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Supraorbital Stimulation Does Not Induce an Antidepressant-like Response in Rats
Brain Stimulation 7 (2014) 301e303
Contents lists available at ScienceDirect
Brain Stimulation journal homepage: www.brainstimjrnl.com
Short Communications
Supraorbital Stimulation Does Not Induce an Antidepressant-like Response in Rats Tatiana Bregman a, Mustansir Diwan a, José N. Nobrega a, Clement Hamani a, b, * a b
Neuroimaging Research Section, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada Division of Neurosurgery, University of Toronto, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 May 2013 Received in revised form 27 September 2013 Accepted 7 November 2013
Background: Neuromodulation therapies are currently being investigated as potential treatments for depression. One of these treatments involves the stimulation of supraorbital branches of the trigeminal nerve. Objective: To show that supraorbital stimulation is effective in preclinical models. Methods: Rats were given supraorbital stimulation at different settings in the forced swim test (FST) and open field. Results: Supraorbital stimulation did not induce an antidepressant-like response in rats undergoing the FST. This is in contrast to other neuromodulation treatments, such as deep brain stimulation, vagus nerve stimulation and electroconvulsive therapy, which are all effective in this paradigm. Conclusions: Supraorbital stimulation was ineffective in rats undergoing the FST. Such findings do not invalidate results of recent clinical trials. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Supraorbital nerve Trigeminal nerve Stimulation Depression Rats
Introduction Invasive neuromodulation strategies, including deep brain stimulation (DBS) [1e3], cortical stimulation [4] and vagus nerve stimulation (VNS) [5,6] are currently being investigated as potential treatments for depression. A less invasive alternative comprises the delivery of electrical stimulation to the supraorbital branch of the trigeminal nerve, either through superficial or subcutaneously implanted electrodes [7e9]. Preliminary results with the use of superficial trigeminal stimulation in depression has been very promising at short-term [8]. One way of confirming the biological response of an intervention is to test its efficacy in preclinical models [10,11]. Though no animal model adequately mimics all aspects of depressive sates, the forced swim test (FST) has been widely used and is well validated [12,13]. In this paradigm, various therapies have been associated with an antidepressant-like response, including different classes of medications, electroconvulsive therapy, VNS and DBS [13e16].
Financial disclosures: C.H. and J.N.N are consultants for St Jude Medical. This study was sponsored by St Jude Medical. The sponsors had no role in study design, collection and interpretation of data or writing the manuscript. * Corresponding author. Neuroimaging Research Section, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada. Tel.: þ1 416 6035771. E-mail address: [email protected] (C. Hamani). 1935-861X/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2013.11.002
We investigate whether supraorbital stimulation induces an antidepressant-like response in rats undergoing testing in the FST and in an open field. Methods and materials Protocols were approved by the Animal Care committee of the Centre for Addiction and Mental Health. Surgical procedure Male SpragueeDawley rats (250e300 g) were anesthetized with halothane. After a midline incision, the subcutaneous tissue was laterally dissected until the supraorbital region was reached. Paddle electrodes (Plastics One, model E363/76; 1 mm in width, 3.25 mm in length and 0.66 mm in thickness) were then placed over this region, connected to a plastic pedestal (Plastics One, model MS 363) and used as cathodes. An epidural screw placed over the somatosensory cortex was connected to the same pedestal and used as the anode (0.5 mm posterior and 1.5 mm lateral to the bregma) [17]. Sham treated animals had electrodes implanted but did not receive stimulation. Controls also had surgery but were not implanted with electrodes. Electrical stimulation Stimulation was conducted with a handheld device (St Jude Medical model 3510). In our previous reports using DBS, currents in the 100e300 mA range induced and antidepressant-like response in
302
T. Bregman et al. / Brain Stimulation 7 (2014) 301e303
Figure 1. Results of supraorbital stimulation in the forced swim test (FST) and open field. In both tests, rats were treated with supraorbital stimulation at 130 Hz or 20 Hz, 90 ms and 400 mA or 200 mA. A) For scoring in the FST, the predominant behavior of the animals (immobility, swimming, or climbing) during the 5 min of the testing was annotated every 5 s (maximal score of 60). As shown in the figure, no differences were recorded when animals receiving stimulation were compared to those given sham stimulation or controls with no electrodes implanted. B, C) In the open field, the time during which the animals explored the apparatus was scored during the first 5 and 30 min of testing. Overall, no significant differences were found across groups. Results expressed as mean standard error.
the forced swim test [16,18]. Taking this into account, we have tested the effects of two different intensities, 200 and 400 mA. The former was the most effective setting in our previous DBS experiments [18]. The second was a midterm parameter between 200 mA and the threshold for side effects with supraorbital stimulation (most rats had muscle contractions leading to eyelid closure at 600 mA). As for the frequency and pulse width, we have chosen settings that are commonly used in neuromodulation studies (90 ms; 130 Hz and 20 Hz). Higher and lower frequencies influence different neural elements [10]. Frequencies in the 130 Hz range were used in clinical studies investigating the effects of external trigeminal stimulation for depression [8].
Behavioral testing Animals underwent the FST one week after the implantation of electrodes. On the first day of testing, rats were individually placed for 15 min in a cylinder filled with 25 1 C water to a depth of 40 cm [16,18]. Thereafter, experimental animals received continuous stimulation for 4 h. On the following day, rats in this group underwent 2 h of stimulation followed by a 5 min swimming session. As in our previous DBS studies [16,18], animals did not receive stimulation during behavioral testing. For the purpose of scoring, we subdivided the 5 min of the test into 5 s segments [19,20]. Only the predominant behavior of the animals (immobility, swimming or climbing) was blindly scored during each segment, with a maximum possible score of 60 (1 point per segment), as previously described. In the FST immobility scores reflect a depressive-like state. One week after the FST, animals received stimulation for 4 h on day 1 and 2 h on day 2, immediately prior to behavioral testing. Locomotor activity was assessed for 30 min in a 0.49 m2 open field (Med Associates) with infrared photo beams placed along the walls. Crossing the beams provided counts of motor activity. The first 5 min of testing were considered to be a measurement of anxiety, as
animals explored a novel environment. The total 30 min of testing were used to measure overall locomotor activity. Statistical analysis ANOVA (Bonferroni post-hoc) was used to compare behavioral data across groups. Statistical significance was set at P 0.05. Results are presented as mean standard error. Results Overall, no significant differences in immobility (P ¼ 0.4; F4,34 ¼ 1.01), swimming (P ¼ 0.5; F4,34 ¼ 0.81), or climbing (P ¼ 0.5; F4,34 ¼ 0.71) were recorded in animals receiving active stimulation at 400 mA 130 Hz (n ¼ 8), 400 mA 20 Hz (n ¼ 8), 200 mA 130 Hz (n ¼ 6), sham treatment (n ¼ 8) or controls (n ¼ 9) (Fig. 1A). Similarly, no differences in exploratory behavior were recorded across groups in the open field (P ¼ 0.9; F4,25 ¼ 0.27 for the first 5 min of testing and P ¼ 0.2; F4,27 ¼ 1.70 for the whole test) (Fig. 1B and C). Discussion In contrast to humans, stimulation of the supraorbital region did not induce an antidepressant-like response in rodents. Such discrepancies may be attributed to several reasons. As only small case series with a short-term follow-up have been published [8], the role of a placebo response is still unknown. In contrast to the implanted subcutaneous electrodes in our study, patients undergoing treatment were only given stimulation through surface electrodes at night [8]. We chose to use a subcutaneous system for two reasons. First, it has been routinely used in patients with facial pain [9]. Second, animals tend to remove surface electrodes, constantly scratching the region in which they are placed while receiving stimulation.
T. Bregman et al. / Brain Stimulation 7 (2014) 301e303
As in humans, the supraorbital nerve is a branch of the trigeminal nerve located right above the orbit. Electrodes in our study were large enough to cover the whole supraorbital area, suggesting that our negative results were unlikely related to a lack of stimulation coverage. As for the stimulation parameters, we chose frequencies commonly used for invasive neuromodulation strategies and amplitudes that were lower than the threshold for side effects. At these settings, animals were fairly comfortable, eating, grooming and behaving normally while receiving treatment. As a final remark, we stress that animal models have important limitations. It is possible that supraorbital stimulation may not work in rats undergoing the FST but be effective in the clinic. References [1] Malone Jr DA, Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN, et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry 2009;65(4):267e75. [2] Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005; 45(5):651e60. [3] Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 2008;33(2):368e77. [4] Kopell BH, Halverson J, Butson CR, Dickinson M, Bobholz J, Harsch H, et al. Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refractory major depressive disorder. Neurosurgery 2011;69(5):1015e29. discussion 1029. [5] George MS, Rush AJ, Marangell LB, Sackeim HA, Brannan SK, Davis SM, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry 2005;58(5):364e73. [6] Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry 2005;58(5):347e54.
303
[7] DeGiorgio CM, Soss J, Cook IA, Markovic D, Gornbein J, Murray D, et al. Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy. Neurology 2013;80(9):786e91. [8] Schrader LM, Cook IA, Miller PR, Maremont ER, DeGiorgio CM. Trigeminal nerve stimulation in major depressive disorder: first proof of concept in an open pilot trial. Epilepsy Behav 2011;22(3):475e8. [9] Slavin KV, Colpan ME, Munawar N, Wess C, Nersesyan H. Trigeminal and occipital peripheral nerve stimulation for craniofacial pain: a single-institution experience and review of the literature. Neurosurg Focus 2006;21(6):E5. [10] Hamani C, Temel Y. Deep brain stimulation for psychiatric disease: contributions and validity of animal models. Sci Transl Med 2012;4(142):142rv148. [11] Hamani C, Nobrega JN. Preclinical studies modeling deep brain stimulation for depression. Biol Psychiatry 2012;72(11):916e23. [12] Cryan JF, Markou A, Lucki I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 2002;23(5):238e45. [13] Cryan JF, Slattery DA. Animal models of mood disorders: recent developments. Curr Opin Psychiatry 2007;20(1):1e7. [14] Krahl SE, Senanayake SS, Pekary AE, Sattin A. Vagus nerve stimulation (VNS) is effective in a rat model of antidepressant action. J Psychiatr Res 2004;38(3): 237e40. [15] Hamani C, Machado DC, Hipolide DC, Dubiela FP, Suchecki D, Macedo CE, et al. Deep brain stimulation reverses anhedonic-like behavior in a chronic model of depression: role of serotonin and brain derived neurotrophic factor. Biol Psychiatry 2012;71(1):30e5. [16] Hamani C, Diwan M, Macedo CE, Brandao ML, Shumake J, Gonzalez-Lima F, et al. Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats. Biol Psychiatry 2010;67(2):117e24. [17] Paxinos G, Watson C. The rat brain in stereotaxic coordinates. Academic Press; 1998. [18] Hamani C, Diwan M, Isabella S, Lozano AM, Nobrega JN. Effects of different stimulation parameters on the antidepressant-like response of medial prefrontal cortex deep brain stimulation in rats. J Psychiatr Res 2010;44(11): 683e7. [19] Detke MJ, Lucki I. Detection of serotonergic and noradrenergic antidepressants in the rat forced swimming test: the effects of water depth. Behav Brain Res 1996;73(1e2):43e6. [20] Detke MJ, Rickels M, Lucki I. Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl) 1995;121(1):66e72.
Contents lists available at ScienceDirect
Brain Stimulation journal homepage: www.brainstimjrnl.com
Short Communications
Supraorbital Stimulation Does Not Induce an Antidepressant-like Response in Rats Tatiana Bregman a, Mustansir Diwan a, José N. Nobrega a, Clement Hamani a, b, * a b
Neuroimaging Research Section, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada Division of Neurosurgery, University of Toronto, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 May 2013 Received in revised form 27 September 2013 Accepted 7 November 2013
Background: Neuromodulation therapies are currently being investigated as potential treatments for depression. One of these treatments involves the stimulation of supraorbital branches of the trigeminal nerve. Objective: To show that supraorbital stimulation is effective in preclinical models. Methods: Rats were given supraorbital stimulation at different settings in the forced swim test (FST) and open field. Results: Supraorbital stimulation did not induce an antidepressant-like response in rats undergoing the FST. This is in contrast to other neuromodulation treatments, such as deep brain stimulation, vagus nerve stimulation and electroconvulsive therapy, which are all effective in this paradigm. Conclusions: Supraorbital stimulation was ineffective in rats undergoing the FST. Such findings do not invalidate results of recent clinical trials. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Supraorbital nerve Trigeminal nerve Stimulation Depression Rats
Introduction Invasive neuromodulation strategies, including deep brain stimulation (DBS) [1e3], cortical stimulation [4] and vagus nerve stimulation (VNS) [5,6] are currently being investigated as potential treatments for depression. A less invasive alternative comprises the delivery of electrical stimulation to the supraorbital branch of the trigeminal nerve, either through superficial or subcutaneously implanted electrodes [7e9]. Preliminary results with the use of superficial trigeminal stimulation in depression has been very promising at short-term [8]. One way of confirming the biological response of an intervention is to test its efficacy in preclinical models [10,11]. Though no animal model adequately mimics all aspects of depressive sates, the forced swim test (FST) has been widely used and is well validated [12,13]. In this paradigm, various therapies have been associated with an antidepressant-like response, including different classes of medications, electroconvulsive therapy, VNS and DBS [13e16].
Financial disclosures: C.H. and J.N.N are consultants for St Jude Medical. This study was sponsored by St Jude Medical. The sponsors had no role in study design, collection and interpretation of data or writing the manuscript. * Corresponding author. Neuroimaging Research Section, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada. Tel.: þ1 416 6035771. E-mail address: [email protected] (C. Hamani). 1935-861X/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brs.2013.11.002
We investigate whether supraorbital stimulation induces an antidepressant-like response in rats undergoing testing in the FST and in an open field. Methods and materials Protocols were approved by the Animal Care committee of the Centre for Addiction and Mental Health. Surgical procedure Male SpragueeDawley rats (250e300 g) were anesthetized with halothane. After a midline incision, the subcutaneous tissue was laterally dissected until the supraorbital region was reached. Paddle electrodes (Plastics One, model E363/76; 1 mm in width, 3.25 mm in length and 0.66 mm in thickness) were then placed over this region, connected to a plastic pedestal (Plastics One, model MS 363) and used as cathodes. An epidural screw placed over the somatosensory cortex was connected to the same pedestal and used as the anode (0.5 mm posterior and 1.5 mm lateral to the bregma) [17]. Sham treated animals had electrodes implanted but did not receive stimulation. Controls also had surgery but were not implanted with electrodes. Electrical stimulation Stimulation was conducted with a handheld device (St Jude Medical model 3510). In our previous reports using DBS, currents in the 100e300 mA range induced and antidepressant-like response in
302
T. Bregman et al. / Brain Stimulation 7 (2014) 301e303
Figure 1. Results of supraorbital stimulation in the forced swim test (FST) and open field. In both tests, rats were treated with supraorbital stimulation at 130 Hz or 20 Hz, 90 ms and 400 mA or 200 mA. A) For scoring in the FST, the predominant behavior of the animals (immobility, swimming, or climbing) during the 5 min of the testing was annotated every 5 s (maximal score of 60). As shown in the figure, no differences were recorded when animals receiving stimulation were compared to those given sham stimulation or controls with no electrodes implanted. B, C) In the open field, the time during which the animals explored the apparatus was scored during the first 5 and 30 min of testing. Overall, no significant differences were found across groups. Results expressed as mean standard error.
the forced swim test [16,18]. Taking this into account, we have tested the effects of two different intensities, 200 and 400 mA. The former was the most effective setting in our previous DBS experiments [18]. The second was a midterm parameter between 200 mA and the threshold for side effects with supraorbital stimulation (most rats had muscle contractions leading to eyelid closure at 600 mA). As for the frequency and pulse width, we have chosen settings that are commonly used in neuromodulation studies (90 ms; 130 Hz and 20 Hz). Higher and lower frequencies influence different neural elements [10]. Frequencies in the 130 Hz range were used in clinical studies investigating the effects of external trigeminal stimulation for depression [8].
Behavioral testing Animals underwent the FST one week after the implantation of electrodes. On the first day of testing, rats were individually placed for 15 min in a cylinder filled with 25 1 C water to a depth of 40 cm [16,18]. Thereafter, experimental animals received continuous stimulation for 4 h. On the following day, rats in this group underwent 2 h of stimulation followed by a 5 min swimming session. As in our previous DBS studies [16,18], animals did not receive stimulation during behavioral testing. For the purpose of scoring, we subdivided the 5 min of the test into 5 s segments [19,20]. Only the predominant behavior of the animals (immobility, swimming or climbing) was blindly scored during each segment, with a maximum possible score of 60 (1 point per segment), as previously described. In the FST immobility scores reflect a depressive-like state. One week after the FST, animals received stimulation for 4 h on day 1 and 2 h on day 2, immediately prior to behavioral testing. Locomotor activity was assessed for 30 min in a 0.49 m2 open field (Med Associates) with infrared photo beams placed along the walls. Crossing the beams provided counts of motor activity. The first 5 min of testing were considered to be a measurement of anxiety, as
animals explored a novel environment. The total 30 min of testing were used to measure overall locomotor activity. Statistical analysis ANOVA (Bonferroni post-hoc) was used to compare behavioral data across groups. Statistical significance was set at P 0.05. Results are presented as mean standard error. Results Overall, no significant differences in immobility (P ¼ 0.4; F4,34 ¼ 1.01), swimming (P ¼ 0.5; F4,34 ¼ 0.81), or climbing (P ¼ 0.5; F4,34 ¼ 0.71) were recorded in animals receiving active stimulation at 400 mA 130 Hz (n ¼ 8), 400 mA 20 Hz (n ¼ 8), 200 mA 130 Hz (n ¼ 6), sham treatment (n ¼ 8) or controls (n ¼ 9) (Fig. 1A). Similarly, no differences in exploratory behavior were recorded across groups in the open field (P ¼ 0.9; F4,25 ¼ 0.27 for the first 5 min of testing and P ¼ 0.2; F4,27 ¼ 1.70 for the whole test) (Fig. 1B and C). Discussion In contrast to humans, stimulation of the supraorbital region did not induce an antidepressant-like response in rodents. Such discrepancies may be attributed to several reasons. As only small case series with a short-term follow-up have been published [8], the role of a placebo response is still unknown. In contrast to the implanted subcutaneous electrodes in our study, patients undergoing treatment were only given stimulation through surface electrodes at night [8]. We chose to use a subcutaneous system for two reasons. First, it has been routinely used in patients with facial pain [9]. Second, animals tend to remove surface electrodes, constantly scratching the region in which they are placed while receiving stimulation.
T. Bregman et al. / Brain Stimulation 7 (2014) 301e303
As in humans, the supraorbital nerve is a branch of the trigeminal nerve located right above the orbit. Electrodes in our study were large enough to cover the whole supraorbital area, suggesting that our negative results were unlikely related to a lack of stimulation coverage. As for the stimulation parameters, we chose frequencies commonly used for invasive neuromodulation strategies and amplitudes that were lower than the threshold for side effects. At these settings, animals were fairly comfortable, eating, grooming and behaving normally while receiving treatment. As a final remark, we stress that animal models have important limitations. It is possible that supraorbital stimulation may not work in rats undergoing the FST but be effective in the clinic. References [1] Malone Jr DA, Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN, et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry 2009;65(4):267e75. [2] Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005; 45(5):651e60. [3] Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 2008;33(2):368e77. [4] Kopell BH, Halverson J, Butson CR, Dickinson M, Bobholz J, Harsch H, et al. Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refractory major depressive disorder. Neurosurgery 2011;69(5):1015e29. discussion 1029. [5] George MS, Rush AJ, Marangell LB, Sackeim HA, Brannan SK, Davis SM, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry 2005;58(5):364e73. [6] Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry 2005;58(5):347e54.
303
[7] DeGiorgio CM, Soss J, Cook IA, Markovic D, Gornbein J, Murray D, et al. Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy. Neurology 2013;80(9):786e91. [8] Schrader LM, Cook IA, Miller PR, Maremont ER, DeGiorgio CM. Trigeminal nerve stimulation in major depressive disorder: first proof of concept in an open pilot trial. Epilepsy Behav 2011;22(3):475e8. [9] Slavin KV, Colpan ME, Munawar N, Wess C, Nersesyan H. Trigeminal and occipital peripheral nerve stimulation for craniofacial pain: a single-institution experience and review of the literature. Neurosurg Focus 2006;21(6):E5. [10] Hamani C, Temel Y. Deep brain stimulation for psychiatric disease: contributions and validity of animal models. Sci Transl Med 2012;4(142):142rv148. [11] Hamani C, Nobrega JN. Preclinical studies modeling deep brain stimulation for depression. Biol Psychiatry 2012;72(11):916e23. [12] Cryan JF, Markou A, Lucki I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 2002;23(5):238e45. [13] Cryan JF, Slattery DA. Animal models of mood disorders: recent developments. Curr Opin Psychiatry 2007;20(1):1e7. [14] Krahl SE, Senanayake SS, Pekary AE, Sattin A. Vagus nerve stimulation (VNS) is effective in a rat model of antidepressant action. J Psychiatr Res 2004;38(3): 237e40. [15] Hamani C, Machado DC, Hipolide DC, Dubiela FP, Suchecki D, Macedo CE, et al. Deep brain stimulation reverses anhedonic-like behavior in a chronic model of depression: role of serotonin and brain derived neurotrophic factor. Biol Psychiatry 2012;71(1):30e5. [16] Hamani C, Diwan M, Macedo CE, Brandao ML, Shumake J, Gonzalez-Lima F, et al. Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats. Biol Psychiatry 2010;67(2):117e24. [17] Paxinos G, Watson C. The rat brain in stereotaxic coordinates. Academic Press; 1998. [18] Hamani C, Diwan M, Isabella S, Lozano AM, Nobrega JN. Effects of different stimulation parameters on the antidepressant-like response of medial prefrontal cortex deep brain stimulation in rats. J Psychiatr Res 2010;44(11): 683e7. [19] Detke MJ, Lucki I. Detection of serotonergic and noradrenergic antidepressants in the rat forced swimming test: the effects of water depth. Behav Brain Res 1996;73(1e2):43e6. [20] Detke MJ, Rickels M, Lucki I. Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl) 1995;121(1):66e72.