  Neuropharmacology of dopamine receptors: Implications in neuropsychiatric diseases Frank I. Tarazi ABSTRAC T. There has been an extraordinary recent accumulation of information concerning the neurobiology and neuropharma- cology of dopamine (DA) receptors in the mammalian central nervous system. Many new DA molecular entities have been cloned, their gene, peptide sequences and structures have been identified, their anatomical distributions in the mammalian brain described, and their pharmacology characterized. Progress has been made toward developing selective ligands and drug-candidates for different DA receptors. The new discoveries have greatly stimulated preclinical and clinical studies to explore the neuropharmacology of DA receptors and their implications in the neuropathophysiology of different neuropsychiatric diseases including schizophrenia, Parkinson’s disease and atten- tion-deficit hyperactivity disorder. Accordingly, it seems timely to review the salient aspects of this specialized area of preclinical neurop- harmacology and its relevance to clinical neuropsychiatry. Key words: antipsychotics, ADHD, basal ganglia, dopamine receptors, Parkinson’s disease, schizophrenia Consolidated Department of Psychiatry and Neuroscience Program, Harvard Medical School; Boston, MA; Mailman Research Center, McLean Division of Massachusetts General Hospital, Belmont, MA , USA. E-mail: ftarazi@hms.harvard.edu D ()     within the mammalian central nervous system (CNS). DA-containing neurons arise mainly from DA cell bodies in the substantia nigra and ventral tegmen- tal area in mid-brain region, and are organized into four major subsystems [Figure ]:1–6 (i) the nigrostriatal system involving neurons projecting from the substantia nigra pars compacta to the caudate-putamen of the basal ganglia. is is the major DA system in the brain as it accounts for about  of the total DA in the brain, and its degenera- tion makes a major contribution to the pathophysiology of Parkinson’s disease; (ii) the mesolimbic system that originates in the midbrain tegmentum and projects to the nucleus accumbens septi and lateral septal nuclei of the basal forebrain as well as the amygdala, hippocampus, and the entorhinal cortex, all of which are considered components of the limbic system and so are of particular interest for the pathophysiology of idiopathic psychiatric disorders; (iii) the mesocortical system, which also arises from neuronal cell bodies in the tegmentum which project their axons to the cerebral cortex, particularly the medial prefrontal regions; (iv) the tuberinfundibular pathway, which is a neuroendocrinological pathway arising from the arcuate and other nuclei of the hypothalamus and ending     :   , : , : , – ©   Dopamine (tarazi( �� �������������������� ��������� �����: �� ���������������� ����-����� ���� ����� ������:������ �� ������������ �� ����������� ��������� ������ ������ ����� ���� ������� ������ ��� ����� ������� ����� �������� ������� ������.����� �������� �� ���� ��������������� ����� ��� ���������������� ������� ����� .������� ����� �� ������� ������� ���� � �������� �� �� ��� �������� .������� ������ ������ ������ � ����� ������ ����� ��� ���� ���� ��������� .��� ������������� �������� ����� ������ ������� �������������� ��������� �������� ������� ��������� ���� ������� �����-������������ ����� ��������� ��� ���� �������� ��� .���� ������ ����� ������ �� ����� ������� �� ��� ���� ����� ����� ������� ������� �������� ��� ������� �������� �� �������-�����.       in the median eminence of the inferior hypothalamus. DA released in this system exerts regulatory effects in the ante- rior pituitary and inhibits the release of prolactin. DA mediates its neurocheantimical and physiological actions via membrane receptor proteins. DA receptors are found on postsynaptic neurons in brain regions that are DA-enriched. In addition, they reside presynaptically on DA neuronal cell bodies and dendrites in the midbrain as well as on their terminals in the forebrain. Stimulation of these ‘autoreceptors’ inhibits DA synthesis by block- ing the activity of tyrosine hydroxylase, the rate-limiting enzymatic step in catecholamine synthesis. In addition, DA autoreceptor activation blocks DA release from presynap- tic membrane-enclosed storage vesicles, and significantly attenuate the firing rate of the DA neurons.7,8 All DA receptor proteins belong to a superfamily of large peptides that are coupled to G-proteins and modified by attached carbohydrate, lipid-ester or phosphate groups. ey are characterized by having seven hydrophobic transmem- brane-spanning regions, as well as a functionally critical third intracytoplasmic loop that interacts with G-proteins and other effector molecules to mediate the physiological and neurochemical effects of the receptors.2–5 e DA receptors were originally differentiated into two major types.9 is was mainly based on the presence or absence of ability of DA to stimulate adenylyl cyclase and produce the second-messenger molecule cyclic-AMP (cAMP) to distinguish receptor types D1 and D2. D1 recep- tors were characterized initially as mediating the stimula- tion of cAMP production. D2 receptors, which inhibit the production of cAMP, were pharmacologically characterized based on the ability of only some DA agents to block ade- nylyl cyclase activity, and on the ability of catecholamines including DA to inhibit the release of prolactin in vivo and in vitro in a cAMP-independent fashion.10 Applications of recent technical advances in molecular genetics have greatly facilitated the isolation and characterization of novel DA receptors, D3, D4 and D5, with different anatomi- cal localization from traditional D1 or D2 receptors. Based upon their pharmacological profiles, including their effects on different signal transduction cascades, these receptors are currently divided into two families: the D1-like family, which includes D1 and D5 receptors, and the D2-like family which includes D2, D3 and D4 receptors.11–13 M O L E C U L A R B I O L O G Y O F D O P A M I N E R E C E P T O R S        1-         D1 receptors e DA D1 receptor is the most abundant DA receptor in the central nervous system. e D1 receptor gene, which lacks any introns, encodes a protein that extends for  amino acids.14 e human gene has been localized to chromosome  [Table ].15 D1 receptors show character- istic ability to stimulate adenylyl cyclase and generate inositol ,,-trisphosphate (IP3) and diacylglycerol via the activation of phospholipase C.16,17 D1 receptors are highly expressed in basal ganglia followed by cerebral cortex, hypothalamus and thalamus. In striatal neurons of the basal ganglia, the mRNA for D1 receptors has been colocalized with mRNA for DARPP- (a DA- and cyclic- AMP-regulated phosphoprotein of molecular mass , daltons, or  kD), suggesting that DARPP- may contrib- ute to the actions of D1 receptors.18–19 D5 receptors e intronless D5 receptor gene encodes a protein that extends for  amino acids [Table ].20 e protein has an overall  homology with the D1 receptor and  if only the seven transmembrane segments are considered. e gene encoding the human D5 protein is located at Figure 1. Schematic organisation of the four major dopamine systems in the brain.2                                            the short arm of chromosome , the same region where the Huntington disease gene has been located.21 It is unknown, however, if there is any functional interaction between the two genes. Molecular studies identified two D5-like pseudogenes that extend for  amino acids and show  homology to the D5 receptor genomic sequence. ese pseudogenes, however, contain stop codons in their coding regions that prevent them from expressing functional receptors. e functions of these pseudogenes, which appear so far to be specific to humans, are not yet known.22 Expression of D5 mRNA is unique and limited to the hippocampus and parafascicular nucleus of the thalamus,23 a thalamic nucleus involved in pain perception, suggest- ing that D5 receptors may be involved in the thalamic processing of painful stimuli.24 D5 receptors, like D1 recep- tors, appear to interact with G-proteins and can stimulate adenylyl cyclase, with relatively high affinity for DA and D1-selective agonists [Table ].20        2-         D2 receptors e DA D2 receptor was the first DA receptor to be cloned.25 e D2 receptor gene encodes a protein that extends for  amino acids [Table ]. Similar to other G-protein coupled receptors, the D2 gene product has seven transmembrane segments, but in contrast to D1-like receptors, the third cytoplasmic domain is long and the carboxyl terminus is short. Unlike the D1-like receptor genes, the D2 receptor gene contains seven introns that are spliced out during mRNA transcription.26 e gene encoding this receptor was found to reside on q-q of human chromosome .27 D2 receptors are involved in several signal transduc- tion cascades, including inhibition of cAMP production,28 inhibition of phosphoinositide turnover,29 activation of potassium channels, and potentiation of arachidonic acid release [Table ].30 D2 receptors are highly expressed in basal ganglia, nucleus accumbens septi, and ventral tegmental area.31 � � ������������������������������������������� � ����� ������������� ����������� �������� ��������������� ������ ����������� ��������� ����������� ������������ ���������� ������������������ � � � � � � ��� �������� �������� �� ��������������� ������������������ ���������������� �������������������� �������� ����������� �������������� ����������������� ������������� �������������� ������ ������� ��� �������� �������� �� ������������ ��������� �������������������� ����������������� ������ ������������������ � � � � � � ��� �������� ��� �������������������� �������������� ���������� ����������������� ��������������� ����������� ��������������� ��������������� ������ �������������� �������������� ������������������ ��� �������� �������� �� �������������������� ������������������� ����������� ������������� �������������� ������������ �������� ���������� ��� �������� ������������� ������� ��� ���������������� ������������� ��������� ����������� ����������� ���������� ���������� �������� ��������� ������ ������ � ���������������������������������������������������������������������������������������� �������������������������������������������������������������������������������������������������������������������������������������������������������������������� ��������������������������������������� ������������������������������������������������������������ �       Molecularly, D2 receptor protein exists in two isoforms derived from the same gene by alternative RNA splicing which occurs during the maturation of the D2 recep- tor pre-mRNA.32 Both isoforms (known as D2L and D2S) vary within each species by the presence or less fre- quent absence of a -amino acid sequence in the third cytoplasmic domain of the D2 receptor peptide chain. Pharmacologically, both isoforms exhibit nearly similar profiles in terms of their affinities to different D2-selective agents, and both inhibit adenylyl cyclase activity. However, they display an opposite regulatory response to DA treat- ment: DA induces up-regulation of D2L isoform and down- regulation of D2S isoform.33 D3 receptors e D3 receptor gene contains five introns and encodes a  amino acid protein.34 e gene encoding this recep- tor resides on chromosome  [Table ].35 e D3 receptors bear close structural and pharmacological similarities to the D2R and, like the genes for D2 receptor variants, D3 mRNA also occurs in longer and shorter spliced forms generated from the same gene.36 Distribution of D3 mRNA indicated that these receptors are mainly expressed in sub- cortical limbic regions including islands of Calleja, nucleus accumbens septi and olfactory tubercle, with low levels of expression in the basal ganglia [Table ].31 Surprisingly, D3R mRNA has also been found in neurons of the cerebellum, which may regulate eye-movements.37 e status of the D3 molecular entity as a functional receptor remains uncer- tain since it neither couples to G-proteins nor consistently transduces an effector mechanism.34,38 However, the struc- tural similarity with D2 receptor raises the possibility that D3 receptor may also inhibit adenylyl cyclase activity in its normal cellular setting. More recent studies reported that D3 receptors might mediate positive regulatory influences of DA on production of the peptide neurotensin.39 D4 receptors e human D4 receptor gene contains four introns and encodes a  amino acid protein.40 e overall homology of the D4 receptor to the D2 and D3 receptors is about  and  respectively, but this homology increases to  for both receptors when only the transmembrane span- ning segments are considered. e gene encoding the human D4 protein is located at the tip of the short arm of chromosome .41 Histoprobes for its mRNA localized this gene product in non-extrapyramidal regions of human brain including hippocampus and frontal cerebral cortex.42 Like the D2 receptors, stimulation of the D4 receptors can inhibit adenylyl cyclase activity and activate release of arachidonic acid in brain neurons [Table ].43 Human, but not primate or rodent, D4 receptors are known to occur in several genomic polymorphic variants that contain from two to eleven repeats of a  base-pair segment expressed in the third cytoplasmic domain.44 Two, four and seven repeats (designated as D4.2, D4.4 and D4.7) are the most common D4 alleles. ese variants may con- tribute to the pathophysiology of certain neuropsychiatric disorders or their improved treatment.4                                e basal ganglia consist of five interconnected subcortical nuclei including the striatum (caudate nucleus and puta- men), globus pallidus, subthalamic nucleus, and substantia nigra pars compacta and pars reticulata.45–47 e medium spiny neurons, which constitute – of the neurons in the striatum, receive the bulk of the incoming excitatory input from the cerebral cortex. ese neurons send their projections through two major striatal output pathways. e direct or striatonigral pathway, where striatal neurons project to the internal segment of the globus pallidus and the substantia nigra pars reticulata and the indirect or striatopallidal pathway where striatal neurons project to the external segment of the globus pallidus, then to the subthalamic nucleus and terminate in the substantia nigra pars reticulata. e later region sends projections to the ventral anterior, ventral lateral and mediodorsal thalamic nuclei, which in turn provide an excitatory input to the cerebral cortex.45–47 In the striatum, the majority of D1 receptors are expressed on striatonigral neurons, whereas D2 receptors are predominately localized to striatopallidal neurons.46,47 Some D4 receptors are co-expressed with the excitatory glutamate NMDA receptors, on terminals of glutama- tergic corticostriatal projections innervating striatum, as well as on medium spiny neurons in striatum.48 Both D2 and D3 subtypes are found on terminals of dopaminergic nigrostriatal neurons projecting from substantia nigra pars compacta to striatum.49 e basal ganglia are involved in programming and initiation of movement, particularly slow movements, and in motor memory and retrieval. Abnormalities in DA neurotransmission in the basal ganglia nuclei and/or their projecting targets have been linked to attention-deficit hyperactivity disorder (ADHD) and schizophrenia.1,2,50 In addition, disorders of the basal ganglia may produce restricted and rigid movements as in Parkinson’s dis- ease or uncontrollable and involuntary movements as in Huntington’s disease.51                                            D O P A M I N E R E C E P T O R S A N D N E U R O P S Y C H I A T R I C D I S E A S E S DA receptors have been implicated in a variety of neu- ropsychiatric disorders, most notably in schizophrenia, Parkinson’s disease and attention-deficit hyperactivity dis- order (ADHD). Other brain disorders in which DA recep- tors are involved or dopaminergic drugs have a therapeutic role are Huntington’s chorea, Tourette’s syndrome, and hyperprolactanemia.          Schizophrenia is one of the most common neuropsychiat- ric diseases affecting  of the general population. is rate is fairly uniform throughout the world, even though the environmental and socio-economical factors vary among different countries. Additional – of the general popula- tion has schizotypal personality disorder, which is a milder form of the disease.52–55 e symptoms of schizophrenia start to develop in late adolescence or early adulthood. e ‘positive’ symptoms include thought disorder, percep- tual disturbances, visual and auditory hallucinations and delusions while the ‘negative’ symptoms include loss of executive functions such as planning and working memory, neglect of hygiene, social isolation and withdrawal from interaction with other people.52–55 Genetic studies suggested that genetic factors play an important role in the pathophysiology of schizophrenia. Monozygotic twins, who have identical genome, show a concordance rate of about –, but in dizygotic twins, the rate drops to only .55–57 ese rates, however, indicate that genetic predisposition alone is insufficient to produce the disease, and that other neurochemical and environmental factors also contribute to the development of the disease. Injuries in the normal development of human brain including maldevelopment of the anatomical organization and connectivity of cortical afferents inner- vating the limbic regions may contribute to neurobiologi- cal substrates for schizophrenia.58 Disturbances in the concentrations and subsequent alterations in the neuro- transmission of different neurotransmitters, including DA, serotonin and glutamate, in different cortical and limbic and extrapyramidal pathways have been also proposed to underlie the pathophysiology of schizophrenia.59–61 Treatment of Schizophrenia Treatment of schizophrenia and other idiopathic psychotic disorders was revolutionized by the serendipitous dis- covery of chlorpromazine (phenothiazine derivative) and haloperidol (butyrophenone derivative) in the s. is was followed by introduction of other effective antipsy- chotic compounds including thioxanthenes (clopentixol, flupentixol, and thiothixene), benzepines (loxapine, clothi- apine and zotepine), diphenylbutylpiperidines (spiperones), indolones (molindone and oxypertine) and other heterocy- clic compounds.1,2 Virtually, all of these drugs, which col- lectively are known as typical antipsychotic drugs, reduce DA neuronal activity, reverse the psychotic symptoms induced by psychostimulants such as amphetamine and cocaine, and block DA D2 receptors in a direct correlation with their antipsychotic efficacy.1,2,62,63 Typical antipsychotics are effective in alleviating the positive symptoms of schizophrenia. However, their effectiveness is limited and non-specific as they fail to significantly improve the cognitive deficits and negative symptoms of schizophrenia. Moreover, treatment with these medications is commonly associated with neuro- logical extrapyramidal and endocrinological side effects, of both acute and delayed nature.1,2 Parkinsonism, a syndrome with similar symptoms to Parkinson’s disease, is the most frequent acute side effect. Other acute side effects include dystonia (sustained contraction of orofacial muscles), akathisia (motor restlessness with anxiety and agitation), and galactorrhea (excessive lactation). ese side effects are the result of D2 receptor blockade in either the stria- tum or pituitary gland.1,2 A potentially life-threatening adverse effect of antipsychotic drug treatment is known as neuroleptic malignant syndrome.64,65 It is characterized by muscle rigidity, dystonia, unstable pulse, blood pres- sure, fever, and elevated serum concentrations of muscle proteins (creatine kinase, myoglobin). e syndrome has been attributed to D2 receptor blockade by typical antip- sychotic agents, but its pathophysiology remains obscure, and may involve hypothalamic and brainstem dysfunction as well as extrapyramidal motor effects mediated by the basal ganglia. Long-term treatment of schizophrenic patients with typical antipsychotic agents has been also associated with tardive dyskinesia, a delayed-onset hyperkinetic movement disorder that is oen irreversible even aer drug discontin- uation.1,2 e most characteristic features of this syndrome are abnormal movements of the mouth, face, extremities, and trunk. DA receptor supersensitivity that results from antipsychotic-induced blockade and upregulation of D2 receptors,66,67 an imbalance in D1/D2 receptor densities in striata of medicated schizophrenic patients,10 or a disrup- tion in γ-amino butyric acid (GABA) neurotransmission in the basal ganglia may contribute to the development of tardive dyskinesia.68,69 All these side effects prompted the search for novel drugs with less risk of the adverse effects of typical       antipsychotics, but similar or even superior antipsychotic effects. is led to the introduction of several new drugs, classified as atypical antipsychotic drugs. e current pro- totype ‘atypical’ antipsychotic agent is clozapine (clozaril®), a dibenzodiazepine derivative. Several basic and clinical studies have provided substantial evidences that clozapine exhibit superior antipsychotic effectiveness over standard antipsychotics, especially in improving negative symptoms and cognitive deficits in schizophrenia. Clozapine is also effective in treatment-resistant schizophrenia, and other poorly responsive primary psychotic disorders, along with its very limited profile of extrapyramidal side effects or hyperprolactinemia.1,2,70,71 e pharmacological basis of the unusual clinical prop- erties of this unique agent remains unclear. Clozapine interacts high or moderate potency at a wide range of neurotransmitter receptors including serotonergic (-HT1A, -HT2A, -HT2C, -HT6, -HT7), acetylcholin- ergic (muscarinic M1–M4), adrenergic (α1, α2, β2), and histaminic (H1) receptors. In contrast, it has only mod- erate affinity for both DA D1 and D2 DA receptors.1,2,70–72 Clozapine has greater affinity for serotonin -HT2A than DA D2 receptors and this receptor-interaction pattern may contribute to its low risk of extrapyramidal side effects.73 Clozapine also displays somewhat greater affinity for D4 than other DA receptors, suggesting that these receptors may represent potential sites of action of clozapine and perhaps other antipsychotic agents.,74–76 Post mortem brain tissue studies reported that D4 receptors are increased in the striata of medicated schizophrenic patients.77,78 In addition, laboratory studies found that repeated admin- istration of clozapine, as well as other typical and atypical antipsychotics increased the abundance of D4 receptors in rat striatum and nucleus accumbens septi.79–82 ese agents also up-regulated D2 receptors in rodent and primate pre- frontal cortex but had little or no effect on D1 or D3 recep- tors.79–83 ese findings support the view that D4 receptors in striatum and nucleus accumbens, as well as D2 receptors in prefrontal cortex are common sites where both typical and atypical antipsychotics mediate their beneficial thera- peutic effects.1,2 In contrast, typical neuroleptics, but not clozapine, also increased D2 receptor binding and expres- sion in rat and monkey striatum.79–83 is selective increase in D2 receptor labelling in the striatum may contribute to the development of neurological side effects typical of standard antipsychotics.1,2 Lack of effect of typical and atypical antipsychotic agents on D1 and D3 receptors sug- gest that these receptors are less likely to be involved in the mechanisms of antipsychotic drug actions.1,2 Despite its favourable characteristics, clinical use of clozapine is complicated by its high risk of potentially fatal bone marrow toxicity, agranulocytosis.1,70,84,85 Patients on clozapine are required to undergo regular monitoring of their complete blood count to ensure that the development of agranulocytosis is detected early. In addition, clozapine has other adverse effects, including dose-dependent risk of epileptic seizures, excessive sedation, significant weight- gain, and a higher incidence of hypertension and type II diabetes mellitus.1,70,84,85 ese side effects collectively le the door opened for developing novel antipsychotic medi- cations with less adverse risk than clozapine, but compara- ble antipsychotic effects. Several newer agents have emerged. Among them are clozapine analogues olanzapine (Zyprexa) and quetiapine (Seroquel), the benzisoxazole derivative risperidone (Risperidal) and its analogue ziprasidone (Geodon).1,2,84,86 Like clozapine, these compounds have multiple sites of molecular interaction, and greater affin- ity for serotonin -HT2A than DA D2 receptors, which again may contribute to their benign extrapyramidal profile.1,2,84,86 ese newer agents have undergone exten- sive pharmacological and behavioural characterization in animals, 86–88 and their therapeutic effects were assessed in many clinical trials.1,85 Despite the favourable clinical profile of most of the second generation of antipsychotic drugs, and their effectiveness in treating psychotic symp- toms of schizophrenia, they are also associated with differ- ent adverse side effects. With the remarkable exception of clozapine, and perhaps quetiapine, other atypical antipsy- chotic agents have brought only relative avoidance of side effects on central neural control of posture and movement, urging continued searches for novel principles of develop- ing novel antipsychotic drugs.1,85       ’     Parkinson’s disease (PD) develops later in life with the average age of onset of  years. PD patients suffer from disturbances of movements (akinesia), increased mus- cle tone (rigidity), tremor (– per second at rest), and postural defects, along with speech and writing problems. ese symptoms progress with a gradual exacerbation along with the progress of the disease.89 Cognitive deficits and psychiatric disturbances are also common in patients with PD. e main cognitive deficits include disturbances in memory, fluency, visuospatial and construction abilities accompanied by dementia.90 e most common psychi- atric disturbances include depression, anxiety, mania and psychosis. PD is observed in more than  of individuals over the age of .91 Genetics may also play a role in the aetiology of PD, but perhaps less prominent than that of                                            schizophrenia. Recent studies have found that mutations in three different proteins (alpha-synuclein, parkin and UCHL) can lead to autosomal dominant form of the disease.92,93 e pathological hallmark of PD is the specific degen- eration of more than  of the nigrostriatal dopaminer- gic neurons and the appearance of intracellular inclusions known as Lewy bodies.94,95 is results in a profound deple- tion of DA in the substantia nigra pars compacta, caudate nucleus, putamen, and causes an increase in striatal D2 receptor levels. e loss of striatal DA will decrease the inhibitory activity of nigrothalamic projections, which in turn will increase the activity of the thalamocortical neu- rons leading to the excitation of motor cortex and spinal motor neurons. e end results will be increased contrac- tion of both flexors and extensors at the same time causing cogwheel rigidity and movement disorder.51,89 e discovery that -methyl--phenyl-,,,-tetrahy- dropyridine (MPTP) can reduce the DA levels in the brain by selectively degenerating the nigrostriatal dopaminergic pathway, and producing a clinical syndrome similar to PD, helped to develop a useful animal model for PD and stimulated new approaches to investigating its pathophysi- ology and therapy.96,97 MPTP is converted by monoamine oxidase B to MPP+ (-methyl--phenyl pyridinium) which is taken up by the DA neurons via presynaptic DA trans- porters. MPP+ is then accumulated in the mitochondria where it inhibits complex I of the mitochondrial electron transport chain. is blocks the process of oxidative phos- phorylation and generates toxic free radicals, which in turn attacks the integrity of cell cytoskeleton and eventually leads to cell death.96–98 Treatment of Parkinson’s disease e simplest way to replace depleted DA would be to administer DA itself. However, DA does not cross the blood brain barrier and therefore its direct administration is ineffective. Levodopa (L–,-dihydroxyphenyl alanine; L-DOPA) is the immediate precursor of DA which read- ily crosses blood brain barrier and is converted to DA by decarboxylation within the remaining few intact dopamin- ergic neurons.99 Administration of levodopa, at least early in the course of the disease, significantly improved tremor, rigidity and motor-impairment in PD patients.89,99 It should be noted, however, that the peripheral tissue conversion of levodopa to DA by aromatic amino acid decarboxylase permits only a small percentage of levodopa to reach the brain. erefore, it is necessary to co-administer with levodopa, selective inhibitors of peripheral decarboxylase enzyme activity that do not cross the blood brain barrier, such as carbidopa (Sinemet) or benserazide (Madopar) to profoundly increase the availability of levodopa in the brain.100,101 Long-term therapy of levodopa is complicated by the fact that the beneficial effects of levodopa start to wear off and patients start to experience response fluctuations with each dose of levodopa despite maintaining the same treatment regimen.102,103 Later, patients starts to show the ‘on/off phenomenon’ in which sudden periods of tremors and rigidity alternate with periods of mobility. Increasing the dose and frequency administration of levodopa can improve this situation, but this increases the risk of dys- kinesias and excessive and involuntary movements.102,103 In addition, patients may experience dopaminergic psychosis. e novel atypical antipsychotic agents, such as clozapine or quetiapine, have been shown to be effective in improv- ing levodopa-induced psychosis.104 Inhibitors of the enzyme monoamine oxidase (MAO) represent another class of drugs for the treatment of PD. Two isoenzymes of MAO (MAO-A and MAO-B) oxidize monoamines. MAO-B is the predominant form in the striatum and is responsible for the oxidative metabolism of striatal DA.105 Deprenyl (Eldepryl), also known as selegiline, is a selective MAO-B inhibitor that irreversibly inhibits MAO and slows the breakdown of DA in the stria- tum. A combination of deprenyl and levodopa is useful in prolonging the effects of levodopa and in reducing the ‘on/off ’ effects.106 Currently, deprenyl is considered as one of the drugs of choice for treatment of early or mild PD.107 However, in more advanced PD patients, deprenyl may accelerate the motor and cognitive side effects of levodopa therapy. Metabolites of deprenyl include amphetamine and methamphetamine, which can cause insomnia, anxiety and mood elevation in treated PD patients.89 An alternative to levodopa or deprenyl therapy is the use of direct DA receptor agonists. ese drugs are more specific in their actions and can selectively target one or more DA receptor subtype, in contrast to the non-selective effects of levodopa or deprenyl. In addition, these agonists are well absorbed orally, have longer duration of actions than levodopa and are more effective in the management of fluctuations in motor activity.108 Four DA receptor agonists are available for treatment of PD: the standard agents, bro- mocriptine (Parlodel) and pergolide (Permax), and the more recently introduced agonists, ropinirole (Requip) and pramipexole (Mirapex).89,108 Bromocriptine is strong D2 receptor agonist with partial antagonistic activity at D1 recep- tors, while pergolide is an active agonist on both DA receptor subtypes. Ropinirole and pramipexole are active agonists at D2/D3 sites with negligible activity at D1 sites.89,108   Despite the progress in PD pharmacotherapy, many medications tend to loss their beneficial effects aer long- term administration. Alternative therapies try to restore DA function by means of intracerebral tissue gras. One approach focuses on transplanting adrenal medulla tissue either into a lateral ventricle or into the striatum itself.109 Another approach is to implant fetal substantia nigra tis- sue with the anticipation that new DA neurons will grow, sprout and restore the lost nigrostriatal dopaminergic con- nectivity. is approach, however, remains controversial due to its ethical implications.110 A third approach involves the use of xenogras, that is tissue gras obtained from other species like pigs or monkeys, although the clinical outcome of these gras have not been well established.111 Neurosurgical intervention to selectively lesion the inner segment of globus pallidus (also known as pallidotomy) has been also utilised in treatment of PD. However, because of the risk of permanent damage to the brain, this treatment remains as the last resort.112        -                      ADHD is a neuropsychiatric condition characterized by inattention, impulsivity and inappropriate behavioural hyperactivity, typically associated with impaired academic and social functioning in school-aged children.50 Several studies have implicated environmental and psychosocial factors, such as pregnancy and delivery complications, marital distress, family dysfunction and low social class as predisposing risk factors for ADHD.50,113 e neuroana- tomical networks involving frontal cortex and basal ganglia are proposed to be critically involved in the pathophysiol- ogy of ADHD.114,115 Neuroimaging studies found that frontal cortex, caudate and globus pallidus were smaller in children diagnosed with ADHD compared to normal controls.116,117 In addition, a functional deficit was detected in the putamen of children with ADHD relative to normal peers.118 ese findings provide a compelling support for the suggested dysfunction in fronto-subcortical pathways in patients diagnosed with ADHD.119 Molecular genetic studies have identified a genetic linkage between ADHD and an allele of DA transporter using a family based association study.120,121 is associa- tion has been supported by the development of genetically altered mice that lack functional DA transporters. Such mice displayed a hyperdopaminergic state that included spontaneous hyperactivity similar to ADHD.122 In addition, an association of D4 receptor polymorphism and clinical ADHD has been also reported.75,76,123,124 is association involves increased incidence of a -repeat allele (recep- tor type D4.7) coding for a -amino acid sequence in the functionally critical third intracytoplasmic loop of the D4 receptor in patients diagnosed with ADHD compared to normal controls. Additional support for possible involve- ment of D4 receptors in ADHD is provided by recent findings that transgenic mice lacking D4 receptors show increased sensitivity to psychostimulants and increased metabolic turnover of striatal DA compared to wild type mice.125           Psychostimulants are considered the first line of treatment for ADHD, since the pathophysiology of ADHD involves deficiency in DA neurotransmission. e most widely used compounds in this class include methylphenidate (Ritalin), amphetamines (Adderall and Dexedrine) and pemoline (Cylert).126,127 ese compounds, which enhance DA neurotransmission, increase synaptic DA by inhibiting the reuptake of DA into presynaptic vesicles (methyl- phenidate, amphetamines and pemoline) or by releasing presynaptic DA into synaptic cle.126–128 Although these compounds are quite effective in alleviating the symp- toms of ADHD and in improving attention and academic performance ADHD patients, they are associated with different side effects. Most notable, all these medications are considered controlled substances of potential abuse. In addition, they cause insomnia, anorexia, jitteriness, and headaches. Moreover, pemoline can cause hepatitis and liver toxicity, and so monitoring liver functions is essential for patients on pemoline.126–128 Antidepressants follow psychostimulants as the second line of choice for treatment of ADHD. e tricyclic antide- pressants (TCAs), such as imipramine, desipramine, venla- faxine and atomoxetine, block the reuptake of monoamine neurotransmitters, especially norepinephrine.126–129 TCAs are effective in controlling abnormal behaviours and reducing cognitive impairment in ADHD patients. ey are also useful if depression or anxiety symptoms co-exit with ADHD.126–129 Antihypertensive drugs such as cloni- dine and guanfacine are also used for treatment of ADHD in young patients. ey are particularly effective against aggressiveness and sleep disturbances. However, car- diovascular monitoring of patients on these medications is recommended.126–128 Finally, recent reports have suggested that selective DA D4 receptor antagonists may provide much-needed inno- vative treatments for ADHD. Motor hyperactivity observed in juvenile rats with neonatal -hydroxydopamine lesions, a laboratory model for ADHD, was reversed in dose- dependent manner by highly selective D4 antagonists, and worsened by selective D4 agonists.130 A direct correlation        was also observed between motor hyperactivity in lesioned rats and increases in D4 receptor levels in rat caudate-puta- men.130 ese findings provided behavioural and pharma- cological evidences for the suggested genetic association between D4 receptor alleles and ADHD.75,76,123,124 It is still premature to judge the effectiveness of D4-antagonists in treatment of ADHD. Post-mortem studies on brain tis- sue from patients diagnosed with ADHD are still needed to clarify the role of D4 receptors in its neuropathology or pathophysiology. In addition, selective D4-antagonists should be tested in clinical trials to determine their safety and effectiveness for treatment of ADHD.75,76 C O N C L U S I O N S e new neuropharmacology of DA receptors and their effectors stimulates renewed interest in many aspects rel- evant to DA neurotransmission, including the molecular control of the DA synthesis and release, as well as the rational development of novel CNS drugs. e advances in molecular biology have revealed the presence of two classi- cal DA receptors (D1 and D2) as well as novel gene products that present novel DA receptors (D3, D4, D5). clarification of the sites of expression of classical and novel DA receptor mRNAs and proteins in mammalian brain, characteriza- tion of their effector systems, and the identification of novel chemical or drug molecules selective for each recep- tor subtype have rapidly advanced the understanding of these novel DA receptors. 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