5-HT1A receptor-dependent control of nigrostriatal dopamine neurotransmission in the pharmacotherapy of Parkinson’s disease and schizophrenia Darakhshan J. Haleem Dysfunctions of the basal ganglia are associated with a number of neurological and psychiatric conditions including Parkinson’s disease and schizophrenia. Current treatments of these disorders are mostly symptomatic and inadequate, and are often associated with a number of unwanted side- effects. The striatum, the terminal region of the nigrostriatal dopamine pathway, is the main input nucleus of the basal ganglia, and dopamine neurotransmission through the nigrostriatal pathway plays a crucial role in the modulation of basal ganglia output and mediated behaviors. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the modulation of dopamine neurotransmission and in improving pharmacotherapy in schizophrenia and Parkinson’s disease. This review concerns the role of 5-HT1A receptors in the modulation of nigrostriatal dopamine neurotransmission, with the aim of providing guidelines for future research to improve pharmacotherapy. The current state of knowledge suggests that drugs simultaneously targeting dopamine D2 and 5-HT1A receptors may improve pharmacotherapy for schizophrenia and Parkinson’s disease. Activation of somatodendritic 5-HT1A receptors in the dorsal raphe nucleus has an important role in the alleviation of extrapyramidal symptoms and levodopa-induced dyskinesia induced by antipsychotic treatment. Drugs acting exclusively through dopamine D2 and 5-HT1A receptors are highly needed to validate the potential role of 5-HT1A receptors in improving therapeutics for Parkinson’s disease and schizophrenia. Behavioural Pharmacology 26:45–58 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Behavioural Pharmacology 2015, 26:45–58 Keywords: basal ganglia, dopamine, 5-hydroxytryptamine 1A receptor, nigrostriatal pathway, Parkinson’s disease, schizophrenia Neuroscience Research Laboratory, Dr Panjwani Center for Molecular Medicine & Drug Research (PCMD), International Center for Chemical and Biological Science (ICCBS), University of Karachi, Karachi, Pakistan Correspondence to Darakhshan J. Haleem, PhD, Neuroscience Research Laboratory, Dr Panjwani Center for Molecular Medicine & Drug Research (PCMD), International Center for Chemical and Biological Science (ICCBS), University of Karachi, Karachi 75270, Pakistan E-mail: darakhshan_haleem@yahoo.com Received 3 September 2014 Accepted as revised 5 November 2014 Introduction Serotonin [5-hydroxytryptamine (5-HT)] and dopamine pathways are often viewed as two different and separate entities in the brain. The cell bodies of dopamine- containing and serotonin-containing neurons are also located in discrete nuclei. Yet a number of brain regions, including the striatum, are innervated by axon terminals of dopamine-containing as well as serotonin-containing neurons (Fig. 1). Important synaptic contacts occur not only between axon terminals but also between cell bodies of dopamine-containing and serotonin-containing neurons (see Haleem, 2013). It is therefore not surprising that changes in the activity of one of these neuronal systems can modulate the activity of the other, as demonstrated by a number of pharmacological studies (Bubar and Cunningham, 2006; Dremencov et al., 2006; Esposito, 2006; Haleem, 2006; Werkman et al., 2006; Alex and Pehek, 2007; Di Giovanni et al., 2008; Di Matteo et al., 2008; Navailles and De Deurwaerdère, 2011). Current treatments for a number of neuropsychiatric dis- eases, including schizophrenia and Parkinson’s disease, are mostly symptomatic and inadequate. Treatments that provide less than satisfactory remission are often associated with a number of unwanted side-effects. The inadequate response rate to current medications and the chronic nature of these diseases suggest a critical need for the develop- ment of new treatment strategies. In this regard, studies on the role of serotonin in the modulation of dopamine neu- rotransmission are becoming increasingly important. At least 14 different types and subtypes of serotonin receptors have been identified (Hoyer et al., 2002). The 5-HT1A receptor subtype occurs on the soma and den- drites of serotonin neurons and also postsynaptically, and has been shown to have an important role in the mod- ulation of motor activity and dopamine neurotransmission (Haleem, 2013; Huot and Fox, 2013; Ohno et al., 2013). Evidence suggests an important role of these receptors in the modulation of dopamine neurotransmission, control of motor activity, and in the pharmacotherapy of schizo- phrenia and Parkinson’s disease. Atypical antipsychotic drugs, which are either direct or indirect 5-HT1A ago- nists, produce fewer extrapyramidal symptoms (EPS), and can treat both positive and negative symptoms and cognitive deficits of schizophrenia (Haleem et al., 2002, 2004, 2007a, 2007b; Meltzer and Sumiyoshi, 2008; Ohno et al., 2009, 2013; Schimizu and Ohno, 2013; Schimizu Review article 45 0955-8810 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/FBP.0000000000000123 Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.