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Cannabinoid cb1 receptor in the modulation of stress coping behavior in mice: the role of serotonin and different forebrain neuronal subpopulations

Contents lists available at Cannabinoid CB1 receptor in the modulation of stress coping behavior in mice:The role of serotonin and different forebrain neuronal subpopulations M. Häring , M. Grieb , K. Monory , B. Lutz F.A. Moreira a Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128 Mainz, Germanyb Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, MG 31270-901, Brazil The endocannabinoid system (ECS) may either enhance or inhibit responses to aversive stimuli, possibly Received 7 July 2011 caused by its modulatory activity on diverse neurotransmitters. The aim of this work was to investigate Received in revised form the involvement of serotonin (5-HT) and catecholamines, as well as the role of glutamatergic and GABAergic cannabinoid type 1 (CB Accepted 2 September 2012 1) receptor, in responses to the antidepressant-like doses of the CB1 receptor agonist D9-tetrahydrocannabinol (THC) and the antagonist rimonabant in the forced swim test(FST). Mice received acute injections of low doses of THC (0.1 or 0.5 mg/kg) or high dose of rimonabant (3 or 10 mg/kg) after treatment with the 5-HT synthesis inhibitor pCPA (100 mg/kg, 4 days), the 5-HT receptor antagonist WAY100635 (1 mg/kg, acute) or the non-selective blocker of catecholamine synthesis, AMPT (20 mg/kg, acute). THC and rimonabant were also tested in mutant mice lacking CB1 receptor in specific forebrain neuronal subpopulations.
Both THC and rimonabant induced antidepressant-like effects, quantified as immobility in the FST.
However, only THC effects were reversed by pCPA or WAY100635. In contrast, only AMPT could attenuatethe rimonabant effect. We also found decreased immobility in mice lacking the CB1 receptor in gluta-matergic cortical neurons, but not in forebrain GABAergic neurons, as compared with wild-type controls.
The effect of THC persisted in mutant mice with CB1 receptor inactivation in GABAergic neurons, whereasrimonabant effects were alleviated in these mutants. Thus, employing both pharmacological and genetictools, we could show that the ECS regulates stress responses by influencing GABAergic, glutamatergicand monoaminergic transmission. The antidepressant-like action of THC depends on serotonergicneurotransmission, whereas rimonabant effects are mediated by CB1 receptor on GABAergic neurons andby catecholamine signaling.
Ó 2012 Elsevier Ltd. All rights reserved.
terminals. As the CB1 receptor is present on both GABAergic andglutamatergic terminals (the endocannabinoid The herb Cannabis sativa induces a diversity of emotional system (ECS) is able to control the activation of both inhibitory and responses ranging from anxiolytic and relaxing effects to the excitatory neurotransmission. Therefore, depending on its specific induction of acute panic attacks (). Similarly, spatio-temporal activation within neuronal circuits, this system can divergent emotional responses have been observed in both humans act as a major "bi-directional" neuromodulator (for a review, see and rodents after the administration of D9-tetrahydrocannabinol (THC), the main psychoactive compound from this plant This "dual" role of endocannabinoid signaling has likely been the reason for a number of contradictory results in rodent models of ). Postsynaptically produced endocannabinoids, the anxiety and depression ( endogenous counterparts of THC, including anandamide and 2- ). This is supported by recent studies, using conditional arachidonoyl glycerol, function as retrograde modulators of mutant mice lacking the CB1 receptor either on GABAergic or glu- synaptic activity, which, through activation of presynaptic CB1 tamatergic neurons, supporting the notion that the two pop- receptor, restrain neurotransmitter release from presynaptic ulations might be important for the biphasic effect ; ). Another explanationmight be a variation in the initial baseline stress level of an animal,which depends on a multitude of genetic, environmental and * Corresponding author. Tel.: þ49 (0)6131 39 25912; fax: þ49 (0)6131 39 23536.
E-mail address: (B. Lutz).
experimental factors. This baseline might alter the activity of the 0028-3908/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
M. Häring et al. / Neuropharmacology 65 (2013) 83e89 Altogether, accumulating evidence supports the involvement of CB1 receptor signaling in the regulation ofmonoaminergic neurotransmission, which could, in turn, mediate a-methyl para-tyrosine endocannabinoid effects in the FST.
receptor, cannabinoid type 1 receptor approaches, we aimed at investigating the contradictory findings endocannabinoid system of ECS modulation in emotion and how serotonergic and cate- cholamine transmission might be involved in. To address this g-amino buryric acid issue, we studied the antidepressant-like effects of the CB1 receptor agonist THC, and the antagonist/inverse agonist rimo- nabant in combination with drugs disrupting serotonergic (with parachlorophenylalanine, pCPA; ) and catecholamine (with a-methyl-para-tyrosine, AMPT; prefrontal cortex ) transmission. Both drugs were also shown to block the antidepressant-like effects of 5-HT or dopamine reuptake inhibitors Furthermore, we included mice 3-carboxamide (also called SR141716) lacking the CB1 receptor in specific neuronal subpopulations, namely in GABAergic forebrain neurons (GABA-CB1 mouse line) and glutamatergic cortical neurons (Glu-CB1 mouse line) to investigate the role of these cells in THC and rimonabant effects.
ECS, thus, resulting in the same behavioral effect induced by This study was performed on adult (3e5 months old) male C57BL/6N mice, as signaling blockade or enhancement) (; well as mutants and littermate controls in a predominant C57BL/6N background.
). Such a dose dependent cannabinoid-induced biphasic Animals were housed in a temperature- and humidity-controlled room with a 12 h effect on the behavioral performance can also be seen in the forced lightedark cycle (lights on at 1 am) and had access to food and water ad libitum. The swim test (FST). One of the most widely used behavioral paradigms experimental protocols were carried out in accordance with the EuropeanCommunities Council Directive of 24 November 1986 (86/609/EEC) and approved by to detect antidepressant-like activities of drugs ( the Ethical Committee on animal care and use of Rhineland-Palatinate, Germany.
). It is based on the observation that Generation, breeding and genotyping of the mutant lines were performed according rodents, when exposed to an inescapable situation (immersion in to previous publications: CBflox/flox;Nex-cre mice (referred to as Glu-CB1 a beaker filled with water), will cease over several minutes to mice (referred to as GABA-CB1 engage in escape-oriented movements and adopt an immobile Animals were in a predominant C57BL/6Nbackground (at least 7 backcrosses) and were group housed (3e5 animals per cage) passive "floating" posture. Acquired immobility is often interpreted until one week before behavioral testing, when they were single housed to avoid as "behavioral despair", mimicking psychomotor impairments behavioral differences between dominant and subordinate animals. All experiments experienced by depressed patients ().
were performed during the second half of the light phase.
A reduction of immobility time in the FST is especially observedafter treatment with a broad range of antidepressants, which 2.2. Drug treatments increase serotonergic and/or noradrenergic neurotransmission(). In this model, CB Injections were given intraperitoneally (i.p.) in a volume of 10 ml/kg body 1 receptor activa- weight. Stock solution of rimonabant (SR141716; NIMH Chemical Synthesis and tion can lead to a decrease or increase of immobility Drug Supply Program) was prepared by solving the lyophilized drug in DMSO (Sigma ; ). Blocking the Aldrich). Working solution contained the respective rimonabant concentration CB1 receptor with SR141716 (rimonabant) can also induce either an dissolved in a 0.9 w/v % NaCl solution containing 2 vol % DMSO and 2.5 vol % pol- antidepressant-like effect () yoxyethylenesorbitan monooleate (Tween-80; Sigma Aldrich). THC (THC Pharm, or increase immobility behavior, depending on the dose Frankfurt, Germany) was warmed and dissolved in 100% ethanol. Working solutioncontained the respective THC concentration dissolved in a 0.9 w/v % NaCl solution containing 0.5 vol % ethanol and 2.5 vol % Tween-80. WAY100635 (SigmaeAldrich) Thus, before we consider the ECS as a valid strategy for devel- was diluted in 0.9 w/v % NaCl solution. pCPA (SigmaeAldrich) was suspended in oping new drugs for the treatment of mood disorders a 0.9 w/v % NaCl solution containing 2.5 vol % Tween-80. AMPT (SigmaeAldrich) was suspended in a 0.9 w/v % NaCl solution containing 10 vol % Tween-80. All vehiclecontrols contained the respective concentration of Tween-80, DMSO and/or ethanol understand the reasons for these complex responses dissolved in a 0.9 w/v % NaCl solution.
Surprisingly, even though marihuana has been used for Single drug injections were given 30 min prior to the experiment. If the mice recreational purposes since centuries, studies on antidepressive were exposed to two different drugs, first drug was applied 45 min and the second potentials of its major component, THC, are still sparse.
drug 30 min before the experiment. pCPA was injected every 24 h for 4 days with the One possible mechanism through which cannabinoids interfere last injection on the day of the FST. For each experiment, vehicle treatment wasgiven as control in the same injection schedule as the respective drug treated mice.
with stress-related responses might be through monoaminergic The doses were selected based on previous works, WAY100635 ( mechanisms. Several studies connected the ECS with serotonergic AMPT pCPA ); SR141716 transmission. Indeed, the CB1 receptor antagonist rimonabant was shown to increase the efflux of 5-HT and noradrenaline in the ratprefrontal cortex (). CB1 receptor is expressed in mouse serotonergic raphe neurons (and innoradrenergic nerve terminals in the rat frontal cortex ( To evaluate potential effects by the drugs on locomotor activity we performed an open field test. The open field was an H 40 cm  W 40 cm  L 40 cm box illuminated ). In addition, CB1 receptor signaling influences the at 200 lux, in which the animal was placed for 5 min to allowed free exploration. The firing rate of serotonergic and noradrenergic neurons in the rat animal movement was recorded, and the distance moved was scored by the SMART raphe nuclei and locus coeruleus, respectively ( program (PanLab, Spain).
M. Häring et al. / Neuropharmacology 65 (2013) 83e89 2.4. Forced swim test (FST) 1 mg/kg (Pretreatment factor: F1,35 ¼ 3.41; p > 0.05; THC factor:F1,35 ¼ 3.07; p > 0.05; Interaction[Pretreatment  THC]: F1,35 ¼ 3.79; The paradigm was performed in a round glass beaker (18 cm in diameter and p ¼ 0.0596; Column comparison 30 cm in height) filled with tap water at 25  0.5 C. The water level was approximately 20 cm to prevent the animal from touching the bottom of the glass.
NewmaneKeuls Multiple Comparison post-test q ¼ 3.846; p < 0.05; The mouse was also unable to climb out off the beaker. The animal was carefully C). In addition, the effect of THC (0.1 mg/kg) was lowered into the water and recorded on DVD for 6 min. The first 2 min were not prevented by a pre-treatment with a low dose (0.5 mg/kg) of evaluated; however, floating behavior was scored for the following 4 min by an rimonabant (Pretreatment factor: F experimenter blind to genotype and treatment. Floating was defined by immo- 1,90 ¼ 5.619; p < 0.05; THC bility of the animal and minimal movements to keep the body's balance. The factor; F1,90 ¼ 1.638; p > 0.05; Interaction[Pretreatment  THC]: functionality of the paradigm was successfully tested by acute i.p. injection of the F1,90 ¼ 4.669; p < 0.05; see Applying rimonabant alone in antidepressant drug imipramine (30 mg/kg), which resulted in a significant higher dose (3 and 10 mg/kg) also resulted in a decreased immo- decrease in floating behavior as compared to saline treated animals (t16 ¼ 10.45; bility (F2,19 ¼ 10.74; p < 0.001; A). Co-administration of pCPA p < 0.001; n ¼ 9).
100 mg/kg (Pretreatment factor: F1,36 ¼ 0.57; p > 0.05; rimonabant 2.5. Statistical analysis factor: F1,36 ¼ 25.97; p < 0.0001; Interaction: F1,36 ¼ 0.15; p > 0.05;B) and WAY100635 (Pretreatment factor: F1,33 ¼ 0.38; Data are presented as mean  standard error of the mean (SEM). All behavioral p > 0.05; rimonabant factor: F1,33 ¼ 52.32; p < 0.0001; endpoints of the open field and FST were analyzed using Student t-test, one-way Interaction[Pretreatment  rimonabant]: F1,33 ¼ 0.29; p > 0.05; C), ANOVA or two-way ANOVA followed by the NewmaneKeuls Multiple Comparison respectively, failed to block the effect of 10 mg/kg rimonabant. In post-test depending on the combination of genotype and treatment factors. Graphsand statistics were generated by GraphPad Prism 4.03 Software. Results were contrast, a per se ineffective dose of 20 mg/kg AMPT attenuated considered to be significant at p < 0.05.
the effect of rimonabant (Pretreatment factor: F1,44 ¼ 14.18;p > 0.05; Rimonabant factor: F1,44 ¼ 30.49; p < 0.01; Interaction[Pretreatment  rimonabant]: F1,44 ¼ 13.43; p < 0.001; In order to test whether THC and rimonabant effects depend on 3.1. Locomotor activity CB1 receptor activation on specific glutamatergic or GABAergicneuronal population, we tested these drugs in conditional mutant To avoid potential disturbing factors related to locomotor mice lacking CB1 receptor specifically in these neuronal subpopu- activity, all drugs were tested in the open field test. In fact none of lations. However, we first characterized the phenotype of these the drugs and doses applied altered the distance moved as animals in the FST, without any treatment. Analyzing the floating compared to respective control groups ().
behavior in the conditional CB1 receptor knock-out mice revealeda significant decrease in floating time for Glu-CB/ 3.2. Antidepressant-like effects (mean  SEM: WT ¼ 82.9  16 s and Glu-CB/ t10 ¼ 3.02; p < 0.01; n ¼ 6; Pre-test not shown but is similar Animals treated with a low dose of THC (0.1 and 0.5 mg/kg) as depicted in without changes in open field activity showed a significant reduction in floating behavior (F2,23 ¼ 4.17;  SEM: WT ¼ 1331  202 cm and Glu- p < 0.05; A). The THC effect of 0.1 mg/kg was prevented by ¼ 1544  498 cm; t16 ¼ 0.39, ns; n ¼ 9). The difference in a pretreatment with the 5-HT synthesis inhibitor pCPA 100 mg/kg phenotype in these animals was annulled by the pretreatment with (Pretreatment factor: F1,68 ¼ 1.77; p > 0.05; THC factor: pCPA (Genotype factor: F1,46 ¼ 1.47; ns; Treatment factor: F1,68 ¼ 10.12; p < 0.01; Interaction[Pretreatment  THC]: F1,68 ¼ 7.33; F1,46 ¼ 1.72; ns; Interaction[Genotype  Treatment]: F1,46 ¼ 4.33; p < 0.01; B) and the 5-HT1A receptor antagonist WAY100635 p < 0.05; On the other hand, CB1 receptor deletion from Table 1Locomotor activity (cm moved in 5 min) in the open field after different pharmacological treatments.
Experimental groups Effects of THC and rimonabant F4,38 ¼ 0.59; ns Interaction of THC with serotonin release Vehicle þ Vehicle Interaction (Rim/pCPA): F1,36 ¼ 0.001; ns Vehicle þ THC [0.1 mg/kg] Vehicle  Rim: F1,36 ¼ 0.56; ns pCPA [100 mg/kg] þ Vehicle Vehicle  pCPA: F1,36 ¼ 0.06; ns pCPA [100 mg/kg] þ THC [0.1 mg/kg] Interaction (Rim/WAY): F1,36 ¼ 0.01; ns WAY [1 mg/kg] þ Vehicle Vehicle  Rim: F1,36 ¼ 0.46; ns WAY [1 mg/kg] þ THC [0.1 mg/kg] Vehicle  WAY: F1,36 ¼ 1.77; ns Interaction of rimonabant with serotonin release Vehicle þ Vehicle Interaction (Rim/pCPA): F1,36 ¼ 0.93; ns Vehicle þ Rim [10 mg/kg] Vehicle  Rim: F1,36 ¼ 0.03; ns pCPA [100 mg/kg] þ Vehicle Vehicle  pCPA: F1,36 ¼ 0.26; ns pCPA [100 mg/kg] þ Rim [10 mg/kg] Interaction (Rim/WAY): F1,36 ¼ 3.63; ns WAY [1 mg/kg] þ Vehicle Vehicle  Rim: F1,36 ¼ 0.003; ns WAY [1 mg/kg] þ Rim [10 mg/kg] Vehicle  WAY: F1,36 ¼ 2.09; ns Interaction of rimonabant with catecholamine release Vehicle þ Vehicle Interaction: F1,41 ¼ 0.103; ns Vehicle þ Rim [10 mg/kg] Vehicle  Rim: F1,41 ¼ 0.097; ns AMPT [20 mg/kg] þ Vehicle Vehicle  AMPT: F1,41 ¼ 1.202; ns AMPT [20 mg/kg] þ Rim [10 mg/kg]

M. Häring et al. / Neuropharmacology 65 (2013) 83e89 Fig. 1. Antidepressant-like effects of THC and the role of serotonin. Treatment with (A) THC (0.1 mg/kg and 0.5 mg/kg) decreased immobility in the forced swim test. The effect ofTHC (0.1 mg/kg) was attenuated when combined (B) with the serotonin synthesis inhibitor pCPA (100 mg/kg), (C) with the 5-HT1A receptor antagonist WAY100635 (WAY; 1 mg/kg),and (D) with a per se non-effective dose of rimonabant (Rim; 0.5 mg/kg). Data are expressed as mean  SEM. n ¼ 9e24; *p < 0.05 (students t-test); #p < 0.05, ##p < 0.01, ###p <0.001 (NewmaneKeuls Multiple Comparison post-test following two-way ANOVA).
forebrain GABAergic neurons had no effect on the performance in situation that Glu-CB/ mice showed already an antidepressant- the FST (mean  SEM: WT ¼ 90.8  26.3 and GABA-CB/ like behavior which cannot be further enhanced by THC.
65.3  17.2; t11 ¼ 0.83, ns; n ¼ 6e7; Pre-test not shown but is These findings suggest that, even though both drugs have similar as depicted in and C). By testing drugs in these antidepressant-like properties, they seem to interfere with animals, we were able to show that the THC effect was still present different circuits, serotonergic transmission being important for the mutants (Genotype factor: F1,67 ¼ 0.622; ns; Treat- behavioral response to low doses of THC, and catecholamines for ment factor: F1,67 ¼ 10.89; p < 0.01; Interaction[Genotype  Treatment]: the rimonabant effects. The antidepressant-like effect of THC is in F1,68 ¼ 0.371; ns; On the contrary, the decrease in floating line with previous data obtained with other cannabinoids induced by a dose of 10 mg/kg rimonabant was not detect- able in GABA-CB/ animals (Genotype factor: F1,33 ¼ 6.97; addition, the role of 5-HT was also proposed previously for this p < 0.05; Treatment factor: F1,33 ¼ 14.64; p < 0.001; class of substances. For instance, demon- Interaction[Genotype  Treatment]: F1,33 ¼ 5.17; p < 0.05; strated that the antidepressant-like effects of WIN-55,212-2,a synthetic cannabinoid agonist, was blocked by pCPA in rats.
Likewise, WAY100635 blocked the effect of cannabidiol, a non-psychotomimetic phytocannabinoid, in mice in the FST ( Our results confirm previous findings on the contradictory roles Finally, the same 5-HT1A receptor antagonist also of the ECS activation and inhibition regarding stress coping. We blocked the anxiolytic-like effects of THC in rats could show that low dose of THC (0.1 and 0.5 mg/kg) or high dose of ). The latter result is highly congruent with our findings, as the CB1 receptor antagonist rimonabant (3 and 10 mg/kg) led to anxiolytic drugs can also have antidepressent-like effects and vice a decrease of immobility, indicating an antidepressant-like behavior. THC effects were prevented by a per se ineffective dose A relevant neuronal circuit in respect to our finding might be the of rimonabant (0.5 mg/kg; proving the CB1 receptor projection between prefrontal cortex (PFC) and serotonergic dependence of the THC effect. Remarkably, inhibition of 5-HT neurons in the raphe nuclei, which is modulated by cannabinoids, as synthesis, and 5-HT1A receptor blockade, respectively, was also proposed by . The PFC, a region highly involved able to prevent the effects of THC, but not of rimonabant. On the in the processing and evaluation of a stressful situation, has strong other hand, using a genetic approach, we could show that the glutamatergic connections with the raphe nuclei antidepressant-like effects of rimonabant, but not of THC for the Interestingly, the connection seems to be indirect, doses used in this study, seem to depend exclusively on CB1 receptor as decrease in excitatory drive leads to an increased 5-HT trans- in GABAergic neurons. Low doses of THC might act mainly via other mission. Thus, the local CB1 receptor activation on glutamatergic CB1 receptor populations, potentially on glutamatergic neurons, terminals in the PFC by the synthetic cannabinoid receptor agonist even though there is no final proof for this notion, due to the WIN55,212 resulted in an increased firing of serotonergic neurons

M. Häring et al. / Neuropharmacology 65 (2013) 83e89 Fig. 2. Antidepressant-like effects of rimonabant and the role of serotonin and catecholamines. Treatment with (A) rimonabant (Rim; 3 and 10 mg/kg) both decreased immobility inthe forced swim test. The decrease in immobility induced by rimonabant (10 mg/kg) was not altered by (B) the serotonin synthesis inhibitor pCPA (100 mg/kg) or (C) the 5-HT1Areceptor antagonist WAY100635 (WAY; 1 mg/kg), however, by (D) the catecholamine synthesis inhibitor AMPT (20 mg/kg). Data are expressed as mean  SEM. n ¼ 9e12; *p < 0.05,***p < 0.001 (students t-test); ###p < 0.001 (NewmaneKeuls Multiple Comparison post-test following two-way ANOVA); ns, non significant.
Earlier studies already suggested that an However, the acute/sub- reduced excitatory input from the PFC is followed by a decreased chronic antidepressant-like effect of this CB1 receptor antagonist activation of inhibitory neurons in the raphe nuclei, leading to an was shown previously in rodents exposed to the FST ( increased 5-HT transmission and subsequently to decreased anxiety ; One explanation could be the chronic and depressive-like behavior use in clinical applications, resulting in the negative side effects.
Regarding the effects of high doses of rimonabant, this seems to Also one should keep in mind the clinical intent to reduce obesity be in contrast with the clinical effects of this drug, which may using rimonabant. Obesity might sensitize the body to an increased induce anxiety and depression in patients (for reviews, see susceptibility toward depressive behavior. Nevertheless, our data Fig. 3. Behavioral phenotype after cell type-specific CB1 receptor deletion, and pharmacological effects with THC and rimonabant. (A) Inactivation of CB1 receptor in corticalglutamatergic neurons led to a decrease in immobility (black bar), which was blocked by the treatment with pCPA (100 mg/kg), comparable as in wild-type controls. (B) Inactivationof CB1 receptor in forebrain GABAergic neurons did not alter immobility (black bar), and the effect of THC (0.1 mg/kg) on immobility is still detectable in mutant mice. (C) The effectof rimonabant (Rim; 10 mg/kg), however, was not present in GABA-CB/ mice. Data are expressed as mean  SEM; n ¼ 10e15; #p < 0.05; ##p < 0.01; ###p < 0.001 (Newmane Keuls Multiple Comparison post-test following two-way ANOVA); yyp<0.01 (two-way ANOVA treatment factor). ns, non significant. Abbreviations: mut, mutant, i.e. Glu-CB/ ; wt, wild-type littermate control, i.e. Glu-CB1 or GABA-CB1 , respectively.
M. Häring et al. / Neuropharmacology 65 (2013) 83e89 strongly suggest that this antagonist/inverse agonist acts via the of antagonist/inverse agonist, on the other hand, dominantly acted inhibition of CB1 receptor on GABAergic terminals, since the via CB1 receptor on GABAergic neurons and depended at least not decrease in floating induced by rimonabant was abolished when mainly on serotonergic transmission, but on catecholamine trans- injected into GABA-CB/ mutant mice. Why inhibiting 5-HT mission. Our data further suggest a two-neuronal subpopulation transmission had no effect on the action of rimonabant is not model in which glutamatergic and GABAergic neurons, under the clear. This seems to be in contrast with neurochemical data, control of the CB1 receptor, seem to be differently sensitive to showing that similar doses of rimonabant increased 5-HT in the prefrontal cortex (). One possibility could be thesystemic increase in GABAergic transmission as the result of the Statement of conflicts of interest blockade of CB1 receptor, which could attenuate the effect of anincreased serotonergic transmission downstream in the stress The authors declare to have no conflicts of interest.
circuit. Also possible would be an assisting role of 5-HT trans-mission after rimonabant treatment. In this respect, Tzavara andcolleagues also showed an increased release of catecholamines as response to rimonabant treatment, thus potentially covering thebehavioral effect of blocking 5-HT transmission We would like to thank Andrea Conrad, Danka Dormann, Anisa ). In consistence with this finding, we were able to attenuate Kosan, and Anne Rohrbacher for genotyping of mutant mice. This the antidepressant-like effect of rimonabant by applying a per se research was supported in part by the German Research Foundation ineffective dose of AMPT, a blocker of catecholamine synthesis. The DFG (to B.L. and K.M.; FOR926, subproject SP3), and by a stipend additional absence of the behavioral effects of rimonabant in the from the Humboldt Foundation (to F.M.).
mice suggests a mechanism for the action of this drug, mediated by catecholamine signaling and controlled by GABA release. Recent finding also suggest an important role for the opioidsystem regarding the antidepressant-like effects of rimonabant Bambico, F.R., Katz, N., Debonnel, G., Gobbi, G., 2007. Cannabinoids elicit (Thus, they were able to block the rimonabant- antidepressant-like behaviour and activate serotonergic neurons through themedial prefrontal cortex. J. Neurosci. 27, 11700e11711.
induced decrease in immobility by interfering with opioid Bambico, F.R., Cassano, T., Dominguez-Lopez, S., Katz, N., Walker, C.D., Piomelli, D., signaling, in particular by blocking the k-opioid receptor Gobbi, G., 2010. Genetic deletion of fatty acid amide hydrolase alters emotional ). Interestingly, the activation of this receptor was also behaviour and serotonergic transmission in the dorsal raphe, prefrontal cortex,and hippocampus. Neuropsychopharmacology 35, 2083e2100.
suggested to increase the noradrenergic drive in the hypothalamic Bambico, F.R., Hattan, P.R., Garant, J.P., Gobbi, G., 2012. Effect of delta-9- paraventricular nucleus ).
tetrahydrocannabinol on behavioral despair and on presynaptic and post- Contrasting with the rimonabant treatment, which seems to Psychiatry 38, 88e96.
depend on CB1 receptors on GABAergic neurons, specific deletion of Berrendero, F., Maldonado, R., 2002. Involvement of the opioid system in the the receptor in GABAergic neurons (GABA-CB/ anxiolytic-like effects induced by D9-tetrahydrocannabinol. Psychopharma- induce an antidepressant-like response. However, GABA-CB/ cology (Berl) 163, 111e117.
Beyer, C.E., Dwyer, J.M., Piesla, M.J., Platt, B.J., Shen, R., Rahman, Z., Chan, K., mice are still responsive to THC, suggesting that GABAergic CB1 Manners, M.T., Samad, T.A., Kennedy, J.D., Bingham, B., Whiteside, G.T., 2010.
receptor is unlikely to be the target of low doses of THC. Therefore, Depression-like phenotype following chronic CB1 receptor antagonism. Neu- we suggest a possible connection to CB robiol. Dis. 39, 148e155.
1 receptor on other neuronal Braida, D., Limonta, V., Malabarba, L., Zani, A., Sala, M., 2007. 5-HT populations. Recent findings in our group have highlighted the involved in the anxiolytic effect of D9-tetrahydrocannabinol and AM404, the importance of glutamatergic CB1 receptors, showing that compa- anandamide transport inhibitor, in Sprague-Dawley rats. Eur. J. Pharmacol. 555, rable doses of CB1 receptor agonist failed to induce an anxiolytic effect in Glu-CB/ Celada, P., Puig, M.V., Casanovas, J.M., Guillazo, G., Artigas, F., 2001. Control of dorsal mutants tested in the elevated plus maze raphe serotonergic neurons by the medial prefrontal cortex: involvement of Due to the fact that Glu-CB/ serotonin-1A, GABAA, and glutamate receptors. J. Neurosci. 21, 9917e9929.
a decrease in floating behavior without treatment, it was not Corrodi, H., Hanson, L.C., 1966. Central effects of an inhibitor of tyrosine hydrox- possible to test the equivalent hypothesis in the FST. A similar ylation. Psychopharmacologia 10, 116e125.
Cryan, J.F., Mombereau, C., 2004. In search of a depressed mouse: utility of models decrease in immobility was previously observed in Glu-CB/ for studying depression-related behaviour in genetically modified mice. Mol.
(). This increased stress-coping behavior in Glu- Psychiatry 9, 326e357.
Egashira, N., Matsuda, T., Koushi, E., Higashihara, F., Mishima, K., Chidori, S., mice is in contrast with other studies in which these mutants Hasebe, N., Iwasaki, K., Nishimura, R., Oishi, R., Fujiwara, M., 2008. D9-tetra- actually showed increased anxiety-like responses ( hydrocannabinol prolongs the immobility time in the mouse forced swim test: ; ; ). Thus, the decrease in involvement of cannabinoid CB1 receptor and serotonergic system. Eur. J.
floating behavior may rather be an inadequate fear response than Pharmacol. 589, 117e121.
El-Alfy, A.T., Ivey, K., Robinsonm, K., Ahmed, S., Radwan, M., Slade, D., Khan, I., a positive stress coping behavior. This situation would prevent ElSohly, M., Ross, S., 2010. Antidepressant-like effect of D9-tetrahydrocannab- a stringent interpretation of a possible antidepressant-like of THC inol and other cannabinoids isolated from Cannabis sativa L. Pharmacol. Bio- effect in Glu-CB/ chem. Behav. 95, 434e442.
Gobbi, G., Bambico, F.R., Mangieri, R., Bortolato, M., Campolongo, P., Solinas, M., The present data also suggest that the behavioral changes in the Cassano, T., Morgese, M.G., Debonnel, G., Duranti, A., Tontini, A., Tarzia, G., may depend on serotonergic transmission, as it Mor, M., Trezza, V., Goldberg, S.R., Cuomo, V., Piomelli, D., 2005. Antide- was blocked by pCPA. Why the inhibition of 5-HT transmission pressant-like activity and modulation of brain monoaminergic transmission blocks this effect is not clear. One possibility might be a continuous by blockade of anandamide hydrolysis. Proc. Natl. Acad. Sci. U. S. A. 102,18620e18625.
over-excitation of the serotonergic neurons via a different pathway Gorzalka, B.B., Hill, M.N., 2011. Putative role of endocannabinoid signaling in the (independent of inhibitory interneurons in the raphe) as suggested above, caused by a general elevated excitatory drive.
psychopharmacol. Biol. Psychiatry 35, 1575e1585.
Griebel, G., Stemmelin, J., Scatton, B., 2005. Effects of the cannabinoid CB1 receptor In summary, by using both pharmacological and genetic antagonist rimonabant in models of emotional reactivity in rodents. Biol.
approaches, we could provide new insights into how to reconcile Psychiatry 57, 261e267.
the contradictory findings on antidepressant-like effect of CB Hall, W., Solowij, N., 1998. Adverse effects of cannabis. Lancet 352, 1611e1616.
Häring, M., Marsicano, G., Lutz, B., Monory, K., 2007. Identification of the cannabi- receptor agonist and antagonist/inverse agonist. Low doses of noid receptor type 1 in serotonergic cells of raphe nuclei in mice. Neuroscience agonist clearly depended on serotonergic transmission. High doses 146, 1212e1219.
M. Häring et al. / Neuropharmacology 65 (2013) 83e89 Häring, M., Kaiser, N., Monory, K., Lutz, B., 2011. Circuit specific functions of endocannabinoid system controls key epileptogenic circuits in the hippo- cannabinoid CB1 receptor in the balance of investigatory drive and exploration.
campus. Neuron 51, 455e466.
PLoS One 6, e26617.
Moreira, F.A., Crippa, J.A., 2009. The psychiatric side effects of rimonabant. Rev. Bras.
Häring, M., Guggenhuber, S., Lutz, B., 2012. Neuronal populations mediating the Psiquiatr 31, 145e153.
effects of endocannabinoids on stress and emotionality. Neuroscience 204, Moreira, F.A., Lutz, B., 2008. The endocannabinoid system: emotion, learning and addiction. Addict. Biol. 13, 196e212.
Hill, M.N., Gorzalka, B.B., 2005. Pharmacological enhancement of cannabinoid CB1 Moreira, F.A., Grieb, M., Lutz, B., 2009. Central side effects of therapies based on CB1 receptor activity elicits an antidepressant-like response in the rat forced swim cannabinoid receptors agonist and antagonists: focus on anxiety and depres- test. Eur. Neuropsychopharmacol. 15, 593e599.
sion. Best Pract. Res. Clin. Endocrinol. Metab. 23, 133e144.
Höschl, C., Svestka, J., 2008. Escitalopram for the treatment of major depression and Muntoni, A.L., Pillolla, G., Melis, M., Perra, S., Gessa, G.L., Pistis, M., 2006. Cannabi- anxiety disorders. Expert Rev. Neurother. 8, 537e552.
noids modulate spontaneous neuronal activity and evoked inhibition of locus Jacob, W., Yassouridis, A., Marsicano, G., Monory, K., Lutz, B., Wotjak, C.T., 2009.
coeruleus noradrenergic neurons. Eur. J. Neurosci. 23, 2385e2394.
Endocannabinoids render exploratory behaviour largely independent of the O'Leary, O.F., Bechtholt, A.J., Crowley, J.J., Hill, T.E., Page, M.E., Lucki, I., 2007.
test aversiveness: role of glutamatergic transmission. Genes Brain Behav. 8, Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test.
Jankowski, M.P., Sesack, S.R., 2004. Prefrontal cortical projections to the rat dorsal Psychopharmacology (Berl) 192, 357e371.
raphe nucleus: ultrastructural features and associations with serotonin and Oropeza, V.C., Mackie, K., Van Bockstaele, E.J., 2007. Cannabinoid receptors are gamma-aminobutyric acid neurons. J. Comp. Neurol. 468, 518e529.
localized to noradrenergic axon terminals in the rat frontal cortex. Brain Res.
Jesse, C.R., Wilhelm, E.A., Bortolatto, C.F., Nogueira, C.W., 2010. Evidence for the 1127, 36e44.
involvement of the noradrenergic system, dopaminergic and imidazoline Patel, S., Hillard, C.J., 2006. Pharmacological evaluation of cannabinoid receptor receptors in the antidepressant-like effect of tramadol in mice. Pharmacol.
ligands in a mouse model of anxiety: further evidence for an anxiolytic role for Biochem. Behav. 95, 344e350.
endogenous cannabinoid signaling. J. Pharmacol. Exp. Ther. 318, 304e311.
Jiang, W., Zhang, Y., Xiao, L., Van Cleemput, J., Ji, S.P., Bai, G., Zhang, X., 2005.
Rey, A.A., Purrio, M., Viveros, M.P., Lutz, B., 2012. Biphasic effects of cannabinoids in Cannabinoids promote embryonic and adult hippocampus neurogenesis anxiety responses: CB1 and GABAB receptors in the balance of GABAergic and and produce anxiolytic and antidepressant-like effects. J. Clin. Invest. 115, Kano, M., Ohno-Shosaku, T., Hashimotodani, Y., Uchigashima, M., Watanabe, M., Steiner, M.A., Marsicano, G., Nestler, E.J., Holsboer, F., Lutz, B., Wotjak, C.T., 2008a.
2009. Endocannabinoid-mediated control of synaptic transmission. Physiol.
Antidepressant-like behavioral effects of impaired cannabinoid receptor type 1 Rev. 89, 309e380.
signaling coincide with exaggerated corticosterone secretion in mice. Psycho- Kaster, M.P., Santos, A.R., Rodrigues, A.L., 2005. Involvement of 5-HT1A receptors in neuroendocrinology 33, 54e67.
the antidepressant-like effects of adenosine in the forced swim test. Brain Res.
Steiner, M.A., Wanisch, K., Monory, K., Marsicano, G., Borroni, E., Bächli, H., Bull. 67, 53e61.
Holsboer, F., Lutz, B., Wotjak, C.T., 2008b. Impaired cannabinoid receptor type 1 Lafenêtre, P., Chaouloff, F., Marsicano, G., 2009. Bidirectional regulation of novelty- signaling interferes with stress-coping behaviour in mice. Pharmacogenomics J.
induced behavioural inhibition by the endocannabinoid system. Neurophar- macology 57, 715e721.
Steiner, M.A., Marsicano, G., Wotjak, C.T., Lutz, B., 2008c. Conditional cannabinoid Laorden, M.L., Castells, M.T., Martínez, M.D., Martínez, P.J., Milanés, M.V., 2000.
receptor type 1 mutants reveal neuron subpopulation-specific effects on behavioral Activation of c-fos expression in hypothalamic nuclei by mu- and kappa- and neuroendocrine stress responses. Psychoneuroendocrinology 33, 1165e1170.
receptor agonists: correlation with catecholaminergic activity in the hypotha- Tzavara, E.T., Davis, R.J., Perry, K.W., Li, X., Salhoff, C., Bymaster, F.P., Witkin, J.M., lamic paraventricular nucleus. Endocrinologist 141, 1366e1376.
Nomikos, G.G., 2003. The CB1 receptor antagonist SR141716A selectively Lockie, S.H., Czyzyk, T.A., Chaudhary, N., Perez-Tilve, D., Woods, S.C., Oldfield, B.J., increases monoaminergic neurotransmission in the medial prefrontal cortex: Statnick, M.A., Tschöp, M.H., 2011. CNS opioid signaling separates cannabinoid implications for therapeutic actions. Br. J. Pharmacol. 138, 544e553.
receptor 1-mediated effects on body weight and mood-related behavior in Viveros, M.P., Marco, E.M., File, S.E., 2005. Endocannabinoid system and stress and mice. Endocrinology 152, 3661e3667.
anxiety responses. Pharmacol. Biochem. Behav. 81, 331e342.
Lucki, I., Dalvi, A., Mayorga, A.J., 2001. Sensitivity to the effects of pharmacologically Weissman, A., Koe, B.K., 1965. Behavioral effects of L-alpha-methyltyrosine, an selective antidepressants in different strains of mice. Psychopharmacology inhibitor of tyrosine hydroxylase. Life Sci. 4, 1037e1048.
(Berl) 155, 315e322.
Wotjak, C.T., 2005. Role of endogenous cannabinoids in cognition and emotionality.
Massa, F., Mancini, G., Schmidt, H., Steindel, F., Mackie, K., Angioni, C., Oliet, S.H., Mini. Rev. Med. Chem. 5, 659e670.
Geisslinger, G., Lutz, B., 2010. Alterations in the hippocampal endocannabinoid Zanelati, T., Biojone, C., Moreira, F.A., Guimaraes, F.S., Joca, S.R., 2010. Antidepres- system in diet-induced obese mice. J. Neurosci. 30, 6273e6281.
sant-like effects of cannabidiol in mice: possible role of 5-HT1A receptors. Br. J.
Monory, K., Massa, F., Egertova, M., Eder, M., Blaudzun, H., Westenbroek, R., Pharmacol. 159, 122e128.
Kelsch, W., Jacob, W., Marsch, R., Ekker, M., Long, J., Rubenstein, J.L., Goebbels, S., Zuardi, A.W., Shirakawa, I., Finkelfarb, E., Karniol, I.G., 1982. Action of cannabidiol on Nave, K.A., During, M., Klugmann, M., Wolfel, B., Dodt, H.U., Zieglgansberger, W., the anxiety and other effects produced by D9-THC in normal subjects.
Wotjak, C.T., Mackie, K., Elphick, M.R., Marsicano, G., Lutz, B., 2006. The Psychopharmacology (Berl) 76, 245e250.

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