1. bookVolume 55 (2021): Issue 2 (April 2021)
Journal Details
First Published
30 Mar 2016
Publication timeframe
4 times per year
access type Open Access

Extra-forebrain impact of antipsychotics indicated by c-Fos or FosB/ΔFosB expression: A minireview

Published Online: 21 May 2021
Volume & Issue: Volume 55 (2021) - Issue 2 (April 2021)
Page range: 120 - 130
Journal Details
First Published
30 Mar 2016
Publication timeframe
4 times per year

It is apparent that the c-Fos and FosB/ΔFosB immunohistochemistry has generally become a useful tool for determining the different antipsychotic (AP) drugs activities in the brain. It is also noteworthy that there are no spatial limits, while to the extent of their identification over the whole brain axis. In addition, they can be in a parallel manner utilized in the unmasking of the brain cell phenotype character activated by APs and by this way also to identify the possible brain circuits underwent to the APs action. However, up to date, the number of APs involved in the extra-striatal studies is still limited, what prevents the possibility to fully understand their extra-striatal effects as a complex as well as differentiate their extra-striatal impact in qualitative and quantitative dimensions. Actually, it is very believable that more and more anatomical/functional knowledge might bring new insights into the APs extra-striatal actions by identifying new region-specific activities of APs as well as novel cellular targets affected by APs, which might reveal more details of their possible side effects of the extra-striatal origin.


Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156, 1686–1696, 1999.10.1176/ajp.156.11.1686 Search in Google Scholar

Beckmann H, Lang RE, Gattaz WF. Vasopressin-oxytocin in cerebrospinal fluid of schizophrenic patients and normal controls. Psychoneuroendocrinology 10, 187–191, 1985.10.1016/0306-4530(85)90056-3 Search in Google Scholar

Badoer E. Hypothalamic paraventricular nucleus and cardiovascular regulation. Clin Exp Pharmacol Physiol 28, 95–99, 2001.10.1046/j.1440-1681.2001.03413.x Search in Google Scholar

Bak M, Fransen A, Janssen J, van Os J, Drukker M. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS One 9, e94112, 2014.10.1371/journal.pone.0094112 Search in Google Scholar

Benarroch EE. The locus coeruleus-norepinephrine system: Functional organization and potential clinical significance. Neurology 73, 1699–1704, 2009.10.1212/WNL.0b013e3181c2937c Search in Google Scholar

Berridge CW, Waterhouse BD. The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42, 33–84, 2003.10.1016/S0165-0173(03)00143-7 Search in Google Scholar

Ceccatelli S, Eriksson M, Hokfelt T. Distribution and coexistence of corticotropin-releasing factor-, neurotensin-, enkephalin-, cholecystokinin-, galanin- and vasoactive intestinal polypeptide/peptide histidine isoleucine-like peptides in the parvocellular part of the paraventricular nucleus. Neuroendocrinology 49, 309–323, 1989.10.1159/000125133 Search in Google Scholar

Chen J, Kelz MB, Hope BT, Nakabeppu Y, Nestler EJ. Chronic Fos-related antigens: stable variants of deltaFosB induced in brain by chronic treatments. J Neurosci 17, 4933–4941, 1997.10.1523/JNEUROSCI.17-13-04933.1997 Search in Google Scholar

Cohen BM, Wan W. The thalamus as a site of action of antipsychotic drugs. Am J Psychiatry 153, 104–106, 1996.10.1176/ajp.153.1.104 Search in Google Scholar

Cohen BM, Wan W, Froimowitz MP, Ennulat DJ, Cherkerzian S, Konieczna H. Activation of midline thalamic nuclei by antipsychotic drugs. Psychopharmacology 135, 37–43, 1998.10.1007/s002130050483 Search in Google Scholar

Dawe GS, Huff KD, Vandergriff JL, Sharp T, O’Neill MJ, Rasmussen K. Olanzapine activates the rat locus coeruleus: in vivo electrophysiology and c-Fos immunoreactivity. Biol Psychiatry 50, 510–520, 2001.10.1016/S0006-3223(01)01171-4 Search in Google Scholar

de Bartolomeis A, Buonaguro EF, Latte G, Rossi R, Marmo F, Iasevoli F, Tomasetti C. Immediate-early genes modulation by antipsychotics: Translational implications for a putative gateway to drug-induced long-term brain changes. Front Behav Neurosci 11, Article 240, 2017.10.3389/fnbeh.2017.00240 Search in Google Scholar

de Lecea L, Kilduff TS, Peyron C, Gao XB, Foye PE, Danielson PE, Fukuhara C, Battenberg ELF, Gautvik VT, Bartlett II FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. PNAS 95, 322–327, 1998.10.1073/pnas.95.1.322 Search in Google Scholar

Denis RGP, Joly-Amado A, Cansell C, Castel J, Martinez S, Delbes AS, Luquet S. Central orchestration of peripheral nutrient partitioning and substrate utilization: implications for the metabolic syndrome. Diabetes Metab 40, 191–197, 2014.10.1016/j.diabet.2013.11.002 Search in Google Scholar

Deutch AY, Ongur D, Duman RS. Antipsychotic drugs induce Fos protein in the PVT: a novel locus of antipsychotic drug action. Neuroscience 66, 337–346, 1995.10.1016/0306-4522(94)00571-L Search in Google Scholar

Deutch AY, Duman RS. The effects of antipsychotic drugs on Fos protein expression in the prefrontal cortex: cellular localization and pharmacological characterization. Neuroscience 377–389, 1996.10.1016/0306-4522(95)00357-6 Search in Google Scholar

Dragunow M, Faull RJ. The use of c-fos as a metabolic marker in neuronal pathway tracing. Neurosci Methods 29, 261–265, 1989.10.1016/0165-0270(89)90150-7 Search in Google Scholar

Fadel J, Bubser M, Deutch AY. Differential activation of orexin neurons by antipsychotic drugs associated with weight gain. J Neurosci 22, 6742–6746, 2002.10.1523/JNEUROSCI.22-15-06742.2002 Search in Google Scholar

Everitt BJ, Meister B, Hokfelt T, Melander T, Terenius L, Rokaeus A, Theodorsson-Norheim E, Dockray G, Edward-son J, Cuello C, Elde R, Goldstein M, Hemmings H, Ouimet C, Walaas I, Greengard P, Vale W, Weber E, Wu JY, Chang KJ. The hypothalamic arcuate nucleus-median eminence complex: immunohistochemistry of transmitters, peptides, and DARPP-32 with special reference to coexistence in dopamine neurons. Brain Res Rev 11, 97–155, 1986.10.1016/0165-0173(86)90001-9 Search in Google Scholar

Fellmann D, Bugnon C, Gouget A. Immunocytochemical demonstration of corticoliberin-like immunoreactivity (CLI) in neurones of the rat amygdala central nucleus (ACN). Neurosci Lett 34, 253–258, 1982.10.1016/0304-3940(82)90184-7 Search in Google Scholar

Fellmann D, Bugnon C, Gouget A. Immunocytochemical demonstration of corticoliberinlike immunoreactivity (CLI) in neurons of the rat central nucleus of the amygdala. JCN 281, 320–333, 1989. Search in Google Scholar

Ferguson AV, Latchford KJ, Samson WK. The paraventricular nucleus of the hypothalamus a potential target for integrative treatment of autonomic dysfunction. Expert Opin Ther Targets 12, 717–727, 2008.10.1517/14728222.12.6.717268292018479218 Search in Google Scholar

Ferretti V, Maltese F, Contarini G, Nigro M, Bonavia A, Huang H, Gigliucci V, Morelli G, Scheggia D, Manago F, Castellani G, Lefevre A, Cancedda L, Chini B, Grinevich V, Papaleo F. Oxytocin signaling in the central amygdala modulates emotion discrimination in mice. Curr Biol 27, 1938–1953, 2019.10.1016/j.cub.2019.04.070 Search in Google Scholar

Fink-Jensen A, Kristensen P. Effects of typical and atypical neuroleptics on Fos protein expression in the rat fore-brain. Neurosci Lett 182, 115–118, 1994.10.1016/0304-3940(94)90220-8 Search in Google Scholar

Gardner DM, Baldessarini RJ, Waraich P. Modern antipsychotic drugs: a critical overview. CMAJ 172, 1703–1711, 2005.10.1503/cmaj.1041064 Search in Google Scholar

Giorgi FS, Ryskalin L, Ruffoli R, Biagioni F, Limanaqi F, Ferrucci M, Busceti CL, Bonuccelli U, Fornai F. The neuro-anatomy of the reticular nucleus locus coeruleus in Alzheimer’s disease. Front Neuroanat 11, 80, 2017.10.3389/fnana.2017.00080 Search in Google Scholar

Hasan MT, Althammer F, Silva da Gouveia M, Goyon S, Eliava M, Lefevre A, Kerspern D, Schimmer J, Raftogianni A, Wahis J, Knobloch-Bollmann HS, Tang Y, Liu X, Jain A, Chavant V, Goumon Y, Weislogel JM, Hurlemann R, Herpertz SC, Pitzer C, Darbon P, Dogbevia GK, Bertocchi I, Larkum ME, Sprengel R, Bading H, Charlet A, Grinevich V. A fear memory engram and its plasticity in the hypothalamic oxytocin system. Neuron 103, 133–146, 2019.10.1016/j.neuron.2019.04.029 Search in Google Scholar

Holets VR, Hokfelt T, Rokaeus A, Terenius L, Goldstein M. Locus coeruleus neurons in the rat containing neuropep-tide Y, tyrosine hydroxylase or galanin and their efferent projections to the spinal cord, cerebral cortex and hypothalamus. Neuroscience 24, 893–906, 1988.10.1016/0306-4522(88)90076-0 Search in Google Scholar

Hou-Yu A, Lamme AT, Zimmerman EA, Silverman AJ. Comparative distribution of vasopressin and oxytocin neurons in the rat brain using a double-label procedure. Neuroendocrinology 44, 235–246, 1986.10.1159/000124651 Search in Google Scholar

Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, Arndt T, Backers L, Rothe P, Cipriani A, Davis J, Salanti G, Leucht S. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 394, 939–951, 2019.10.1016/S0140-6736(19)31135-3 Search in Google Scholar

Imaki T, Xiao-Quan W, Shibasaki T, Yamada K, Harada S, Chikada N, Naruse M, Demura H. Stress-induced activation of neuronal activity and corticotropin-releasing factor gene expression in the paraventricular nucleus is modulated by glucocorticoids in rats. J Clin Invest 96, 231–238, 1995.10.1172/JCI1180261851937615792 Search in Google Scholar

Joly-Amado A, Cansell C, Denis RGP, Delbes AS, Castel J, Martinez S, Luquet S. The hypothalamic arcuate nucleus and the control of peripheral substrates. Best Pract Res Clin Endocrinol Metab 28, 725–737, 2014.10.1016/j.beem.2014.03.00325256767 Search in Google Scholar

Joshi RS, Panicker MM. Identifying the In Vivo cellular correlates of antipsychotic drugs. eNEURO 5, (e0220-18), 1–14, 2018.10.1523/ENEURO.0220-18.2018 Search in Google Scholar

Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 20, 68–100, 1999.10.1210/edrv.20.1.0357 Search in Google Scholar

Kilduff T, Peyron C. The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 23, 359–365, 2000.10.1016/S0166-2236(00)01594-0 Search in Google Scholar

Kiss A, Pirnik Z, Bundzikova J, Mikkelsen JD. Different antipsychotics elicit different effects on magnocellular oxytocinergic and vasopressinergic neurons as revealed by Fos immunohistochemistry. J Neurosci Res 88, 677–685, 2010.10.1002/jnr.2222619774673 Search in Google Scholar

Kiss A, Majercikova Z. Repeated asenapine treatment does not participate in the mild stress induced FosB/ΔFosB expression in the rat hypothalamic paraventricular nucleus neurons. Neuropeptides 61, 57–65, 2017.10.1016/j.npep.2016.10.00327756486 Search in Google Scholar

Kiss A. c-Fos expression in the hypothalamic paraventricular nucleus after a single treatment with a typical haloperidol and nine atypical antipsychotics: a pilot study Endocr Regul 52, 93–100, 2018.10.2478/enr-2018-001129715183 Search in Google Scholar

Kiss A, Osacka J. Effect of amisulpride, olanzapine, quetiapine, and aripiprazole single administration on c-Fos expression in the rat vasopressinergic and oxytocinergic neurons of the rat hypothalamic paraventricular nucleus. Neuropeptides 87, 102148, 2021.10.1016/j.npep.2021.10214833887540 Search in Google Scholar

Knobloch HS, Charlet A, Hoffmann LC, Eliava M, Khrulev S, Cetin AH, Osten P, Schwarz MK, Seeburg PH, Stoop R, Grinevich V. Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 73, 553–66, 2012.10.1016/j.neuron.2011.11.03022325206 Search in Google Scholar

Korf J, Andries D, Sebens JB. On the unique profile of action of clozapine as assessed with fos-protein induction in rat brain regions. Acta Neuropsych 9, 55–57, 1997.10.1017/S092427080003679626972126 Search in Google Scholar

LeDoux J. The amygdala. Curr Biol 17, R868–R874, 2007.10.1016/j.cub.2007.08.00517956742 Search in Google Scholar

Li Y, Li S, Wei C, Wang H, Sui N, Kirouac GJ. Orexins in the paraventricular nucleus of the thalamus mediate anxiety-like responses in rats. Psychopharmacology (Berl) 212, 251–265, 2010.10.1007/s00213-010-1948-y Search in Google Scholar

Li Y, Dong X, Li S, Kirouac GJ. Lesions of the posterior paraventricular nucleus of the thalamus attenuate fear expression. Front Behav Neurosci 8, 94, 2014.10.3389/fnbeh.2014.00094 Search in Google Scholar

Magnuson DJ, Gray TS. Amygdala directly innervates parvocellular paraventricular hypothalaimic CRF, vasopressin and oxytocin containing cells. Society for Neur-oscience Abstracts 14, 1288, 1988. Search in Google Scholar

Majercikova Z, Kiss A. Impact of repeated asenapine treatment on FosB/ΔFosB expression in neurons of the rat central nucleus of the amygdala: colocalization with corticoliberine (CRH) and effect of an unpredictable mild stress preconditioning. Endocr Regul 49, 58–67, 2015.10.4149/endo_2015_02_58 Search in Google Scholar

Marcilhac A, Siaud P. Identification of projections from the central nucleus of the amygdala to the paraventricular nucleus of the hypothalamus which are immunoreactive for corticotrophin-releasing hormone in the rat. Exp Physiol 82, 273–281, 1997.10.1113/expphysiol.1997.sp004022 Search in Google Scholar

Meltzer HY. Update on typical and atypical antipsychotic drugs. An Rev Med 64, 393–406, 2013.10.1146/annurev-med-050911-161504 Search in Google Scholar

Nishioka T, Anselmo-Franci JA, Li P, Callahan MF, Morris M. Stress increases oxytocin release within the hypothalamic paraventricular nucleus. Brain Res 781, 57–61, 1998.10.1016/S0006-8993(97)01159-1 Search in Google Scholar

Ohashi K, Hamamura T, Lee Y, Fujiwara Y, Suzuki H, Kuroda S. Clozapine- and olanzapine-induced Fos expression in the rat medial prefrontal cortex is mediated by b-adrenoceptors. Neuropsychopharmacology 23, 162–169, 2000.10.1016/S0893-133X(00)00105-6 Search in Google Scholar

Olpe HR, Steinmann M. Responses of locus coeruleus neurons to neuropeptides. Prog Brain Res 88, 241–248, 1991.10.1016/S0079-6123(08)63813-3 Search in Google Scholar

Park SW, Choi SM, Lee JG, Lee CH, Lee SJ, Kim NR, Kim YH. Differential effects of ziprasidone and haloperidol on immobilization-stress-induced CRF mRNA expression in the hypothalamic paraventricular nucleus of rats. Neuropsychobiology 63, 29–34, 2011a.10.1159/00032228821063130 Search in Google Scholar

Park JI, Zhao T, Huang GB, Sui ZY, Li CR, Han EH, Chung YC. Effects of aripiprazole and haloperidol on Fos-like Immunoreactivity in the prefrontal cortex and amygdala. Clin Psychopharmacol Neurosci 9, 36–43, 2011b.10.9758/cpn.2011.9.1.36356865323431025 Search in Google Scholar

Penzo MA, Robert V, Tucciarone J, De Bundel D, Wang M, Van Aelst L, Darvas M, Parada LF, Palmiter RD, He M, Huang ZJ, Li B. The paraventricular thalamus controls a central amygdala fear circuit. Nature 519, 455–459, 2015.10.1038/nature13978 Search in Google Scholar

Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS. Neurons containing hypocretin (Orexin) project to multiple neuronal systems. J Neurosci 18, 9996–10015, 1998.10.1523/JNEUROSCI.18-23-09996.1998 Search in Google Scholar

Pinna A, Morelli M. Differential induction of Fos-like-immunoreactivity in the extended amygdala after haloperidol and clozapine. Neuropsychopharmacology 21, 93–100, 1999.10.1016/S0893-133X(98)00136-5 Search in Google Scholar

Pitkanen A, Savander V, LeDoux JE. Organization of intra-amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala. Trends Neurosci 20, 517–523, 1997.10.1016/S0166-2236(97)01125-9 Search in Google Scholar

Qin C, Li J, Tang K. The paraventricular nucleus of the hypothalamus: development, function, and human diseases. Endocrinology 159, 3458–3472, 2018.10.1210/en.2018-00453 Search in Google Scholar

Rajkumar R, See LKY, Dawe GS. Acute antipsychotic treatments induce distinct c-Fos expression patterns in appetite-related neuronal structures of the rat brain. Brain Res 1508, 34–43, 2013.10.1016/j.brainres.2013.02.050 Search in Google Scholar

Roberts MM, Robinson AG, Fitzsimmons MD, Grant F, Lee WS, Hoffman GE. C-fos expression in vasopressin and oxytocin neurons reveals functional heterogeneity within magnocellular neurons. Neuroendocrinology 57, 388–400, 1993.10.1159/000126384 Search in Google Scholar

Robertson GS, Fibiger HC. Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. Neuroscience 46, 315–328, 1992.10.1016/0306-4522(92)90054-6 Search in Google Scholar

Robertson GS, Fibiger HC. Effects of olanzapine on regional c-Fos expression in rat forebrain. Neuropsychopharmacology 14, 105–110, 1996.10.1016/0893-133X(95)00196-K Search in Google Scholar

Sagar HJ, Sullivan EV, Gabrieli JDE, Corkin S, Growdon JH. Temporal ordering and short-term memory deficits in Parkinson’s disease. Brain 111, 525–539, 1988.10.1093/brain/111.3.5253382911 Search in Google Scholar

Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JRS, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585, 1998.10.1016/S0092-8674(00)80949-6 Search in Google Scholar

Samuels ER, E Szabadi E. Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function Part I: Principles of Functional Organisation. Curr Neuropharmacol 6, 235–253, 2008.10.2174/157015908785777229 Search in Google Scholar

Sara S. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 10, 211–223, 2009.10.1038/nrn2573 Search in Google Scholar

Shiosaka S, Sakanaka M, Inayaki S, Senba E, Haia Y, Taratsuki K, Takagi H, Kawai Y, Tahyama M. Putative neurotransmitters in the amygdaloid complex with special reference to peptidergic pathways. In Chemical Neuroanatomy, Raven Press, New York (ed. Empson PC), 359–389, 1983. Search in Google Scholar

Stefanidis A, Verty ANA, Allen AM, Owens NC, Cowley MA, Oldfield BJ. The role of thermogenesis in antipsychotic drug-induced weight gain. Obesity 17, 16–24, 2008.10.1038/oby.2008.468 Search in Google Scholar

Sumner BEH, Cruise LA, Slattery DA, Hill DR, Shahid M, Henry B. Testing the validity of c-fos expression profiling to aid the therapeutic classification of psychoactive drugs. Psychopharmacology 171, 306–321, 2004.10.1007/s00213-003-1579-7 Search in Google Scholar

Swanson LW, Kuypers HGJM. The paraventricular nucleus of the hypothalamus: Cytoarchitectonic subdivisions and organization of projections to the pituitary, dorsal vagal complex, and spinal cord as demonstrated by retrograde fluorescence double-labeling methods. J Comp Neurol 194, 555–570, 1980.10.1002/cne.901940306 Search in Google Scholar

Swanson LW, Sawchenko PE. Paraventricular nucleus: a site for the integration of neuroendocrine and autonomic mechanisms. Neuroendocrinology 31, 410–417, 1980.10.1159/000123111 Search in Google Scholar

Wan W, Ennulat DJ, Cohen BM. Acute administration of typical and atypical antipsychotic drugs induces distinctive patterns of Fos expression in the rat forebrain. Brain Res 688, 95–104, 1995.10.1016/0006-8993(95)00544-Z Search in Google Scholar

Wan XQ, Zeng F, Huang XF, Yang HQ, Wang L, Shi YC, Zhang ZH, Lin S. Risperidone stimulates food intake and induces body weight gain via the hypothalamic arcuate nucleus 5-HT2c receptor-NPY pathway. CNS Neurosci Ther 26, 558–556, 2020.10.1111/cns.13281716379231880085 Search in Google Scholar

Wu Q, Howell MP, Palmiter RD. Ablation of neurons expressing agouti-related protein activates Fos and gliosis in postsynaptic target regions. J Neurosci 28, 9218–9226, 2008.10.1523/JNEUROSCI.2449-08.2008259711318784302 Search in Google Scholar

Xiao M, Ding J, Wu L, Han Q, Wang H, Zuo G, Hu G. The distribution of neural nitric oxide synthase-positive cerebrospinal fluid-contacting neurons in the third ventricular wall of male rats and coexistence with vasopressin or oxytocin. Brain Res 1038, 150–162, 2005.10.1016/j.brainres.2005.01.03215757631 Search in Google Scholar

Xiao W, Fan Z, Xu-Feng H, He Y, Lan W, Yan-Chuan S, Zhi Z, Shu L. Risperidone stimulates food intake and induces body weight gain via the hypothalamic arcuate nucleus 5-HT2c receptor-NPY pathway. CNS Neurosci Ther 26, 558–566, 2020.10.1111/cns.13281716379231880085 Search in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo