"The Role Of Neurotransmitters In Haloperidol-Induced Catalepsy: A Comprehensive Review Of The Current Understanding”

"The Role Of Neurotransmitters In Haloperidol-Induced Catalepsy: A Comprehensive Review Of The Current Understanding”


  • Vandana Gupta
  • Lokesh Verma


Haloperidol, Catalepsy, Neurotransmitters, Dopamine, Serotonin, GABA (Gamma-Aminobutyric Acid)


Background: The role of neurotransmitters in haloperidol-induced catalepsy has been a subject of extensive research. Haloperidol, a widely used antipsychotic medication, is known to induce motor disturbances resembling Parkinsonian symptoms, including catalepsy. Understanding the neurotransmitter mechanisms underlying this phenomenon is crucial for improving therapeutic strategies and minimizing side effects.

Main Body: This comprehensive review explores the intricate interplay of neurotransmitters in haloperidol-induced catalepsy. Dopamine, a key player, exhibits dysregulation in response to haloperidol, impacting the nigrostriatal pathway. Additionally, serotonin, glutamate, and GABAergic systems contribute to the complex neurochemical alterations. The review synthesizes evidence from preclinical and clinical studies, shedding light on the dynamic interactions that culminate in cataleptic manifestations.

Short Conclusion: In conclusion, unraveling the neurotransmitter intricacies in haloperidol-induced catalepsy is a critical step towards refining antipsychotic interventions. Insights gained from this review pave the way for targeted therapeutic approaches, aiming to mitigate motor side effects while preserving the efficacy of haloperidol in psychiatric treatment.

Author Biographies

Vandana Gupta

Sanjeev Agrawal Global Educational (SAGE) University, Bhopal, Sahara Bypass Road, Katara Hills, Extension, Bhopal, Madhya Pradesh 462022

Lokesh Verma

Sanjeev Agrawal Global Educational (SAGE) University, Bhopal, Sahara Bypass Road, Katara Hills, Extension, Bhopal, Madhya Pradesh 462022


Amorim, M. A. F., de Oliveira, D. R., da Silva Júnior, F. P., & de Almeida, A. A. (2016). Catalepsy: a review of its pathophysiology and therapeutic interventions. Pharmacology Biochemistry and Behavior, 143, 108-116.

Sanger, D. J., & Blackman, A. (2003). Animal models of catalepsy: a comparison. Neuroscience & Biobehavioral Reviews, 27(5), 518-527.

Pazos, M. R., Núñez, E., Benito, C., Tolón, R. M., Romero, J., & Hillard, C. J. (2013). Cannabinoid CB1 receptors regulate neuronal sensitivity to pre-synaptic inhibition in the striatum. Journal of Physiology, 591(4), 969-982.

Northoff G. (2002). What catatonia can tell us about "top-down modulation": a neuropsychiatric hypothesis. Behavioral and Brain Sciences, 25(5), 555–577. doi: 10.1017/S0140525X02000029.

Gupta A, Lang AE, Prasad S. (2009). Levodopa-induced catalepsy in Parkinson disease. Neurology, 73(20), 1704–1705. doi: 10.1212/WNL.0b013e3181c1deb.

.Dhossche DM, Stoppelbein L, Rout UK. (2009). Etiopathogenesis of catatonia: generalizations and working hypotheses. Journal of ECT, 25(4), 231-239. doi: 10.1097/YCT.0b013e31819b12e6.

Seeman P, Tallerico T. (1998). Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Molecular Psychiatry, 3(2), 123-134. doi:10.1038/sj.mp.4000341.

.Kapur S, Seeman P. (2001). Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis. American Journal of Psychiatry, 158(3), 360-369. doi:10.1176/appi.ajp.158.3.360.

Leucht S, Cipriani A, Spineli L, et al. (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet, 382(9896), 951-962. doi:10.1016/S0140-6736(13)60733-3.

Cutler AJ. (2014). The use of atypical antipsychotics in bipolar disorder. Journal of Clinical Psychiatry, 75(9), 958-966.

Taylor D, Paton C, Kapur S. (2018). The Maudsley Prescribing Guidelines in Psychiatry. 13th Edition. Wiley-Blackwell.

Volkow ND, Fowler JS, Wang GJ, Baler R, Telang F. (2009). Imaging dopamine's role in drug abuse and addiction. Neuropharmacology, 56 Suppl 1(Suppl 1), 3-8. doi:10.1016/j.neuropharm.2008.05.022.

Howes OD, Kapur S. (2009). The dopamine hypothesis of schizophrenia: version III--the final common pathway. Schizophrenia Bulletin, 35(3), 549-562. doi:10.1093/schbul/sbp006.

Swanson JM, Volkow ND. (2008). Dopamine transporters, ADHD and stimulant drugs. Journal of Addictive Diseases, 27(1), 15-25. doi:10.1300/j069v27n01_03.

Olney, J. W., & Farber, N. B. (1995). Glutamate receptor dysfunction and schizophrenia. Archives of General Psychiatry, 52(12), 998-1007.

Javitt, D. C., & Zukin, S. R. (1991). Recent advances in the phencyclidine model of schizophrenia. American Journal of Psychiatry, 148(10), 1301-1308.

Sanacora, G., & Banasr, M. (2013). From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. Biological Psychiatry, 73(12), 1172-1179.

Löscher, W., & Schmidt, D. (2006). New horizons in the development of antiepileptic drugs: the search for new targets. Epilepsy Research, 69(3), 183-207.

Sieghart, W. (2015). Allosteric modulation of GABA(A) receptors via multiple drug-binding sites. Advances in pharmacology (San Diego, Calif.), 72, 53–96. https://doi.org/10.1016/bs.apha.2014.08.001

Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABA(B) receptors. Physiological reviews, 84(3), 835–867. https://doi.org/10.1152/physrev.00036.2003

Hodge, C. W., & Cox, A. A. (1998). The regulation of GABA(A) receptor function in the brain by ethanol. Alcohol and alcoholism (Oxford, Oxfordshire), 33(6), 513–524.

Eggermann E, Serafin M, Bayer L, et al. (2003). The wake-promoting hypocretin-orexin neurons are in an intrinsic state of membrane depolarization. J Neurosci, 23(34), 1557-1562. doi:10.1523/JNEUROSCI.23-34-01557.2003

Carhart-Harris RL, Nutt DJ. (2017). Serotonin and brain function: a tale of two receptors. J Psychopharmacol, 31(9), 1091-1120.

Hedlund PB. (2009). The 5-HT7 receptor and disorders of the nervous system: an overview. Psychopharmacology (Berl), 206(3), 345-354.

Cools R, Roberts AC, Robbins TW. (2008). Serotoninergic regulation of emotional and behavioural control processes. Trends Cogn Sci, 12(1), 31-40.

Cowen PJ. (2008). Serotonin and depression: pathophysiological mechanism or marketing myth? Trends Pharmacol Sci, 29(9), 433-436.

Sarter M, Bruno JP. (1997). Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res Brain Res Rev, 23(1-2), 28-46. Doi:10.1016/s0165-0173(96)00011-2

Mesulam, M. M. (2004). The cholinergic innervation of the human cerebral cortex. Prog Brain Res, 145, 67-78. doi:10.1016/s0079-6123(03)45004-8.

Woolf NJ, Butcher LL. (2011). Cholinergic systems mediate action from movement to higher consciousness. Behav Brain Res, 221(2), 488-498. doi:10.1016/j.bbr.2010.11.044.

Strange, P.G. (2017). Antipsychotic drug action: antagonism, inverse agonism or partial agonism. Trends Pharmacol Sci, 38(10), 899-916.

Creese, I., Burt, D.R., & Snyder, S.H. (1976). Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science, 192(4238), 481-483.

Kapur, S., & Mamo, D. (2003). Half a century of antipsychotics and still a central role for dopamine D2 receptors. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 27(7), 1081-1090.

Arnt, J., & Skarsfeldt, T. (1998). Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence. Neuropsychopharmacology, 18(2), 63-101. doi: 10.1016/S0893-133X(97)00194-6.

Meltzer, H. Y., Massey, B. W., & Horiguchi, M. (2011). Serotonin receptors as targets for drugs useful to treat psychosis and cognitive impairment in schizophrenia. Current opinion in pharmacology, 11(5), 535-542. doi: 10.1016/j.coph.2011.07.001.

Seeman, P., & Kapur, S. (2000). Schizophrenia: more dopamine, more D2 receptors. Proceedings of the National Academy of Sciences, 97(13), 7673-7675.

Beaulieu, J. M., Gainetdinov, R. R., & Caron, M. G. (2007). The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends in pharmacological sciences, 28(4), 166-172.

Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications. Cambridge University Press.

Da Cunha, I. C., et al. (2007). Involvement of D1/D2 dopamine receptors in the catalepsy induced by haloperidol in rats. Neuropharmacology, 52(6), 1285-1290.

Guo, X. L., et al. (2014). Antipsychotic-like effect of N-n-butyl haloperidol iodide in mice. Pharmacology Biochemistry and Behavior, 122, 196-203.

Samuels, B. A., & Hen, R. (2011). Novelty-suppressed feeding in the mouse. Methods in Molecular Biology, 829, 141-153.

Yamamoto M, Watanabe M, Kurosawa M, et al. (1997). Decrease in dopamine D2 receptor density in the striatum of rats after haloperidol administration: a quantitative autoradiographic study. Brain Res, 766(1-2), 231-236. doi:10.1016/S0006-8993(97)00571-4.

Sánchez-Pernaute R, García-Segura LM, Del Río J, Frechilla D. (2000). Reduced dopamine release and turnover in the striatum of 6-hydroxydopamine-lesioned rats after acute and chronic haloperidol treatment. J Neurochem, 74(3), 1155-1163. doi:10.1046/j.1471-4159.2000.741155.x.

Koda K, Ago Y, Cong Y, Kita Y, Takuma K, Matsuda T. (1999). The role of acetylcholine in the haloperidol-induced catalepsy in rats. Eur J Pharmacol, 372(1), 49-56. doi:10.1016/S0014-2999(99)00152-6.

de la Mora MP, Gallegos-Cari A, Arizmendi-García Y, Marcellino D, Fuxe K. (2000). Role of glutamate neurotransmission in the induction and maintenance of catalepsy of haloperidol in the rat. Brain Res Bull, 52(1), 15-21. doi:10.1016/S0361-9230(99)00275-8.

Andrade C, Srihari BS, Reddy KP, Chandramma L. (2005). Catalepsy induced by haloperidol in a patient with schizophrenia. Indian J Psychiatry, 47(1), 57-58.

Grunze H, Braunig P, Walden J. (1989). Catalepsy associated with haloperidol treatment. J Clin Psychopharmacol, 9(1), 74-76.

Iaboni A, O’Brien ES. (2003). Cataleptic reaction to haloperidol in a child with autism. J Dev Behav Pediatr, 24(2), 139-140.

Meyer JH, et al. (2006). Elevated Serotonin Transporter Binding in Major Depressive Disorder Assessed Using Positron Emission Tomography and [11C]DASB. Biol Psychiatry, 60(3), 231-235.

Abi-Dargham A, et al. (2000). Increased Dopamine D2 Receptor Occupancy and Elevated Amphetamine-Induced Dopamine Release in Schizophrenia. Proc Natl Acad Sci, 97(11), 6134-6139.

Kantarci K, et al. (2017). Proton Magnetic Resonance Spectroscopy in Alzheimer’s Disease: Preclinical Evidence of a Hypometabolism and Hypoxic State. JAMA Neurol, 74(6), 650-656.

Hasler G, et al. (2007). Reduced Prefrontal Glutamate/Glutamine and γ-Aminobutyric Acid Levels in Major Depression Determined Using Proton Magnetic Resonance Spectroscopy. Arch Gen Psychiatry, 64(2), 193-200.

Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci, 9(1), 46-56. doi:10.1038/nrn2297.

Jenner P. (2003). Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson’s disease. Curr Opin Neurol, 16 Suppl 1, S3-S7. doi:10.1097/00019052-200300001-00002.

Rogawski MA. (1999). Glutamate receptors as targets for antiepileptic drugs. Adv Neurol, 79, 979-999.

Andersen JK. (2004). Oxidative stress in neurodegeneration: cause or consequence? Nat Med, 10 Suppl, S18-S25. doi:10.1038/nrn1434.

Kobayashi K. et al. (2006). Changes in brain morphology in experimental catalepsy: A voxel-based morphometry study in rats. Eur J Neurosci, 24(3), 879-884. doi:10.1111/j.1460-9568.2006.04961.

Silbersweig D.A. et al. (1995). Increased cerebral blood flow in medial prefrontal cortex during mirror-reversal learning in catatonia. Am J Psychiatry, 152(5), 739-741. doi:10.1176/ajp.152.5.739.

Krack P. et al. (2001). Invasive investigations: PET and SPECT. Movement Disorders, 16(3), 510-521. doi:10.1002/mds.1137.

Helmich R.C. et al. (2012). The cerebral basis of Parkinsonian tremor: A network perspective. Movement Disorders, 27(6), 789-795. doi:10.1002/mds.24924.

Beaulieu, J. M., & Gainetdinov, R. R. (2011). The physiology, signaling, and pharmacology of dopamine receptors. Pharmacological Reviews, 63(1), 182-217.

Nichols, D. E., & Nichols, C. D. (2008). Serotonin receptors. Chemical Reviews, 108(5), 1614-1641.

Bowery, N. G., Hudson, A. L., & Price, G. W. (1987). GABAB receptor pharmacology. Annual Review of Pharmacology and Toxicology, 27(1), 475-500.

Parsons, M. P., & Raymond, L. A. (2014). Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron, 82(2), 279-293.

Blokland, A., & Prickaerts, J. (2017). The role of nicotinic acetylcholine receptors in the pathophysiology of Alzheimer’s disease and Parkinson’s disease. Behavioural Brain Research, 325, 317-327.

Lindenbach D, Bishop C. (2013). Critical involvement of the motor cortex in the pathophysiology and treatment of Parkinson’s disease. Neuroscience, 235, 89-103.

Waldmeier PC, et al. (2007). Structure-activity studies in a novel series of 4-phenyl-2-substituted-aminopyrimidines as benzodiazepine receptor agonists with potential utility in the treatment of epilepsy and anxiety. Journal of Medicinal Chemistry, 50(19), 4757-4769.

Factor SA. (2008). The clinical spectrum of freezing of gait in Parkinson’s disease. Movement Disorders, 23(Suppl 2), S431-S437.

Verhagen Metman L, et al. (2005). Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology, 64(5), 876-880.

Stambolic V, et al. (1996). Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 95(1), 29-39.