NOS-containing neurons, by modulating the activity of medium spiny neurons in response to cortical inputs, also play an important role in the expre ssion of synap- tic plasticity at corticostriatal synapses (Centonze et al., 1999, 2003c). Therefore, the striatum, by processing the informa- tion flow from various inputs and sending output to targets that generate behaviors (Grace, 2000), plays a key role in adaptive plasticity in corticobasal ganglia as well as in pathological responses in PD. Acknowledgments The authors would like to thank Laurent Gregoire for helping in the management of the references in the text and Gilles Chabot for preparing the figures. This work is supported by grants from the Canadian Institutes of Health Research (CIHR) to TDP, PJB and CR. PS holds a fellowship from CIHR-RX&D. References Aizman O, Brismar H, Uhlen P et al. (2000). Anatomical and physiological evidence for D-1 and D-2 dopamine receptor coloc alization in neostriatal neurons. Nat Neu- rosci3:226–230. Akil H, Owens C, Gutstein H et al. (1998). Endogenous opioids: overview and current issues. Drug Alcohol Depend 51: 127–140. Alberch J, Perez-Na varro E, Canals JM (2002). Neuropro- tection by neurotrophins and GDNF family member s in the excitotoxic model of Huntington’s disease. Brain Res Bull 57: 817–822. Alexander GE, Crutcher MD (1990). Functional architec- ture of basal gangl ia circuits—neural substrates of paral- lel processing. Trends Neurosci 13: 266–271. Alexi T, Hughes PE, Roon-Mom WM et al. (1999). The IGF-I amino-terminal tripeptide glycine-proline-gluta- mate (GPE) is neuroprotective to striatum in the quinoli- nic acid lesion a nimal model of Huntin gton’s disease. Exp Neuro l 159: 84–97. Alger BE (2002). Retrograde signaling in the regulation of synaptic transmission: focus on endocann abinoids. Prog Neurobiol 68: 247–286. Aliaga E, Carcamo C, Abarca J et al. (2000). Transient increase of brain derived neurotrophic factor mRNA expression in substantia nigra reticulata after partial lesion of the nigrostriatal dopaminergic pathway. Brain Res Mol Brain Res 79: 150–155. Allen JM, Cross AJ, Crow TJ et al. (1985). Dissociation of neuropeptide Y and somatostatin in Parkinson’s disease. Brain Res 337: 197–200. AnJJ,BaeMH,ChoSRetal.(2004).AlteredGABAergic neurotransmission in mice lacking dopamine D2 recep- tors. M ol Cell Neurosci 25: 732–741. Angulo JA, McEwen BS (1994). Molecular aspects of neu- ropeptide regulation and function in the corpus striatum and nucleus accumbens. Brain Res Rev 19: 1–28. Arai H, Sirinathsinghji DJ, Emson PC (1987). Depletion in substance P- and neurokinin A-like immunoreactivity in substantia nigra after ibotenate-induced lesions of stria- tum. Neurosci Res 5: 167–171. Arenas E, Alberch J, Pereznavarro E et al. (19 91). Neuro- kinin receptors differentially mediate endogenous acetyl- choline-release evoked by tachykinins in the neostriatum. J Neurosci 11: 2332–2338. Arenas E, Perez-Navarro E, Alberch J et al. (1993). Selec- tive resistance of tachykinin-responsive cholinergic neu- rons in the quinolinic acid lesioned neostriatum. Brain Res 603: 317–320 . Arluison M, De La Manche I (1980). High-resolution radio- autographic study of the serotonin innervation of the rat corpus striatum after intraventricular administration of [ 3 H]5-hydroxytryptamine. Neuroscience 5: 229–240. Augood SJ, Herbison AE, Emson PC (199 5). Localization of GAT-1 G ABA transporter mRNA in rat striatum: cel- lular coexpression with GAD67 mRNA, GAD67 immu- noreactivity, and parvalbumin mRNA. J Neurosci 15: 865–874. Augood SJ, Wa ldvogel HJ, Munkle MC et al. (1999). Localization of calcium-binding proteins and GABA transporter (GAT-1) messenger RNA in the human sub- thalamic nucleus. Neuroscience 88: 521–534. Azzi M, Gully D, Hea ulme M et al. (1994). N eurotensin receptor interaction with dopaminergic systems in the guinea-pig brain shown by neurotensin r eceptor antago- nists. Eur J Pharmacol 255: 167–174. Bai L , Xu H, Collins JF et al. (2001). Molecular and func- tional analysis of a novel neuronal vesicular glutamate transporter. J Biol Chem 276: 36764–36769. Baik JH , Picetti R, Saiardi A et al. (1995). Parkinsonian- like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377: 424–428. Balasubramaniam A (2003). Neuropeptide Y (NPY) family of hormones: progress in the development of receptor selective agonists and antagonists. Curr Pharm Des 9: 1165–1175. Bamford NS, Zhang H, Schmitz Y et al. (2004). Heterosy- naptic dopamine neurotransmission selects sets of corti- costriatal terminals. Neuron 42: 653–663. Barker R (1986). Substance P and Parkinson’s disease: a causal relationship? J Theor Biol 120: 353–362. Barker R (1991). Substance P and neurodegenerative disor- ders. A speculative review. Neuropeptides 20: 73–78. Barker R (1996). Tachykinins, neurotrophism and neurodegen- erative diseases: a critical review on the possible role of tachykinins in the aetiology of CNS diseases. Rev Neurosci 7: 187–214. Barker R, Larner A (1992). Substance P and multiple sclerosis. Med Hypotheses 37: 40–43. Barker R, Dunnett S, Fawcett J (1993). A selective tachykinin receptor agonist promotes differentiation but not survival of rat chromaffin cells in vitro. Exp Brain Res 92: 467–472. 50 P. SAMADI ET AL. NOS-containing neurons, by modulating the activity of medium spiny neurons in response to cortical inputs, also play an important role in the expre ssion of synap- tic plasticity at corticostriatal synapses (Centonze et al., 1999, 2003c). Therefore, the striatum, by processing the informa- tion flow from various inputs and sending output to targets that generate behaviors (Grace, 2000), plays a key role in adaptive plasticity in corticobasal ganglia as well as in pathological responses in PD. Acknowledgments The authors would like to thank Laurent Gregoire for helping in the management of the references in the text and Gilles Chabot for preparing the figures. This work is supported by grants from the Canadian Institutes of Health Research (CIHR) to TDP, PJB and CR. PS holds a fellowship from CIHR-RX&D. References Aizman O, Brismar H, Uhlen P et al. (2000). Anatomical and physiological evidence for D-1 and D-2 dopamine receptor coloc alization in neostriatal neurons. Nat Neu- rosci3:226–230. Akil H, Owens C, Gutstein H et al. (1998). Endogenous opioids: overview and current issues. Drug Alcohol Depend 51: 127–140. Alberch J, Perez-Na varro E, Canals JM (2002). Neuropro- tection by neurotrophins and GDNF family member s in the excitotoxic model of Huntington’s disease. Brain Res Bull 57: 817–822. Alexander GE, Crutcher MD (1990). Functional architec- ture of basal gangl ia circuits—neural substrates of paral- lel processing. Trends Neurosci 13: 266–271. Alexi T, Hughes PE, Roon-Mom WM et al. (1999). The IGF-I amino-terminal tripeptide glycine-proline-gluta- mate (GPE) is neuroprotective to striatum in the quinoli- nic acid lesion a nimal model of Huntin gton’s disease. Exp Neuro l 159: 84–97. Alger BE (2002). Retrograde signaling in the regulation of synaptic transmission: focus on endocann abinoids. Prog Neurobiol 68: 247–286. Aliaga E, Carcamo C, Abarca J et al. (2000). Transient increase of brain derived neurotrophic factor mRNA expression in substantia nigra reticulata after partial lesion of the nigrostriatal dopaminergic pathway. Brain Res Mol Brain Res 79: 150–155. Allen JM, Cross AJ, Crow TJ et al. (1985). Dissociation of neuropeptide Y and somatostatin in Parkinson’s disease. Brain Res 337: 197–200. AnJJ,BaeMH,ChoSRetal.(2004).AlteredGABAergic neurotransmission in mice lacking dopamine D2 recep- tors. M ol Cell Neurosci 25: 732–741. Angulo JA, McEwen BS (1994). Molecular aspects of neu- ropeptide regulation and function in the corpus striatum and nucleus accumbens. Brain Res Rev 19: 1–28. Arai H, Sirinathsinghji DJ, Emson PC (1987). Depletion in substance P- and neurokinin A-like immunoreactivity in substantia nigra after ibotenate-induced lesions of stria- tum. Neurosci Res 5: 167–171. Arenas E, Alberch J, Pereznavarro E et al. (19 91). Neuro- kinin receptors differentially mediate endogenous acetyl- choline-release evoked by tachykinins in the neostriatum. J Neurosci 11: 2332–2338. Arenas E, Perez-Navarro E, Alberch J et al. (1993). Selec- tive resistance of tachykinin-responsive cholinergic neu- rons in the quinolinic acid lesioned neostriatum. Brain Res 603: 317–320 . Arluison M, De La Manche I (1980). High-resolution radio- autographic study of the serotonin innervation of the rat corpus striatum after intraventricular administration of [ 3 H]5-hydroxytryptamine. Neuroscience 5: 229–240. Augood SJ, Herbison AE, Emson PC (199 5). Localization of GAT-1 G ABA transporter mRNA in rat striatum: cel- lular coexpression with GAD67 mRNA, GAD67 immu- noreactivity, and parvalbumin mRNA. J Neurosci 15: 865–874. Augood SJ, Wa ldvogel HJ, Munkle MC et al. (1999). Localization of calcium-binding proteins and GABA transporter (GAT-1) messenger RNA in the human sub- thalamic nucleus. Neuroscience 88: 521–534. Azzi M, Gully D, Hea ulme M et al. (1994). N eurotensin receptor interaction with dopaminergic systems in the guinea-pig brain shown by neurotensin r eceptor antago- nists. Eur J Pharmacol 255: 167–174. Bai L , Xu H, Collins JF et al. (2001). Molecular and func- tional analysis of a novel neuronal vesicular glutamate transporter. J Biol Chem 276: 36764–36769. Baik JH , Picetti R, Saiardi A et al. (1995). Parkinsonian- like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377: 424–428. Balasubramaniam A (2003). Neuropeptide Y (NPY) family of hormones: progress in the development of receptor selective agonists and antagonists. Curr Pharm Des 9: 1165–1175. Bamford NS, Zhang H, Schmitz Y et al. (2004). Heterosy- naptic dopamine neurotransmission selects sets of corti- costriatal terminals. Neuron 42: 653–663. Barker R (1986). Substance P and Parkinson’s disease: a causal relationship? J Theor Biol 120: 353–362. Barker R (1991). Substance P and neurodegenerative disor- ders. A speculative review. Neuropeptides 20: 73–78. Barker R (1996). Tachykinins, neurotrophism and neurodegen- erative diseases: a critical review on the possible role of tachykinins in the aetiology of CNS diseases. Rev Neurosci 7: 187–214. Barker R, Larner A (1992). Substance P and multiple sclerosis. Med Hypotheses 37: 40–43. Barker R, Dunnett S, Fawcett J (1993). A selective tachykinin receptor agonist promotes differentiation but not survival of rat chromaffin cells in vitro. Exp Brain Res 92: 467–472. 50 P. SAMADI ET AL. Chapter 3 Neurophysiology of basal ganglia diseases ALFREDO BERARDELLI* Department of Neurosciences and Neuromed Institute, Universita ` La Sapienza, Rome, Italy The a natomical s tructures of the basal ganglia are connected to each other by a ne twork of i nterconnections and t he functional organization is based on the connec- ti ons wi th t h al am us and c orti cal terri tori es ( Albin et al., 1989; Alexander a nd Crutcher, 1990; Mink, 1996; Parent and Hazrati, 1995). Movement disorders (parkinsonisms, dystonias and choreas) can be considered the r esult of alterat ions i n the c ort ico-stria to-thalamo-cortical circui t (DeLong, 1990 ). Func tional connections of the b asal gang lia with other structures o f the ne rvous s ys tem (brain- stem and spina l cord) are a lso r elevant in the pa thophy- siolog y of mov ement disorders. A significant part o f o ur speculations on the p hysiological role of the basal ganglia in huma n b eings d erives from studie s cor rela ting n euro- physiological deficits with specific lesions of the b asal gang lia structures (Bera rde lli & C ur ra ` ,2002). In this chapter we will review the neuro physiolo gi- cal findings descr ibed in patient s with Parki nson’s disease (PD), dystonia and Hunti ngton ’s disease (HD). 3.1. Parkinson’s disease In recent years, considerable advances have taken place in the understanding of the pathophysiology of PD. In experiments conducted on animals rendered parkinso- nian through the administration of 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP), and more recently in parkinsonian patients undergoing surgery for deep brain stimulation, the activity from specific neuron popu- lations can be recorded through electrodes implanted directly into the basal ganglia nuclei. After nigral degen- eration there is an altered neuronal output from the subthalamic nucleus and globus pallidus (Hutchison et al., 1997). This abnormal neuronal activity brings about a functional change in the motor circuits that link the basal ganglia to the motor cortical area. Striatal dopa- mine depletion in PD reduces the activity of thalamic nuclei projecting to the frontal lobe, leading to cortical deafferentation. Such alterations are held responsible for the motor disturbances typical of PD (Berardelli et al., 2001). Move ment slowne ss (bradykin esia), toge ther with muscular rig idity and tremors, are amo ng the principal symptoms of PD. Pathophysi ologica l stud ies have demonstrat ed that brady kinesia is in part cause d by defective preparati on of volun tary move ment. The usual way of inve stigatin g moveme nt prepa ration of a volun tary move ment is to study the reaction time (RT). The RT ref ers to the interv al elapsing betwee n the stim ulus to move and moveme nt initiatio n. The RT include s stim ulus processi ng, the use of work- ing memory for the retri eval of stimulus map pings and the gener ation o f predict ions and decisi on-maki ng. Several studies have provided evidence that parkinso- nian patients have an increased RT (Evarts et al., 1981; Jahanshahi et al., 1992), particularly for the more difficult tasks. Preparation of movements can also be studied by recording the slow-rising negative electro- encephalogram (EEG) potentials generated before the onset of a voluntary movement (premotor potentials). The premotor potential begins about 2 s before the onset of a voluntary movement and is thought to be generated in the primary and non-primary cortical motor a reas. In patients with PD, t he pr emo t or po ten tials have reduced amplitude, probably owing to reduced activation of cortical motor areas, particularly of supple- mentary motor areas (Dick et al., 1989; Jahanshahi et al., 1995). Besides causing defective movement preparation, PD also leads to alterations in movement execution. Studies on electromyogram (EMG) and kinematic activity show that parkinsonian patients have difficulty *Correspondence to: Professor Alfredo Berardelli, Department of Neurological Sciences and Neuromed Institute, Universita ` La Sapienza, Viale dell’ Universita ` , 30, 00185 Roma, Italy. E-mail: alfredo.berardelli@uniroma1.it, Tel: þ 39-06-4991-4700, Fax: 39-06-4991-4700. Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved Chapter 4 Dopamine receptor pharmacology RICHARD B. MAILMAN 1,2 * AND XUEMEI HUANG 2 1 Departments of Psychiatry, 1 Pharmacology, 2 Neurology and Medicinal Chemistry, University of North Carolina School of Medicine, Chapel Hill, NC, USA 4.1. Dopamine receptor biology 4.1.1. Bac kground Despite a h alf-centu ry of rese arch since the first drugs that bind to dopamin e rece ptors (e.g. chlorpr omazine) were used in clinical med icine, the under lying mechani sms are still poorl y under stood. The biochem - ical assays developed by Arvid Ca rlsson and othe rs ( Carlsson, 195 9), as well as histologi cal tec hniques ( Hillarp et al., 1966 ), paved the way for understa nding dopam ine functi on in the brai n. These stud ies showed there were three major dopamin e path ways, including the nigrost riatal (from cells in the A9 region) , the mesolim bic-cor tical (from cells in the A10 o r v entral tegmen tum) and the tuberoi nfundibular (hypot ha- lami c) system ( Ungerstedt , 19 71a). This early aware- ness of the chemoar chitec ture of dopam ine systems opened the doors to an u nderstandin g of the functi onal role of dopam ine in comple x phenom ena med iated by the brain areas modulated by do pamine. Indee d, soon after the disco very of chlorpr omazin e, it was demon - strat ed that decrease s in acute agitati on, hallucinat ions and othe r psycho tic sign s and sym ptoms were fre - quent ly accompa nied by disturb ing and unwa nted neuro logical side-effe cts (drug-in duced parkinso nism, akathesi a and acute dyst onic reac tions), now known as extrapyr amidal side -effects. This similarity of acute drug- induced neurologica l side-effe cts and Parkinson ’s disease ( Ehringer and Hor nykiewicz , 1960; Hornyki ewicz, 1971 ) sugges ted a mechanist ic relat ionship ( Carl sson and Lindqv ist, 1963 ) that marked the beginning of the field of dopamine receptor pharmacology. Al though dopam ine recepto rs had been hypothe- sized for nearly a decad e, the first dir ect bioch emical mechanism linked to them cam e from the labo ratory of Paul Greenga rd, who demonst rated that dopamin e could dose-depe ndent ly stimula te the synt hesis of the second-m essenger cyclic adenos ine monoph osphate (cAMP: Kebabi an et al., 1972 ) in a fashion that was antagonized by antipsy chotic d rugs ( Clement-Cor mier et al., 1974 ). Th e fact that bo th phenothi azine and thioxanthi ne antipsy chotics com petitively inhibited the dopamin e-stimulat ed act ivity of adenyl ate cyclase in p roportion to their clini cal po tency led to the notion that thi s was the major funct ional mec hanism o f dopa- mine in the cent ral nervo us system ( Clement-Cor mier et al., 1974 ; Iversen, 1975 ). However, with the introduction of new antipsychotics in still newer s tructural c lasses (e.g. b utyrophenones and benzamides), marked discrepancies b ecame apparent. Fo r e xam ple, m a ny of t he se new b ehaviorally potent antipsychotics h ad littl e potency in inhibiting dopa- mine -stimulated a de nylate cyclas e ( Trabucchietal., 19 75 ). T h is d iscre pa nc y led to the idea tha t two ty pe s of dopamine receptors existed. One class was the o riginal ade nylate c ycla se -linked r ece ptor f irst repor ted b y G ree n- gar d’s gr ou p ( Keba bia n e t al. , 19 72 ), that bound w ith high-affinity thioxanthines a nd ph en oth iaz ine antip sy - chotics, but not drugs of the butyrophenone or benza- mide classes (Garau et al., 197 8). The other class of dopamine receptor was not linked to stimulation of ade- nylate cyclase, but bou nd all of these drugs in proportion to their clinical potency (Burt et al., 1976; Creese et al., 1976; Seeman et al., 1976). This differentiation, coupled with other information about the localization and func- tion of dopamine receptors, led to the specific h ypothesis *Correspondence to: Dr Richard B. Mailman, CB # 7160, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7160, USA. E-mail: richard_mailman@med.unc.edu, Tel: þ 1-919-966-3205, Fax: þ 1-966-1844. Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson’s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 2007 Elsevier B.V. All rights reserved Section 2 General aspects of Parkinson’s disease . Italy. E-mail: alfredo.berardelli@uniroma1.it, Tel: þ 3 9-0 6-4 99 1-4 700, Fax: 3 9-0 6-4 99 1-4 700. Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson s disease and related disorders, Part. Tel: þ 1-9 1 9-9 6 6-3 20 5, Fax: þ 1-9 6 6-1 844. Handbook of Clinical Neurology, Vol. 83 (3rd series) Parkinson s disease and related disorders, Part I W.C. Koller, E. Melamed, Editors # 20 07 Elsevier. Brismar H, Uhlen P et al. (20 00). Anatomical and physiological evidence for D-1 and D -2 dopamine receptor coloc alization in neostriatal neurons. Nat Neu- rosci3 :22 6 23 0. Akil H, Owens C, Gutstein