLK-1, ↓ BDNF, ↓ CREB, ↓ PKC, ↓ NCAM, ↓ synapsin I	Alfonso et al. (2006)
All	Real time RT-PCR	Social defeat	↑ CRF, ↑ GR	Marini et al. (2006)
CA1, CA3	Microarray, Real time RT-PCR, ISH	Repeated restraint	444 Genes differentially expressed, ↓ Grb2, ↓ Pip5k1b, ↓ Gstp2	Ejchel-Cohen et al. (2006)
All	RT-PCR	Repeated Morris water maze stress	↓ GR, ↑ pro-CRH and CRH-R1	Aguilar-Valles et al. (2005)
CA1	ISH	Acute restraint and adrenalectomy	↔ Arc	Mikkelsen and Larsen (2006)

ISH, in situ hybridization; ICC, immunocytochemistry; CVUS, chronic variable unpredictable stress; DG, dentate gyrus; SAGE, serial analysis of gene expression; GPDH, glycerol phosphate dehydrogenase; MR, mineralocorticoid receptor; GR, glucocorticoid receptor; PPA2, phosphatase 2A; NGF, nerve growth factor; M6a, membrane glycoprotein 6a; CLK-1, CDC-like kinase 1; GNAQ, G-protein alpha q; NCAN, neural cell adhesion molecule; Grb2, growth factor receptor-bound protein 2; Pip5k1b, phosphatidylinositol-4-phosphate 5-kinase, type 1 beta; and Gstp2, glutathione S-transferase, pi2

Table II.  Gene expression changes in the hippocampal formation induced by antidepressant treatments.

Hippocampal regions	Molecular approach	Antidepressant treatment	Effect	References
All	ISH, RT-PCR, Southern blot	SSRI	↓ SERT	Lesch et al. (1993)
DG	ISH	Imipramine	- ↑ 5-HT2C	Tohda and Watanabe (1996)
All	ISH;	Desipramine or fluoxetine	Fluoxetine: ↑ CREB and- ↓ SP1; desipramine: ↑ GRE	Frechilla et al. (1998)
CA1, CA2, CA3, CA4,	ISH;	Imipramine or citalopram	↔ Zeta, ↓ epsilon 1, ↓ epsilon 2-subunits of NMDA receptor	Boyer et al. (1998)
All	Quantitative RT-PCR	Fluoxetine	↑ AA-NAT	Uz and Manev (1999)
Hippocampal cultured cells	RT-PCR, ICC	Desipramine, amitriptyline, mianserin or paroxetine	↑ GR	Okugawa et al. (1999)
CA3, DG	ICC in CRE–LacZ transgenic mice.	Fluoxetine	↑ CRE-mediated gene expression, ↑ phosphorylation of CREB	Thome et al. (2000)
CA1-3, DG	ISH	Buspirone, fluoxetine, 8-OH-DPAT or moclobemide	↑ GR (8-OH and moclobemide), ↓ GR (buspirone and fluoxetine), ↑ NGFI-A (moclobemide, 8-OH-DPAT, fluoxetine)	Bjartmar et al. (2000)
DG, CA1-4	ISH	Fluoxetine or venlafaxine	↓ MR	Yau et al. (2001)
DG	ISH	Fluoxetine, paroxetine, sertraline or tranylcypromine	Time-dependent ↓ (4 h) or ↑ BDNF (24 after last injection)	Coppell et al. (2003)
CA!	ISH	Venlafaxine, paroxetine or desipramine	↑ Arc mRNA;	Pei et al. (2003)
All	SAGE	Forced swimming test with moclobemide, clorgyline or amitriptyline	53 Genes differently expresses, 89 genes changed by drugs	Drigues et al. (2003)
All	Two-dimensional protein gel electrophoresis	Venlafaxine or fluoxetine	23 Protein spots modulated by drug treatment	Khawaja et al. (2004)
All	Real-time RT-PCR	Psychosocial stress with clomipramine	Stress ↓ NGF, M6a, CLK-1, ↑ GNAQ clomipramine prevented stress-induced effects	Alfonso et al. (2004)
DG	ICC	7-Nitro-indazole	↑ PSA-NCAM, pCREB, 5-HT and TPH	Park et al. (2004)
DG, CA1, CA3,	ISH	Fluoxetine	↑ GC	Yau et al. (2004)
CA1, CA2, CA3, DG	ICC	Imipramine with restraint stress	↓ Stress induced ↑ c-fos	de Medeiros et al. (2005)
All	RT-PCR	Fluoxetine	↑ Serotonin N-acetyltransferase, per2, clock, Bmal1, cry1, NPAS2 and ↓ per1	Uz et al. (2005)
DG, CA1	ISH	Fluoxetine	↑ BDNF	Molteni et al. (2006)
All	Real time RT-PCR	Imipramine and metyrapone	↑ BDNF	Rogoz and Legutko (2005)
All	Real time RT-PCR	Mirtazepine	↑ BDNF	Rogoz et al. (2005)
All	RT-PCR	Fluoxetine, desipramine or phenelzine with corticosterone	Fluoxetine and phenelzine prevented ↓ BDNF mRNA induced by corticosterone	Dwivedi et al. (2006)
All	Northern blot	MPEP (selective mGlu5 receptor antagonist)	↑ BDNF	Legutko et al. (2006)

SERT, serotonin transporter; GRE, glucocorticoid response element; AA-NAT, N-acetyltransferase; Bmal1, brain and muscle ARNT-like protein; Cry1, cryptochrome 1; CRE, cAMP response element; CREB, CRE binding protein; NGFI-A, nerve growth factor-induced clone A; Npas2, neuronal PAS2; NGF, nerve growth factor; M6a, membrane glycoprotein 6a; CLK-1, CDC-like kinase 1; GNAQ, G-protein alpha q; per1-2, period homolog 1-2; PSA-NCAM, polysialylated-neural cell adhesion molecule; and TPH, tryptophan hydroxylase.

Figure 1 Post-stress facilitation of serotonin-mediated neurotransmission in the dorsal hippocampus prevents the behavioural consequences of stress. Male Wistar rats (n = 7–23) were submitted to inescapable footshocks (40 shocks, 1 mA, 10 s) or habituation (30 min) in a shuttle box. Immediately afterwards, they received bilateral intra-hippocampal injections of saline (Sal) or zimelidine (Zim, 20 or 100 nmols/0.5 μl), a selective serotonin reuptake inhibitor, and were tested 24 h later wit escapable footshocks (30 sound-signalled shocks, 0.8 mA, 10 s). Data are expressed as the mean ± SEM number of escape and/or avoidance failures in each block (summation of five individual trials). * Indicates significant difference from respective Sal-treated group (p < 0.05, ANOVA followed by Duncan test, modified from Joca et al. (2003), with kind permission from Elsevier).

Figure 2 Post-stress facilitation of noradrenaline-mediated neurotransmission in the dorsal hippocampus does not prevent the behavioural consequences of stress. Male Wistar rats (n = 11–14) were submitted to inescapable footshocks (40 shocks, 1 mA, 10 s) or habituation (30 min) in a shuttle box. Immediately afterwards, they received bilateral intra-hippocampal injections of Sal or desipramine (DIM, 3 or 30 nmols/0.5 μl), a selective noradrenaline reuptake inhibitor and were tested 24 h later with escapable footshocks (30 sound-signalled shocks, 0.8 mA, 10 s). Data are expressed as the mean ± SEM number of escape and/or avoidance failures in each block (summation of five individual trials). There was no significant difference between treatments (modified from Joca et al. (2006), with kind permission from Elsevier).

Figure 3 Pre-stress facilitation of noradrenaline-mediated neurotransmission in the dorsal hippocampus also does not prevent the behavioural consequences of stress. However, it facilitates helpless behaviour in control (non-stressed) animals. Male Wistar rats (n = 7–19) received bilateral intra-hippocampal injections of Sal or desipramine (DIM, 30 nmols/0.5 μl) and immediately afterwards were submitted to inescapable footshocks (40 shocks, 1 mA, 10 s) or habituation (30 min) in a shuttle box. All animals were tested 24 h later with escapable footshocks (30 sound-signalled shocks, 0.8 mA, 10 s). Data are expressed as the mean ± SEM number of escape and/or avoidance failures in each block (summation of five individual trials). * Indicates significant difference from respective Sal-treated group (t-test, p < 0.05, (modified from Joca et al. (2006), with kind permission from Elsevier).

Figure 4 Subchronic treatment with a NOS inhibitor increases BDNF expression in the hippocampus. The figure shows stained cells for BDNF in the hippocampal formation after (a) vehicle, (b) imipramine (15 mg/kg) and (c) 7-nitro-indazole (60 mg/kg), a preferential nNOS inhibitor, treated rats. They received three i.p. injections (0, 5 and 24 h) and were killed 24 h after the last injection, the hippocampus was removed and processed for BDNF immunohistochemistry (primary anti-BDNF antibody: rabbit polyclonal antibody raised against a peptide mapping at the N-terminus of BDNF of human origin, Santa Cruz Biotechnology, Santa Cruz, CA, USA; 1:800). Note BDNF signal (dark stained cells) only in (b) and (c). DG, dentate gyrus; CA, ammons horn. Bar = 150 μm.

Figure 5 Severe stress, activating the NMDA/NO pathway, can impair normal hippocampal functioning, predisposing to helplessness and depressive symptoms. Conversely, serotonin can counteract the stress-induced damage to the hippocampus, restoring normal functioning and allowing coping and stress adaptation. These effects are probably mediated by 5-HT_1A receptors. GCs have a permissive role in NMDA damaging effects and at high levels, can impair 5-HT_1A-mediated neurotransmission. Clinical studies using tryptophan depletion and results obtained with direct intra-hippocampal drug injections suggest that serotonin, glutamate and NO can also interfere with hippocampal function independently of cellular remodelling and neurogenesis.

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