Recent evidence suggests that non-selective cannabinoid receptor agonists may regulate serotonin 2A (5-HT 2A ) receptor neurotransmission in brain. The molecular mechanisms of this regulation are unknown, but could involve cannabinoid-induced enhanced interaction between 5-HT 2A and dopamine D2 (D 2 ) receptors. Here, we present experimental evidence that Sprague-Dawley rats treated with a non-selective cannabinoid receptor agonist (CP55,940, 50 µg/kg, 7 days, i.p.) showed enhanced co-immunoprecipitation of 5-HT 2A and D 2 receptors and enhanced membrane-associated expression of D 2 and 5-HT 2A receptors in prefrontal cortex (PFCx). Furthermore, 5-HT 2A receptor mRNA levels were increased in PFCx, suggesting a cannabinoid-induced upregulation of 5-HT 2A receptors. To date, two cannabinoids receptors have been found in brain, CB1 and CB2 receptors. We used selective cannabinoid agonists in a neuronal cell line to study mechanisms that could mediate this 5-HT 2A receptor upregulation. We found that selective CB2 receptor agonists upregulate 5-HT 2A receptors by a mechanism that seems to involve activation of Gai G-proteins, ERK1/2, and AP-1 transcription factor. We hypothesize that the enhanced cannabinoid-induced interaction between 5-HT 2A and D 2 receptors and in 5-HT 2A and D 2 receptors protein levels in the PFCx might provide a molecular mechanism by which activation of cannabinoid receptors might be contribute to the pathophysiology of some cognitive and mood disorders.

References

Abood, ME, Martin, BR ( 1996 ) Molecular neurobiology of the cannabinoid receptor . Int.Rev.Neurobiol 39: 197 – 221 .

Google Scholar Crossref | Medline | ISI

Akash, KG, Balarama, KS, Paulose, CS ( 2008 ) Enhanced 5-HT(2A) receptor status in the hypothalamus and corpus striatum of ethanol-treated rats . Cell Mol Neurobiol 28: 1017 – 1025 .

Google Scholar Crossref | Medline | ISI

Albizu, L, Holloway, T, Gonzalez-Maeso, J. ( 2011 ) Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors . Neuropharmacology 61: 770 – 777 .

Google Scholar Crossref | Medline | ISI

Albizua, E, Gallardo, M, Barrio, S. ( 2011 ) Differential expression of JAK2 and Src kinase genes in response to hydroxyurea treatment in polycythemia vera and essential thrombocythemia . Ann Hematol 90: 939 – 946 .

Google Scholar Crossref | Medline | ISI

Baltzis, D, Qu, LK, Papadopoulou, S. ( 2004 ) Resistance to vesicular stomatitis virus infection requires a functional cross talk between the eukaryotic translation initiation factor 2alpha kinases PERK and PKR . J Virol 78: 12747 – 12761 .

Google Scholar Crossref | Medline | ISI

Barrio, S, Gallardo, M, Albizua, E. ( 2011 ) Epigenomic profiling in polycythaemia vera and essential thrombocythaemia shows low levels of aberrant DNA methylation . J Clin Pathol 64: 1010 – 1013 .

Google Scholar Crossref | Medline | ISI

Best, JL, Amezcua, CA, Mayr, B. ( 2004 ) Identification of small-molecule antagonists that inhibit an activator: Coactivator interaction . Proc Natl Acad Sci U S A 101: 17622 – 17627 .

Google Scholar Crossref | Medline | ISI

Bokoch, GM, Katada, T, Northup, JK. ( 1983 ) Identification of the predominant substrate for ADP-ribosylation by islet activating protein . J Biol Chem 258: 2072 – 2075 .

Google Scholar Medline | ISI

Borroto-Escuela, DO, Romero-Fernandez, W, Tarakanov, AO. ( 2010 ) Dopamine D2 and 5-hydroxytryptamine 5-HT(A) receptors assemble into functionally interacting heteromers . Biochem Biophys Res Commun 401: 605 – 610 .

Google Scholar Crossref | Medline | ISI

Bouaboula, M, Poinot-Chazel, C, Marchand, J. ( 1996 ) Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression . Eur J Biochem 237: 704 – 711 .

Google Scholar Crossref | Medline

Boundy, VA, Luedtke, RR, Artymyshyn, RP. ( 1993 ) Development of polyclonal anti-D2 dopamine receptor antibodies using sequence-specific peptides . Mol Pharmacol 43: 666 – 676 .

Google Scholar Medline | ISI

Brusco, A, Tagliaferro, P, Saez, T. ( 2008 ) Postsynaptic localization of CB2 cannabinoid receptors in the rat hippocampus . Synapse 62: 944 – 949 .

Google Scholar Crossref | Medline | ISI

Burns, DJ, Bloomenthal, J, Lee, MH. ( 1990 ) Expression of the alpha, beta II, and gamma protein kinase C isozymes in the baculovirus-insect cell expression system. Purification and characterization of the individual isoforms . J Biol Chem 265: 12044 – 12051 .

Google Scholar Medline | ISI

Campbell, JS, Seger, R, Graves, JD. ( 1995 ) The MAP kinase cascade . Recent Prog Horm Res 50: 131 – 159 .

Google Scholar Medline

Carrasco, GA, Van de Kar, LD ( 2003 ) Neuroendocrine pharmacology of stress . Eur J Pharmacol 463: 235 – 272 .

Google Scholar Crossref | Medline | ISI

Casey, PJ, Graziano, MP, Gilman, AG ( 1989 ) G protein beta gamma subunits from bovine brain and retina: Equivalent catalytic support of ADP-ribosylation of alpha subunits by pertussis toxin but differential interactions with Gs alpha . Biochemistry 28: 611 – 616 .

Google Scholar Crossref | Medline | ISI

Celada, P, Puig, M, Amargos-Bosch, M. ( 2004 ) The therapeutic role of 5-HT1A and 5-HT2A receptors in depression . J Psychiatry Neurosci 29: 252 – 265 .

Google Scholar Medline | ISI

Chalecka-Franaszek, E, Chen, H, Chuang, DM ( 1999 ) 5-Hydroxytryptamine2A receptor stimulation induces activator protein-1 and cyclic AMP-responsive element binding with cyclic AMP-responsive element-binding protein and Jun D as common components in cerebellar neurons . Neuroscience 88: 885 – 898 .

Google Scholar Crossref | Medline | ISI

Chang, F, Steelman, LS, Lee, JT. ( 2003 ) Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: Potential targeting for therapeutic intervention . Leukemia 17: 1263 – 1293 .

Google Scholar Crossref | Medline | ISI

Chrivia, JC, Kwok, RP, Lamb, N. ( 1993 ) Phosphorylated CREB binds specifically to the nuclear protein CBP . Nature 365: 855 – 859 .

Google Scholar Crossref | Medline | ISI

Ciruela, A, Dixon, AK, Bramwell, S. ( 2003 ) Identification of MEK1 as a novel target for the treatment of neuropathic pain . Br J Pharmacol 138: 751 – 756 .

Google Scholar Crossref | Medline | ISI

Cottet, M, Albizu, L, Comps-Agrar, L. ( 2011 ) Time resolved FRET strategy with fluorescent ligands to analyze receptor interactions in native tissues: Application to GPCR oligomerization . Methods Mol Biol 746: 373 – 387 .

Google Scholar Crossref | Medline

Crippa, JA, Zuardi, AW, Martin-Santos, R. ( 2009 ) Cannabis and anxiety: A critical review of the evidence . Hum Psychopharmacol 24: 515 – 523 .

Google Scholar Crossref | Medline | ISI

Cyr, M, Landry, M, Di Paolo, T ( 2000 ) Modulation by estrogen-receptor directed drugs of 5-hydroxytryptamine-2A receptors in rat brain . Neuropsychopharmacology 23: 69 – 78 .

Google Scholar Crossref | Medline | ISI

Dal Toso, R, Sommer, B, Ewert, M. ( 1989 ) The dopamine D2 receptor: Two molecular forms generated by alternative splicing . EMBO J 8: 4025 – 4034 .

Google Scholar Medline | ISI

Darmani, NA, Reeves, SL ( 1996 ) The mechanism by which the selective 5-HT 1A receptor antagonist S-(-)UH 301 produces head-twitches in mice . Pharmacol Biochem Behav 55: 1 – 10 .

Google Scholar Crossref | Medline | ISI

De Almeida, J, Palacios, JM, Mengod, G ( 2008 ) Distribution of 5-HT and DA receptors in primate prefrontal cortex: Implications for pathophysiology and treatment . Prog Brain Res 172: 101 – 115 .

Google Scholar Crossref | Medline | ISI

Demuth, DG, Molleman, A ( 2006 ) Cannabinoid signalling . Life Sci 78: 549 – 563 .

Google Scholar Crossref | Medline | ISI

den Boon, FS, Chameau, P, Schaafsma-Zhao, Q. ( 2012 ) Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors . Proc Natl Acad Sci U S A 109: 3534 – 3539 .

Google Scholar Crossref | Medline | ISI

Doly, S, Madeira, A, Fischer, J. ( 2004 ) The 5-HT2A receptor is widely distributed in the rat spinal cord and mainly localized at the plasma membrane of postsynaptic neurons . J Comp Neurol 472: 496 – 511 .

Google Scholar Crossref | Medline | ISI

Dresen, S, Ferreiros, N, Putz, M. ( 2010 ) Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds . J Mass Spectrom 45: 1186 – 1194 .

Google Scholar Crossref | Medline | ISI

Du, YL, Wilcox, BD, Teitler, M. ( 1994 ) Isolation and characterization of the rat 5-hydroxytryptamine type 2 receptor promoter: Constitutive and inducible activity in myometrial smooth muscle cells . Mol Pharmacol 45: 1125 – 1131 .

Google Scholar Medline | ISI

Esteve, PO, Chicoine, E, Robledo, O. ( 2002 ) Protein kinase C-zeta regulates transcription of the matrix metalloproteinase-9 gene induced by IL-1 and TNF-alpha in glioma cells via NF-kappa B . J Biol Chem 277: 35150 – 35155 .

Google Scholar Crossref | Medline | ISI

Fanjul, A, Dawson, MI, Hobbs, PD. ( 1994 ) A new class of retinoids with selective inhibition of AP-1 inhibits proliferation . Nature 372: 107 – 111 .

Google Scholar Crossref | Medline | ISI

Felder, CC, Dickason-Chesterfield, AK, Moore, SA ( 2006 ) Cannabinoids biology: The search for new therapeutic targets . Mol Interv 6: 149 – 161 .

Google Scholar Crossref | Medline

Ferry, RC, Molinoff, PB ( 1996 ) Regulation of 5-HT 2A receptor mRNA in P11 cells . Behav Brain Res 73: 187 – 191 .

Google Scholar Crossref | Medline | ISI

Ferry, RC, Unsworth, CD, Molinoff, PB ( 1993 ) Effects of agonists, partial agonists, and antagonists on the regulation of 5-hydroxytryptamine 2 receptors in P11 cells . Mol Pharmacol 43: 726 – 733 .

Google Scholar Medline | ISI

Fribourg, M, Moreno, JL, Holloway, T. ( 2011 ) Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs . Cell 147: 1011 – 1023 .

Google Scholar Crossref | Medline | ISI

Fuxe, K, Marcellino, D, Borroto-Escuela, DO. ( 2010 ) The changing world of G protein-coupled receptors: From monomers to dimers and receptor mosaics with allosteric receptor-receptor interactions . J Recept Signal Transduct Res 30: 272 – 283 .

Google Scholar Crossref | Medline | ISI

Galiegue, S, Mary, S, Marchand, J. ( 1995 ) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations . Eur J Biochem / FEBS 232: 54 – 61 .

Google Scholar Crossref | Medline

Garcia-Gutierrez, MS, Garcia-Bueno, B, Zoppi, S. ( 2012 ) Chronic blockade of cannabinoid CB(2) receptors induces anxiolytic-like actions associated to alterations in GABA(A) receptors . Br J Pharmacol 165: 951 – 964 .

Google Scholar Crossref | Medline | ISI

Garcia-Gutierrez, MS, Perez-Ortiz, JM, Gutierrez-Adan, A. ( 2010 ) Depression-resistant endophenotype in mice overexpressing cannabinoid CB(2) receptors . Br J Pharmacol 160: 1773 – 1784 .

Google Scholar Crossref | Medline | ISI

Gong, JP, Onaivi, ES, Ishiguro, H. ( 2006 ) Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain . Brain Res 1071: 10 – 23 .

Google Scholar Crossref | Medline | ISI

Gorantla, S, Makarov, E, Roy, D. ( 2010 ) Immunoregulation of a CB2 receptor agonist in a murine model of neuroAIDS . J Neuroimmune Pharmacol 5: 456 – 468 .

Google Scholar Crossref | Medline | ISI

Henquet, C, Murray, R, Linszen, D. ( 2005 ) The environment and schizophrenia: The role of cannabis use . Schizophr Bull 31: 608 – 612 .

Google Scholar Crossref | Medline | ISI

Herkenham, M ( 1991 ) Characterization and localization of cannabinoid receptors in brain: An in vitro technique using slide-mounted tissue sections . NIDA Res Monogr 112: 129 – 145 .

Google Scholar Medline

Hill, MN, Sun, JC, Tse, MT. ( 2006 ) Altered responsiveness of serotonin receptor subtypes following long-term cannabinoid treatment . Int J Neuropsychopharmacol 9: 277 – 286 .

Google Scholar Crossref | Medline | ISI

Hillard, CJ, Manna, S, Greenberg, MJ. ( 1999 ) Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1) . J Pharmacol Exp Ther 289: 1427 – 1433 .

Google Scholar Medline | ISI

Horner, KA, Gilbert, YE, Noble, ES ( 2011 ) Differential regulation of 5-HT(2A) receptor mRNA expression following withdrawal from a chronic escalating dose regimen of D-amphetamine . Brain Res 1390: 10 – 20 .

Google Scholar Crossref | Medline | ISI

Howlett, AC ( 2005 ) Cannabinoid receptor signaling . Handb Exp Pharmacol 168: 53 – 79 .

Google Scholar Crossref

Huang, C, Ma, WY, Dawson, MI. ( 1997 ) Blocking activator protein-1 activity, but not activating retinoic acid response element, is required for the antitumor promotion effect of retinoic acid . Proc Natl Acad Sci U S A 94: 5826 – 5830 .

Google Scholar Crossref | Medline | ISI

Jacobson, PB, Kuchera, SL, Metz, A. ( 1995 ) Anti-inflammatory properties of Go 6850: A selective inhibitor of protein kinase C . J Pharmacol Exp Ther 275: 995 – 1002 .

Google Scholar Medline | ISI

Karin, M ( 1995 ) The regulation of AP-1 activity by mitogen-activated protein kinases . J Biol Chem 270: 16483 – 16486 .

Google Scholar Crossref | Medline | ISI

Karin, M, Liu, Z, Zandi, E ( 1997 ) AP-1 function and regulation . Curr Opin Cell Biol 9: 240 – 246 .

Google Scholar Crossref | Medline | ISI

Khan, ZU, Mrzljak, L, Gutierrez, A. ( 1998 ) Prominence of the dopamine D2 short isoform in dopaminergic pathways . Proc Natl Acad Sci U S A 95: 7731 – 7736 .

Google Scholar Crossref | Medline | ISI

Kim, HH, Ahn, KS, Han, H. ( 2005 ) Decursin and PDBu: Two PKC activators distinctively acting in the megakaryocytic differentiation of K562 human erythroleukemia cells . Leuk Res 29: 1407 – 1413 .

Google Scholar Crossref | Medline | ISI

Kindlundh-Hogberg, AM, Svenningsson, P, Schioth, HB ( 2006 ) Quantitative mapping shows that serotonin rather than dopamine receptor mRNA expressions are affected after repeated intermittent administration of MDMA in rat brain . Neuropharmacology 51: 838 – 847 .

Google Scholar Crossref | Medline | ISI

Kuepper, R, van, OJ, Lieb, R. ( 2011 ) Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study . BMJ 342: d738 .

Google Scholar Crossref | Medline

Kwok, RP, Lundblad, JR, Chrivia, JC. ( 1994 ) Nuclear protein CBP is a coactivator for the transcription factor CREB . Nature 370: 223 – 226 .

Google Scholar Crossref | Medline | ISI

Large, M, Sharma, S, Compton, MT. ( 2011 ) Cannabis use and earlier onset of psychosis: A systematic meta-analysis . Arch Gen Psychiatry 68: 555 – 561 .

Google Scholar Crossref | Medline

Lawford, BR, Young, R, Noble, EP. ( 2006 ) The D2 dopamine receptor (DRD2) gene is associated with co-morbid depression, anxiety and social dysfunction in untreated veterans with post-traumatic stress disorder . Eur Psychiatry 21: 180 – 185 .

Google Scholar Crossref | Medline | ISI

Lefkowitz, RJ, Shenoy, SK ( 2005 ) Transduction of receptor signals by beta-arrestins . Science 308: 512 – 517 .

Google Scholar Crossref | Medline | ISI

Lohse, MJ ( 2006 ) G protein-coupled receptors:Too many dimers? Nat Methods 3: 972 – 973 .

Google Scholar Crossref | Medline | ISI

Lukasiewicz, S, Faron-Gorecka, A, Kedracka-Krok, S. ( 2011 ) Effect of clozapine on the dimerization of serotonin 5-HT(2A) receptor and its genetic variant 5-HT(2A)H425Y with dopamine D(2) receptor . Eur J Pharmacol 659: 114 – 123 .

Google Scholar Crossref | Medline | ISI

Lukasiewicz, S, Polit, A, Kedracka-Krok, S. ( 2010 ) Hetero-dimerization of serotonin 5-HT(2A) and dopamine D(2) receptors . Biochim Biophys Acta 1803: 1347 – 1358 .

Google Scholar Crossref | Medline | ISI

Martiny-Baron, G, Kazanietz, MG, Mischak, H. ( 1993 ) Selective inhibition of protein kinase C isozymes by the indolocarbazole Go 6976 . J Biol Chem 268: 9194 – 9197 .

Google Scholar Medline | ISI

Milligan, G ( 2004 ) G protein-coupled receptor dimerization: Function and ligand pharmacology . Mol Pharmacol 66: 1 – 7 .

Google Scholar Crossref | Medline | ISI

Mischak, H, Kolch, W, Goodnight, J. ( 1991 ) Expression of protein kinase C genes in hemopoietic cells is cell-type- and B cell-differentiation stage specific . J Immunol 147: 3981 – 3987 .

Google Scholar Medline | ISI

Montezinho, LP, Castro, MM, Duarte, CB. ( 2006 ) The interaction between dopamine D2-like and beta-adrenergic receptors in the prefrontal cortex is altered by mood-stabilizing agents . J Neurochem 96: 1336 – 1348 .

Google Scholar Crossref | Medline | ISI

Munro, S, Thomas, KL, Abu-Shaar, M ( 1993 ) Molecular characterization of a peripheral receptor for cannabinoids . Nature 365: 61 – 65 .

Google Scholar Crossref | Medline | ISI

Murineddu, G, Lazzari, P, Ruiu, S. ( 2006 ) Tricyclic pyrazoles. 4. Synthesis and biological evaluation of analogues of the robust and selective CB2 cannabinoid ligand 1-(2′,4′-dichlorophenyl)-6-methyl-N-piperidin-1-yl-1,4-dihydroindeno[1,2-c ]pyrazole-3-carboxamide . J Med Chem 49: 7502 – 7512 .

Google Scholar Crossref | Medline | ISI

Nam, J, Kim, K ( 2008 ) Abnormal motor function and the expression of striatal dopamine D2 receptors in manganese-treated mice . Biol Pharm Bull 31: 1894 – 1897 .

Google Scholar Crossref | Medline | ISI

Newton, AC ( 1995 ) Protein kinase C: Structure, function, and regulation . J Biol Chem 270: 28495 – 28498 .

Google Scholar Crossref | Medline | ISI

Onaivi, ES, Ishiguro, H, Gong, JP. ( 2008 ) Brain Neuronal CB2 Cannabinoid Receptors in Drug Abuse and Depression: From Mice to Human Subjects . PLoS ONE 3: e1640 .

Google Scholar Crossref | Medline | ISI

Ortega-Alvaro, A, Aracil-Fernandez, A, Garcia-Gutierrez, MS. ( 2011 ) Deletion of CB2 cannabinoid receptor induces schizophrenia-related behaviors in mice . Neuropsychopharmacology 36: 1489 – 1504 .

Google Scholar Crossref | Medline | ISI

Page, K, Li, J, Corbit, KC. ( 2002 ) Regulation of airway smooth muscle cyclin D1 transcription by protein kinase C-delta . Am J Respir Cell Mol Biol 27: 204 – 213 .

Google Scholar Crossref | Medline | ISI

Pelletier, JP, Fernandes, JC, Brunet, J. ( 2003 ) In vivo selective inhibition of mitogen-activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes . Arthritis Rheum 48: 1582 – 1593 .

Google Scholar Crossref | Medline

Roessner, V, Sagvolden, T, Dasbanerjee, T. ( 2010 ) Methylphenidate normalizes elevated dopamine transporter densities in an animal model of the attention-deficit/hyperactivity disorder combined type, but not to the same extent in one of the attention-deficit/hyperactivity disorder inattentive type . Neuroscience 167: 1183 – 1191 .

Google Scholar Crossref | Medline | ISI

Rutkowska, M, Jachimczuk, O ( 2004 ) Antidepressant-like properties of ACEA (arachidonyl-2-chloroethylamide), the selective agonist of CB1 receptors . Acta Pol Pharm 61: 165 – 167 .

Google Scholar Medline

Schiller, L, Donix, M, Jahkel, M. ( 2006 ) Serotonin 1A and 2A receptor densities, neurochemical and behavioural characteristics in two closely related mice strains after long-term isolation . Prog Neuropsychopharmacol Biol Psychiatry 30: 492 – 503 .

Google Scholar Crossref | Medline | ISI

Seger, R, Krebs, EG ( 1995 ) The MAPK signaling cascade . FASEB J 9: 726 – 735 .

Google Scholar Crossref | Medline | ISI

Singh, R, Jia, C, Garcia, F. ( 2010 ) Activation of the JAK-STAT pathway by olanzapine is necessary for desensitization of serotonin2A receptor-stimulated phospholipase C signaling in rat frontal cortex but not serotonin2A receptor-stimulated hormone release . J Psychopharmacol 24: 1079 – 1088 .

Google Scholar SAGE Journals | ISI

Singh, RK, Shi, J, Zemaitaitis, BW. ( 2007 ) Olanzapine increases RGS7 protein expression via stimulation of the Janus tyrosine kinase-signal transducer and activator of transcription signaling cascade . J Pharmacol Exp Ther 322: 133 – 140 .

Google Scholar Crossref | Medline | ISI

Sobolewski, A, Jourdan, KB, Upton, PD. ( 2004 ) Mechanism of cicaprost-induced desensitization in rat pulmonary artery smooth muscle cells involves a PKA-mediated inhibition of adenylyl cyclase . Am J Physiol Lung Cell Mol Physiol 287: L352 – 359 .

Google Scholar Crossref | Medline | ISI

Thomas, BF, Gilliam, AF, Burch, DF. ( 1998 ) Comparative receptor binding analyses of cannabinoid agonists and antagonists . J Pharmacol Exp Ther 285: 285 – 292 .

Google Scholar Medline | ISI

Toullec, D, Pianetti, P, Coste, H. ( 1991 ) The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C . J Biol Chem 266: 15771 – 15781 .

Google Scholar Medline | ISI

Toya, Y, Schwencke, C, Ishikawa, Y ( 1998 ) Forskolin derivatives with increased selectivity for cardiac adenylyl cyclase . J Mol Cell Cardiol 30: 97 – 108 .

Google Scholar Crossref | Medline | ISI

Usiello, A, Baik, JH, Rouge-Pont, F. ( 2000 ) Distinct functions of the two isoforms of dopamine D2 receptors . Nature 408: 199 – 203 .

Google Scholar Crossref | Medline | ISI

Wang, X, Dow-Edwards, D, Anderson, V. ( 2004 ) In utero marijuana exposure associated with abnormal amygdala dopamine D2 gene expression in the human fetus . Biol Psychiatry 56: 909 – 915 .

Google Scholar Crossref | Medline | ISI

Weisstaub, NV, Lira, A, Zhou, M. ( 2004 ) Altered anxiety-related behaviors in 5-HT2A receptor knock out mice . Neuroscience Abst 468.10.

Google Scholar

Wiley, JL, Barrett, RL, Lowe, J. ( 1995 ) Discriminative stimulus effects of CP 55,940 and structurally dissimilar cannabinoids in rats . Neuropharmacology 34: 669 – 676 .

Google Scholar Crossref | Medline | ISI

Willins, DL, Meltzer, HY ( 1997 ) Direct injection of 5-HT 2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats . J Pharmacol Exp Ther 282: 699 – 706 .

Google Scholar Medline | ISI

Zarruk, JG, Fernandez-Lopez, D, Garcia-Yebenes, I. ( 2012 ) Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection . Stroke 43: 211 – 219 .

Google Scholar Crossref | Medline | ISI