Glucocorticoid receptors in the prefrontal cortex regulate dopamine

International Journal of Neuropsychopharmacology (2013), 16, 1799–1807. doi:10.1017/S1461145713000187

© CINP 2013

ARTICLE

Glucocorticoid receptors in the prefrontal cortex regulate dopamine efflux to stress via descending glutamatergic feedback to the ventral tegmental area Kelly A. Butts and Anthony G. Phillips Department of Psychiatry, University of British Columbia, Vancouver, Canada

Abstract Enhanced dopamine (DA) efflux in the medial prefrontal cortex (mPFC) is a well-documented response to acute stress. We have previously shown that glucocorticoid receptors in the mPFC regulate stress-evoked DA efflux but the underlying mechanism is unknown. DA neurons in the ventral tegmental area (VTA) receive excitatory input from and send reciprocal projections to the mPFC. We hypothesize that blockade of prefrontal glucocorticoid receptors can reduce activity of descending glutamatergic input to the VTA, thereby attenuating stress-evoked DA efflux in the mPFC. Using in vivo microdialysis, we demonstrate that acute tail-pinch stress leads to a significant increase in glutamate efflux in the VTA. Blockade of prefrontal glucocorticoid receptors with the selective antagonist CORT 108297 attenuates stress-evoked glutamate efflux in the VTA together with DA efflux in the mPFC. Furthermore, blockade of ionotrophic glutamate receptors in the VTA attenuates stress-evoked DA efflux in the mPFC. We also examine the possible role of glucocorticoid-induced synthesis and release of endocannabinoids acting presynaptically via cannabinoid CB1 receptors to inhibit GABA release onto prefrontal pyramidal cells, thus enhancing descending glutamatergic input to the VTA leading to an increase in mPFC DA efflux during stress. However, administration of the cannabinoid CB1 receptor antagonist into the mPFC does not attenuate stress-evoked DA efflux in the mPFC. Taken together, our data indicate that glucocorticoids act locally within the mPFC to modulate mesocortical DA efflux by potentiation of glutamatergic drive onto DA neurons in the VTA. Received 17 November 2012; Reviewed 29 January 2013; Revised 5 February 2013; Accepted 7 February 2013; First published online 16 April 2013 Key words: Acute stress, dopamine, glucocorticoid receptor, prefrontal cortex, ventral tegmental area.

Introduction Enhanced dopamine (DA) efflux in the medial prefrontal cortex (mPFC) is a well-documented response to acute stress. We have previously shown that administration of the glucocorticoid receptor (GR) antagonist, RU-38486, into the mPFC significantly attenuates DA efflux in the mPFC and working memory impairments induced by exposure to acute tail-pinch stress (Butts et al., 2011). However, the underlying mechanism(s) by which the GR regulates stress-evoked DA efflux in the mPFC remains to be determined.

Address for correspondence: Dr A. G. Phillips, University of British Columbia, Department of Psychiatry, Room 430-5950 University Boulevard, V6T 1Z3, Vancouver, BC, Canada. Tel: 604 822 0379 Fax: 604 827 3373 Email: [email protected]

DA neurons in the ventral tegmental area (VTA) receive excitatory input from and extend reciprocal projections to the mPFC (Carr and Sesack, 2000). Local application of ionotropic glutamate receptor antagonists or functional inactivation of the DA cell bodies with lidocaine in the VTA decreased stressevoked DA efflux in the mPFC (Enrico et al., 1998; Butts et al., 2011) suggesting that glucocorticoids released after acute stress may enhance descending glutamatergic feedback to the VTA. This is supported by evidence from the drug addiction field showing that deletion of GR in post-synaptic neurons innervated by DA terminals, but not in DA-releasing neurons, was associated with a reduction in spontaneous neural activity, firing rate and frequency of burst events in DA neurons, together with decreased glucocorticoid-induced cocaine self-administration by mice (Ambroggi et al., 2009).

1800 K. A. Butts and A. G. Phillips Enhanced glutamatergic transmission in mPFC pyramidal neurons following exposure to acute stressors occurs through a GR-dependent mechanism (Yuen et al., 2009). Emerging evidence suggests a possible role of the endocannabinoid system in mediating GR activation into changes in glutamatergic transmission in mPFC neurons. Under conditions of acute stress, glucocorticoids trigger the synthesis and release of the endocannabinoid ligands, N-arachidonylethanolamine and 2-arachidonylglycerol (Di et al., 2003; Tasker et al., 2006; Hill et al., 2010). Endocannabinoid release from the post-synaptic cell acts on cannabinoid receptor subtype 1 (CB1) receptors localized on pre-synaptic glutamatergic, or GABAergic terminals, to inhibit subsequent neurotransmitter release (Di et al., 2003; Tasker et al., 2006; Hill et al., 2010). Activation of GRs in the mPFC can trigger endocannabinoid release which functions pre-synaptically via cannabinoid CB1 receptors to inhibit GABA release onto prefrontal pyramidal cells. This in turn leads to increased activity in descending glutamatergic input to the hypothalamus, thereby inhibiting the hypothalamic–pituitary–adrenal axis (Hill et al., 2011). A similar mechanism within the mPFC may explain how stress-induced elevation of glucocorticoids may mediate indirect activation of glutamatergic afferents to the VTA leading subsequently to increased DA efflux in the mPFC. This hypothesis is tested directly by blockade of CB1 receptors in the mPFC during exposure to acute stress. We used in vivo microdialysis to investigate the role of the GR in mediating enhanced glutamatergic drive to the VTA. Using a selective GR antagonist, devoid of any progesterone activity, we demonstrate that local GR blockade in the mPFC attenuates stressevoked glutamate efflux in the VTA and DA efflux in the mPFC. In contrast, blocking CB1 receptors in the mPFC failed to attenuate stress-evoked DA efflux. Antagonism of ionotropic glutamate receptor in the VTA attenuated DA efflux in the mPFC evoked by tail-pinch stress.

Drugs Stock solutions were made and dissolved in artificial cerebrospinal fluid (aCSF): RU-38486 (Tocris Biosciences, USA) was dissolved in ethanol. CORT 108297 (Corcept Therapeutics, USA) and CNQX, AP5, AM251 and NIDA41020 (Tocris Bioscience) were dissolved in DMSO. Neither ethanol nor DMSO exceeded 0.1% when dissolved in aCSF. In vivo microdialysis Rats (∼280–310 g) were implanted with stainless steel guide cannulae (19 gauge × 15 mm) directly above the mPFC (3.0 mm AP, ± 0.6 mm ML from bregma, 4.6 mm DV from dura) and/or VTA (−5.8 mm AP, ± 0.6 mm ML, 8.0 mm DV). One week after surgery, microdialysis probes were implanted 14–16 h before experiments. Probes were concentric in design with silica inlet/outlet lines and a dialysis surface consisting of a semi-permeable membrane 1 or 2 mm in length (340 μm outer diameter; 65 000 molecular weight cutoff; Filtral 12; Hospal, UK). Typical in vitro probe (2 mm membrane) recovery of an external DA and glutamate standard is 18 ± 1% at room temperature. Microdialysis probes were connected to an Instech dual-channel liquid swivel and perfused continuously at 1.0 μl/min with aCSF [10 mM sodium phosphate, 1.2 mM CaCl2, 3.0 mM KCl, 1.0 mM MgCl2, 147.0 mM NaCl (pH 7.4)] using a 2.5-ml gas-tight syringe (Hamilton, UK) and a syringe pump (model 22; Harvard Apparatus, USA). Samples were collected at 15-min intervals. Following establishment of a stable baseline (four samples, 0.05, two-tailed Student’s t test; Fig. 2d). Blockade of ionotropic glutamate receptors in the VTA reduces stress-evoked DA efflux in the mPFC We next perfused the AMPA receptor antagonist, CNQX (50 μM) and the NMDA receptor antagonist,

Glucocorticoid modulation of dopamine efflux 1803 (a)

(b) 40

Stress

Vehicle

35

CNQX/AP5

30 150

AUC

DA (% baseline)

200

25 20

*

15

100

10 5 CNQX/AP5 or vehicle VTA

50 –60

–30

0

30

60

0 90

120

150

Vehicle

CNQX/AP5

Time (min) Fig. 3. Ionotrophic glutamate receptors in the ventral tegmental area (VTA) mediate stress-evoked dopamine (DA) efflux in the medial prefrontal cortex (mPFC). (a) Time course of the change from baseline of DA efflux in the mPFC measured from while animals were subject to tail-pinch stress (15 min; grey-shaded box). CNQX or AP5 (horizontal black line) were perfused into the VTA via reverse microdialysis. All values are expressed as percent change from baseline ± S.E.M. (n = 8, vehicle; n = 6, CNQX and AP5). (b) Histogram depicting mean area under curve (AUC; ± S.E.M.) for the change in DA efflux relative to baseline for 90 min after the initiation of stress (* p < 0.05).

AP5 (200 μM), into the VTA via reverse microdialysis while measuring DA efflux in the mPFC during tail-pinch stress. Local perfusion of CNQX and AP5 into the VTA has been previously shown to decrease DA efflux in the mPFC during handling stress (Enrico et al., 1998). Blockade of ionotropic glutamate receptors in the VTA significantly decreased stressevoked DA efflux in the mPFC (n = 8 vehicle treatment group, n = 6 CNQX and AP5 treatment group; Fig 3a), measured by AUC (mean ± S.E.M.) over 90 min poststress (p < 0.05; Fig. 3b). Cannabinoid CB1 receptors do not modulate stress-evoked DA efflux in the mPFC We also examined the possible role of glucocorticoidinduced synthesis and release of endocannabinoids which may act presynaptically via cannabinoid CB1 receptors to inhibit GABA release onto prefrontal pyramidal cells, thus enhancing descending glutamatergic input to the VTA during stress leading to increased DA efflux in the mPFC (Hill et al., 2011). When administered locally into the mPFC, neither the CB1 receptor antagonist AM-251 (10 μM) nor NIDA41020 (10 μM) had a significant effect on stress-induced DA efflux in the mPFC (n = 8 vehicle, n = 9 AM-251, n = 8 NIDA41020; Fig. 4a) as measured by comparison of AUCs (p > 0.05, two-tailed Student’s t test; Fig. 4b). Histology Histological analysis confirmed the location of all microdialysis probes from all experiments to be

localized in either the prelimbic or infralimbic areas of the mPFC and the VTA (Fig. 5).

Discussion The present study provides the novel observation that glutamate efflux in the VTA is increased in a phasic manner after exposure to tail-pinch stress that can be attenuated by reverse microdialysis of the selective GR antagonist CORT 108297 into the mPFC. Furthermore, blockade of ionotropic glutamate receptors in the VTA leads to a significant reduction in stressevoked DA efflux in the mPFC. These data support the hypothesis that glucocorticoids act locally within the mPFC to modulate mesocortical DA efflux by potentiation of glutamatergic drive onto DA neurons in the VTA. As similar effects were obtained in a recent study with the progesterone and GR antagonist RU-38486 (Butts et al. 2011), using the selective GR antagonist CORT 108297 (Asagami et al., 2011; Belanoff et al., 2011), the present data suggest that the observed attenuation of stress-induced DA efflux is mediated by a glucocorticoid and not a progesterone receptor. These results also support our contention that the mPFC is the primary site of glucocorticoid regulation of mesocortical DA neurons during stress. Although we observed a significant increase in stress-induced glutamate efflux in the VTA, a similar increase in glutamate efflux in the mPFC was not seen in the same animals. Previous studies examining the effects of handling stress on glutamate efflux also

1804 K. A. Butts and A. G. Phillips (a)

(b) Stress

200

Vehicle

45

AM-251

40 35

NIDA41020

30

AUC

DA (% baseline)

250

150

25 20 15

100

10 5 AM-251, NIDA41020, or vehicle mPFC

50 –60

–30

0

30

60

90

120

0 150

Vehicle

AM-251

NIDA41020

Time (min) Fig. 4. Stress-evoked dopamine (DA) efflux in the medial prefrontal cortex (mPFC) is not mediated by cannabinoid CB1 receptors. (a) Time course of the change from baseline of DA efflux in the mPFC in rats subjected to tail-pinch stress (15 min; grey-shaded box). AM-251 or NIDA41020 (horizontal black line) was perfused into the mPFC via reverse microdialysis. All values are expressed as percent change from baseline ± S.E.M. (n = 8, vehicle; n = 7, AM-251; n = 8, NIDA41020). (b) Histogram depicting mean area under curve (AUC; ± S.E.M.) for the change in DA efflux relative to baseline for 90 min after the initiation of stress.

+3.70 mm

+2.70 mm

+3.20 mm

–5.60 mm

–5.80 mm

–6.04 mm

–6.30 mm

Fig. 5. Placements of microdialysis probes. Each vertical black bar represents the active membrane surface location of a microdialysis probe in the medial prefrontal cortex or ventral tegmental area. Not all probes are shown, because of overlapping placements.

failed to detect an increase in the mPFC (Timmerman et al., 1999; Del Arco and Mora, 2001). However, these negative findings differ from previous observations demonstrating an increase in glutamate release in the mPFC of rats exposed to acute restraint or tailpinch stress using brain microdialysis (Moghaddam, 1993; Bagley and Moghaddam, 1997). Furthermore, Hascup and colleagues employed enzyme-based microelectrode arrays to measure an increase in neuronally derived glutamate in the mPFC after exposure

to both tail-pinch and restraint stress (Hascup et al., 2011, 2012). One possible explanation for our failure to observe a significant increase in mPFC glutamate efflux with a tail-pinch stressor may reflect the relatively mild nature of this stimulus. Alternatively, the detection limit of the analytical system used in the present study (0.05 μM) may not have had sufficient sensitivity. Previous studies examining the mechanisms by which acute stress or corticosterone administration

Glucocorticoid modulation of dopamine efflux 1805 regulates glutamatergic transmission have focused on identifying the transcriptional targets of GR activation. Yuen and colleagues demonstrated that the stressinduced delayed and sustained potentiation of NMDAR- and AMPAR-mediated synaptic currents in layer V mPFC pyramidal cells mediated by GR activation occurs through the induction of serum- and glucocorticoid-inducible kinases and the activation of Rab4 that regulates receptor trafficking and function of NMDARs and AMPARs (Yuen et al., 2009, 2011). Revest and colleagues demonstrated that activation of GRs leads to an increase in the expression of the transcription factor early gene response-1 in the hippocampus (Revest et al., 2005, 2010). This, in turn, can increase expression of synapsin-Ia/Ib, the most highly expressed hippocampal presynaptic vesicle-associated phosphoproteins (Revest et al., 2005, 2010), which exert direct control over the release of neurotransmitters, such as glutamate (Nichols et al., 1992; Jovanovic et al., 2000). In contrast, in the present study, the increase in stress-evoked glutamate efflux in the VTA was observed within 15 min. As this short time-frame of action is too rapid to be mediated by means of the classical genomic GR pathway as described above, the immediate effects of acute stress may instead be regulated by a non-genomic membrane receptor-mediated mechanism (Prager and Johnson, 2009; Groeneweg et al., 2011). Emerging evidence suggests that corticosterone may rapidly affect neuronal signalling by binding to membrane-associated corticosterone receptors (Orchinik et al., 1991; Dallman, 2005; Haller et al., 2008; Prager and Johnson, 2009) and anatomical data confirm that GRs are localized to membranes and synapses (Liposits and Bohn, 1993; Johnson et al., 2005). These membrane receptors have been shown to rapidly change neuronal excitability through direct actions on ion channels or intracellular signalling messengers (ffrench-Mullen, 1995; Tasker et al., 2006; Prager and Johnson, 2009; Groeneweg et al., 2012). Relatively few studies have examined the possible role of rapid non-genomic mechanisms in mediating corticosterone signalling in the mPFC (Groeneweg et al., 2011). However, a recent behavioural study conducted by Barsegyan and colleagues demonstrated that administration of corticosterone conjugated to the membrane impermeable protein, bovine serum albumin, into the mPFC impaired performance on a working memory task (Barsegyan et al., 2010). This effect was prevented by co-administration of RU-38486 and discovered to be mediated by a membrane GR-induced facilitation of a noradrenergic signal transduction pathway within the mPFC (Barsegyan et al.,

Stress

Corticosterone

PFC GR Pyramidal neuron

Dopaminergic Glutamatergic

VTA

DA neuron

Fig. 6. Schematic depiction of the anatomical connections between the medial prefrontal cortex (mPFC) and ventral tegmental area (VTA) proposed to mediate stress-evoked dopamine (DA) efflux in the medial mPFC. Specifically, we hypothesize that elevated circulating corticosterone during stress activates putative membrane glucocorticoid receptors (GR) on prefrontal glutamatergic projection neurons that terminate on DA neurons in the VTA. Increased activation of these projection neurons by corticosterone would subsequently increase VTA DA neuron cell firing thereby augmenting DA release in the mPFC (black line indicates the glutamatergic projection, the grey line depicts the mesocortical dopaminergic projection).

2010). Accordingly, we propose that corticosterone acts on a putative membrane GR of layer V pyramidal neurons in the mPFC (Fig. 6). Activation of layer V cortical neurons, the principal projection neurons of the mPFC, would, in turn, enhance glutamatergic drive onto DA neurons in the VTA, leading to an increase in DA efflux in the mPFC (Fig. 6; Carr and Sesack, 2000). As previously mentioned, the endocannabinoid signalling molecules are a well-studied retrograde messenger system regulated by membrane GRs (Tasker et al., 2006). Therefore, we investigated whether the

1806 K. A. Butts and A. G. Phillips present findings may be mediated by glucocorticoidinduced synthesis and release of endocannabinoids that would in turn act presynaptically via cannabinoid CB1 receptors to remove GABAergic inhibition of layer V pyramidal neurons in the mPFC (Hill et al., 2011) and thus enhancing DA efflux in the mPFC. However, blockade of CB1 receptors in the mPFC failed to attenuate stress-evoked DA efflux. Although the concentration of AM-251 and NIDA-41020 used in the present study was effective in previous behavioural and electrophysiological experiments (Di et al., 2003; Miller et al., 2007; Sousa et al., 2011), the possibility remains that a higher concentration of these drugs is required to produce positive effects. However, given this finding, it is noteworthy that glucocorticoidinduced synthesis and release of endocannabinoids acting presynaptically via cannabinoid CB1 receptors to inhibit GABA release in the mPFC was not observed until 1 h after stress exposure (Hill et al., 2011). Future studies examining other rapid GR-mediated non-genomic mechanisms regulating corticosterone signalling in mPFC projection neurons are warranted. In summary, blockade of GRs within the mPFC with a selective antagonist attenuates stress-evoked DA and glutamate efflux in the mPFC and VTA, respectively. Blockade of ionotrophic glutamate receptors in the VTA also reduces stress-evoked DA efflux in the mPFC, thereby confirming an important contribution of mPFC GRs to the modulation of ‘topdown’ feedback control of mesocortical DA neurons (Phillips et al., 2008). Together, these findings may offer a partial explanation of stress-induced disruption and possibly facilitation of cognitive functions mediated by neural activity within the mPFC. Acknowledgements We thank Dr Joseph Belanoff for his generous donation of CORT 108297, Dr Soyon Ahn, Kitty So and Giada Vacca for technical assistance with the HPLC, and Dr Allan Young and Lasse Dissing-Olesen for helpful advice and feedback. Statement of Interest A.G.P. serves on the board of Allon Therapeutics Inc. and owns shares in the company. References Ambroggi F, Turiault M, Milet A, Deroche-Gamonet V, Parnaudeau S, Balado E, Barik J, van der Veen R, Maroteaux G, Lemberger T, Schutz G, Lazar M, Marinelli

M, Piazza PV, Tronche F (2009) Stress and addiction: glucocorticoid receptor in dopaminoceptive neurons facilitates cocaine seeking. Nat Neurosci 12:247–249. Asagami T, Belanoff JK, Azuma J, Blasey CM, Clark RD, Tsao PS (2011) Selective glucocorticoid receptor (GR-II) antagonist reduces body weight gain in mice. J Nutr Metab 2011:235389. Bagley J, Moghaddam B (1997) Temporal dynamics of glutamate efflux in the prefrontal cortex and in the hippocampus following repeated stress: effects of pretreatment with saline or diazepam. Neuroscience 77:65–73. Barsegyan A, Mackenzie SM, Kurose BD, McGaugh JL, Roozendaal B (2010) Glucocorticoids in the prefrontal cortex enhance memory consolidation and impair working memory by a common neural mechanism. Proc Natl Acad Sci U S A 107:16655–16660. Belanoff JK, Blasey CM, Clark RD, Roe RL (2011) Selective glucocorticoid receptor (type II) antagonists prevent weight gain caused by olanzapine in rats. Eur J Pharmacol 655:117–120. Butts KA, Weinberg J, Young AH, Phillips AG (2011) Glucocorticoid receptors in the prefrontal cortex regulate stress-evoked dopamine efflux and aspects of executive function. Proc Natl Acad Sci USA 108:18459–18464. Carr DB, Sesack SR (2000) Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J Neurosci 20:3864–3873. Dallman MF (2005) Fast glucocorticoid actions on brain: back to the future. Front Neuroendocrinol 26:103–108. Del Arco A, Mora F (2001) Dopamine release in the prefrontal cortex during stress is reduced by the local activation of glutamate receptors. Brain Res Bull 56:125–130. Di S, Malcher-Lopes R, Halmos KC, Tasker JG (2003) Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 23:4850–4857. Enrico P, Bouma M, de Vries JB, Westerink BH (1998) The role of afferents to the ventral tegmental area in the handling stress-induced increase in the release of dopamine in the medial prefrontal cortex: a dual-probe microdialysis study in the rat brain. Brain Res 779:205–213. ffrench-Mullen JM (1995) Cortisol inhibition of calcium currents in guinea pig hippocampal CA1 neurons via G-protein-coupled activation of protein kinase C. J Neurosci 15:903–911. Groeneweg FL, Karst H, de Kloet ER, Joels M (2011) Rapid non-genomic effects of corticosteroids and their role in the central stress response. J Endocrinol 209:153–167. Groeneweg FL, Karst H, de Kloet ER, Joels M (2012) Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling. Mol Cell Endocrinol 350:299–309. Haller J, Mikics E, Makara GB (2008) The effects of nongenomic glucocorticoid mechanisms on bodily functions

Glucocorticoid modulation of dopamine efflux 1807 and the central neural system. A critical evaluation of findings. Front Neuroendocrinol 29:273–291. Hascup ER, Hascup KN, Pomerleau F, Huettl P, Hajos-Korcsok E, Kehr J, Gerhardt GA (2012) An allosteric modulator of metabotropic glutamate receptors [mGluR (2)], (+)-TFMPIP, inhibits restraint stress-induced phasic glutamate release in rat prefrontal cortex. J Neurochem 122:619–627. Hascup KN, Hascup ER, Stephens ML, Glaser PE, Yoshitake T, Mathe AA, Gerhardt GA, Kehr J (2011) Resting glutamate levels and rapid glutamate transients in the prefrontal cortex of the Flinders Sensitive Line rat: a genetic rodent model of depression. Neuropsychopharmacology 36:1769–1777. Hill MN, Patel S, Campolongo P, Tasker JG, Wotjak CT, Bains JS (2010) Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output. J Neurosci 30:14980–14986. Hill MN, McLaughlin RJ, Pan B, Fitzgerald ML, Roberts CJ, Lee TT, Karatsoreos IN, Mackie K, Viau V, Pickel VM, McEwen BS, Liu QS, Gorzalka BB, Hillard CJ (2011) Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response. J Neurosci 31:10506–10515. Johnson LR, Farb C, Morrison JH, McEwen BS, LeDoux JE (2005) Localization of glucocorticoid receptors at postsynaptic membranes in the lateral amygdala. Neuroscience 136:289–299. Jovanovic JN, Czernik AJ, Fienberg AA, Greengard P, Sihra TS (2000) Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci 3:323–329. Liposits Z, Bohn MC (1993) Association of glucocorticoid receptor immunoreactivity with cell membrane and transport vesicles in hippocampal and hypothalamic neurons of the rat. J Neurosci Res 35:14–19. Miller DK, Rodvelt KR, Constales C, Putnam WC (2007) Analogs of SR-141716A (Rimonabant) alter d-amphetamine-evoked [3H] dopamine overflow from preloaded striatal slices and amphetamine-induced hyperactivity. Life Sci 81:63–71. Moghaddam B (1993) Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem 60:1650–1657.

Nichols RA, Chilcote TJ, Czernik AJ, Greengard P (1992) Synapsin I regulates glutamate release from rat brain synaptosomes. J Neurochem 58:783–785. Orchinik M, Murray TF, Moore FL (1991) A corticosteroid receptor in neuronal membranes. Science 252:1848–1851. Phillips AG, Vacca G, Ahn S (2008) A top-down perspective on dopamine, motivation and memory. Pharmacol Biochem Behav 90:236–249. Prager EM, Johnson LR (2009) Stress at the synapse: signal transduction mechanisms of adrenal steroids at neuronal membranes. Sci Signal 2:re5. Revest JM, Di Blasi F, Kitchener P, Rouge-Pont F, Desmedt A, Turiault M, Tronche F, Piazza PV (2005) The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids. Nat Neurosci 8:664–672. Revest JM, Kaouane N, Mondin M, Le Roux A, Rouge-Pont F, Vallee M, Barik J, Tronche F, Desmedt A, Piazza PV (2010) The enhancement of stress-related memory by glucocorticoids depends on synapsin-Ia/Ib. Mol Psychiatry 15:1125, 1140–1151. Sousa VC, Assaife-Lopes N, Ribeiro JA, Pratt JA, Brett RR, Sebastiao AM (2011) Regulation of hippocampal cannabinoid CB1 receptor actions by adenosine A1 receptors and chronic caffeine administration: implications for the effects of Delta9-tetrahydrocannabinol on spatial memory. Neuropsychopharmacology 36:472–487. Tasker JG, Di S, Malcher-Lopes R (2006) Minireview: rapid glucocorticoid signaling via membrane-associated receptors. Endocrinology 147:5549–5556. Timmerman W, Cisci G, Nap A, de Vries JB, Westerink BH (1999) Effects of handling on extracellular levels of glutamate and other amino acids in various areas of the brain measured by microdialysis. Brain Res 833:150–160. Yuen EY, Liu W, Karatsoreos IN, Feng J, McEwen BS, Yan Z (2009) Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc Natl Acad Sci USA 106:14075–14079. Yuen EY, Liu W, Karatsoreos IN, Ren Y, Feng J, McEwen BS, Yan Z (2011) Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory. Mol Psychiatry 16:156–170.