Perspective Chapter: The Role of Dopamine Receptors in Neuropsychiatric Diseases

Abstract

Dopamine is a key regulator neurotransmitter in the important cognitive and intellectual functions of the brain. This neurotransmitter in a structure of catecholamine is responsible for motivation, movement, reward-punishment, mood, memory, attention and more functions in central nervous system. This large effect area gives dopamine high importance in the pathophysiology of neuropsychiatric diseases. Dopamine shows its effects through dopamine receptors that are G protein-coupled receptors ranging from D1 to D5. Changes in the activity of these receptors are associated with diseases like schizophrenia, Parkinson’s disease and addiction. This relationship between dopamine receptors and neuropsychiatric diseases has made these receptors main target in the strategy of clinic researches. Cognitive physiological functions of dopamine and the role of dopamine receptors in the common neuropsychiatric diseases are focused in this chapter.

1. Introduction

1.1 General cognitive functions of dopamine

Dopamine is a monoamine neurotransmitter synthesized from tyrosine and is precursor for epinephrine and norepinephrine. Dopamine is responsible for plenty of different body functions from visual physiology in retina to motor activity controlled by basal ganglia and a lot of emotional and cognitive functions controlled by limbic system and prefrontal cortex. Among functions of dopamine in the Central Nervous System (CNS), there are voluntary movement, reward, formation of conditioned reflexes, sleep regulation, feeding, affect, attention, olfaction, vision, hormonal regulation, sympathetic regulation, penile erection and more [1]. Even in other body regions except for brain, dopamine has important effects on immune, cardiovascular, gastrointestinal and urinary system, as well [2].

Dopamine decreases signal transduction of gap junctions between retina neurons after increase in light intensity. This change provides cone receptors to be more active than rod receptors during daylight. The release of dopamine from interplexiform cells increases and stimulates the D2-like receptors on cone and rods. Intracellular Cyclic Adenosine Monophosphate (cAMP) and Protein Kinase A (PKA) activity reduces, resulting in the reduction in the conductance of gap junctions between cones and rods. This regulatory mechanism provides cones to be more active than rods during high amount of light during the daytime [3].

Dopaminergic system follows the stages of ingestion from seconds to minutes and this provides learning about the consequences of ingestion, as well [4]. According to the taste of food or drink, neurons in Ventral Tegmental Area (VTA) secrete dopamine, providing cues for next preferences of food [5]. Dopaminergic release activity in VTA is pivotal for post-ingestion-related food seeking [6].

Dopaminergic substantia nigra neurons secrete dopamine in CNS. These neurons project into the striatal region of the basal ganglia and other brain regions like prefrontal cortex. Dopamine has both inhibitory and excitatory effects on different neurons in the brain. These different effects emerge through different dopamine receptors and their different intracellular secondary messenger systems.

1.2 Dopaminergic pathways in the brain

There are four major dopaminergic pathways in the CNS. Dopaminergic neurons from A9 region supply dopamine into the nigrostriatal pathway, neurons from A10 supply dopamine into the mesolimbic and mesocortical pathways and neurons from A8 supply dopamine into the tuberoinfundibular pathway [7].

Dopaminergic pathways come from substantia nigra, VTA and arcuate nucleus of medial hypothalamus. Nigrostriatal system comes from substantia nigra to dorsal striatum. Sensorial-motor coordination, cognitive integration and habituation are related to dopaminergic neurotransmission in the nigrostriatal system. The mesolimbic pathway between the VTA and the ventral striatum and between the hippocampus and the amygdala is associated with feelings of pleasure, reward and desire. Sense originated from this pathway provides existence of the emotion. Mesocortical pathway is projected from VTA and into the prefrontal dorsolateral, temporal, parietal and anterior cingulate cortex regions. This pathway is related to addiction and memory. Tuberoinfundibular pathway is composed of dopaminergic neurons projected from arcuate nucleus of hypothalamus and into the eminentia media. Dopamine synthesized from the tuberoinfundibular pathway regulates the secretion of the prolactin from the adenohypophysis.

1.3 G protein-coupled receptors

G Protein-Coupled Receptors (GPCR) are found only in eukaryotic cells. They are also called “7 transmembrane receptors” because their protein structure folds the cell membrane seven times. This is a feature unique to G protein-coupled receptors. While ligand binds to the outer surface of the cell in the transmembrane protein, there is a G protein on the inner surface of the cell, and this protein consists of three subunits, alpha, beta and gamma. G protein alpha and gamma subunits are attached to the cell membrane by the lipid anchor (lipid raft). Dopamine receptors are among the G protein-coupled receptors. These receptors exist in the vertebrate CNS. Abnormal changes in the dopaminergic neurotransmission in the brain are related to some neuropsychiatric diseases like schizophrenia, PD and addiction.

1.3.1 Dopamine receptors

There have been detected five dopamine receptor subtypes, ranging from D1 to D5. Effects of dopamine emerge through these five GPCR [8]. D1-like receptors and D2-like receptors are two main groups in the classification of the dopamine receptors. They are grouped according to their similar intracellular mechanisms. D1 and D5 belong to D1-like receptor family. D2, D3 and D4 belong to D2-like receptor family (Table 1).

Receptor	Gene	Structure	Intracellular signal transduction	Mechanism of action	Synaptic location
D1	DRD1	D1-like	Gs/activation of adenylate cyclase	Increase in cAMP	Postsynaptic
D2	DRD2	D2-like	Gi/inhibition of adenylate cyclase	Decrease in cAMP	Presynaptic and postsynaptic
D3	DRD3	D2-like	Gi/inhibition of adenylate cyclase	Decrease in cAMP	Presynaptic and postsynaptic
D4	DRD4	D2-like	Gi/inhibition of adenylate cyclase	Decrease in cAMP	Presynaptic and postsynaptic
D5	DRD5	D1-like	Gs/activation of adenylate cyclase	Increase in cAMP	Postsynaptic

Table 1.

General properties of dopamine receptors.

Effects of the same type of dopamine receptors may vary between different brain regions. This phenomenon occurs thanks to the different intracellular signal transduction pathways [9]. Gs related increase in cAMP and Gi related decrease in cAMP in the cytoplasm of the neuron, phospholipase C pathway, regulation of the arachidonic acid secretion, regulation of Na-H exchanger and Na-K ATPase activity are among these different pathways.

Neurotransmission of dopamine is regulated by autoreceptors on the dopaminergic neurons, enzymatic degradation in the neurosynaptic space, presynaptic Dopamine Transporters (DAT) and other neurotransmitters like γ-Aminobutyric Acid (GABA), glutamate and serotonin. Besides, activity of dopamine receptors is regulated by Dopamine Receptor Interacting Proteins (DRIPs).

1.3.1.1 D1 receptors

It was firstly that dopamine was shown in brain as a neurotransmitter in 1957 [10]. Besides it was found that dopamine was concentrated in basal ganglion region in the CNS thanks to spectrofluorometry technique and D1 receptor activity increased the cAMP and PKA level in the cytoplasm of target cells [9].

There are D1 receptors in different regions of the brain like limbic system, hypothalamus, thalamus, olfactory tubercle, nucleus accumbens and striatum. D1 receptors are responsible for neurotransmission in the striato-thalamo-cortical circuit. D1 receptors provide the activation of adenylate cyclase and thus increase the cAMP in the cytoplasm of the target neuron. Increase in the cAMP level stimulates the phosphorylation of the cAMP-related protein kinase and cAMP-regulated phosphoprotein (DARPP-32), (Figure 1). DARPP-32 amplifies the intracellular effects of PKA and regulates the synaptic plasticity in prefrontal cortex projected by dopaminergic neurons [11]. Some D1 and D2 receptor subtypes regulate the activity of the Ca⁺², K⁺ and Na⁺ ion currents in cell membrane through the different G protein subunits [12].

Figure 1.

Schematic representation of the intracellular signal transduction mechanism of the D1-like receptors. ECF, Extracellular Fluid; ICF, Intracellular Fluid; ER, Endoplasmic Reticulum; PLC, Phospholipase C; PKA, Protein Kinase A; DARPP-32, Dopamine and cAMP Regulated Phosphoprotein; IP3, Inositol Triphosphate; mTOR, Mammalian Target of Rapamycin; ERK, Extracellular Signal-Regulated Kinase; green arrow, activator pathway; blue arrow, inhibitor pathway.

Effort-based decision-making is mostly related to dopaminergic system through D1 receptors. Neuropsychiatric disorders like schizophrenia and Major Depression (MD) continue with low desire to exert effort and psychomotor retardation [13]. Changes in the effort-based decision-making is seen in schizophrenia, MD, bipolar disorder, eating disorders and autism [14]. Unwillingness to effort for rewards is a specific characteristic of some neuropsychiatric diseases related to dopaminergic system like schizophrenia [15] and PD [16]. However, willingness to effort for food rewards is increased in some eating disorders and obesity [17].

1.3.1.2 D2 receptors

D2-like receptors, couple with Gi protein, inhibit adenylate cyclase and activate K⁺ channels. D2 receptors have roles on survival of dopaminergic neurons [1] and neuronal growth [18, 19]. D2 receptors are found in the dorsal striatum, nucleus accumbens, ventral tegmental region and substantia nigra, which are areas of intense dopaminergic innervation.

D2 receptor activity provides the inhibition of the adenylate cyclase, the regulation of the activity of the ion channels like Ca⁺² and K⁺ and production of the phosphoinositide. Type of activity of the D2 receptor in the neuron depends on the type of neuron that synthesizes the receptor thanks to the different intracellular signal transducing mechanisms.

Contrary to D1 receptors, D2 receptors show both presynaptic autoreceptor and postsynaptic activity. D2 receptors are in the dopaminergic axonal terminals, soma and dendrites. D2 receptor modulator drugs are useful against schizophrenia and PD. An important amount of the highest global sales of medicines in 2017 were antipsychotic drugs like aripiprazole, olanzapine and quetiapine that target GPCR like dopamine receptors [20]. D2 receptors in the adenohypophysis regulate the inhibition of the secretion of the prolactin and alpha-MSH.

Catalepsy in patients with schizophrenia because of the antipsychotics like haloperidol may result from its effects on long form of D2 receptors [21].

There is an increase in the amount of postsynaptic D2 receptors in patients with schizophrenia. This condition leads to dopamine supersensitivity and psychotic reactions in these patients [22, 23]. While D2 receptor density is increased, D1 is not changed in the basal ganglia of patients with schizophrenia compared with control subjects [7].

Anhedonia, basic symptom of MD, is associated with the decrease in the sensitivity of the D2 and D3 receptors in the limbic system related to reward [7]. While D1 receptor density is decreased, D2 is not changed or increase in basal ganglia of patients with MD compared with control subjects [7]. In drug abusers, D2 receptor level is decreased in striatum [24]. D2 dopamine receptor density is altered, while D1 is not changed in PD. In earlier stages of PD, D2 receptor level is increased, however in the later stages level of D2 receptor is decreased [7, 25].

In some genetic studies, it has been reported that variations in D2, D3 and D4 dopamine receptor genes are related to schizophrenia and response to antipsychotic drugs [26, 27, 28]. Abnormalities in the D2 dopamine receptor gene are related to substance abuse [29].

In the clinical psychopharmacology experiments, it has been reported that D2 receptor is the main target of both typical and atypical antipsychotic drugs and drugs to treat PD [30]. However, many drugs targeting D2 are non-specific and affect unrelated receptors in therapy strategy. This condition results in some serious life threatening adverse effects in patients [31].

Aripiprazole is a partial agonist of the D2 dopamine receptors and affects the inhibition exerted by Gi on cAMP accumulation. Aripiprazole antagonizes the D2 receptor activity on the postsynaptic D2 receptors, while it activates D2 autoreceptors on the presynaptic D2 receptors and hence, antipsychotic effect occurs in a biased pharmacodynamics mechanism [7].

PKC regulates the D2 [32] and D3 [33] dopamine receptors through functional desensitization, receptor internalization and intracellular trafficking. Because of the different location of their phosphorylation and pseudosubstrate sites, D2S and D2L isoforms have different levels of sensitivity for desensitization by PKC [34]. Ethanol potentiates the D1 dopamine receptors through the phosphorylation by PKC [35].

A synonym mutation of human D2 receptor gene (C957T) is reported that results in the reduction in the dopamine induced up-regulation of the D2 receptors by changing mRNA stability [36]. C957T in a European American population is associated with schizophrenia and alcoholism [37].

In a recent animal study where male adult mice were used, it was reported that alterations in D2 receptor levels in purkinje cells in the cerebellum change sociability and preference for social novelty without affecting motor functions. In this study, it has been implied that although the regulation of reward, emotion and social interaction is largely related to monoaminergic system in limbic regions, the contribution of dopaminergic neurotransmission targeting D2 receptors on the purkinje cells in cerebellum cannot be ignored [38].

1.3.1.3 D3 and D4 receptors

D3 and D4 receptors belong to the group of D2-like receptors. Dopamine has 10–30 times more affinity to D3 and D4 receptors than D2. D3 receptors are found in the limbic system and nucleus accumbens.

D3 receptors are related to locomotor activity. Because it has important role on apathy in PD, D3 receptor may be targeted to treat motivational deficits [39]. Levodopa induced dyskinesia and psychosis in patients with PD may be prevented by antagonizing D3 receptors through new therapy strategies [40]. Activation of nicotinic acetylcholine receptors on dopaminergic neurons shows neurotrophic effects on these neurons together with D3 receptors. This functional complex composed of nicotinic acetylcholine receptors and D3 receptors is a heterodimeric modulator on dopaminergic neuronal growth [41]. This heterodimeric mechanism of action may be new target for anti-Parkinson drug design studies.

D4 receptors are found in frontal cortex, mesencephalon, amygdala, hippocampus and medulla oblongata. D4 receptors are found in the external of the CNS like heart and kidney, as well. D4 has important roles in the formation of novelty seeking behavior. Similar to D2, the amount of the D4 receptors are in a high level in the postmortem brain of the schizophrenia patients. Clozapine, an atypical antipsychotic, has high affinity to D4 receptors.

1.3.1.4 D5 receptors

D5 receptors are D1-like receptors and exist in the hippocampus, hypothalamus, prefrontal cortex and striatum in CNS. D5 receptors are responsible for the inhibition of locomotor activity [42].

1.4 Intracellular signal pathways of dopamine receptors

While Gsα increases the activity of adenylate cyclase, Gi decreases. D1-like receptors increase cAMP activity and D2-like receptors decrease it [43]. One of the most important consequences of the stimulation or suppression of cAMP formation is the activation or suppression of protein kinase A. Hence, some differences related to receptor type emerge in the cellular metabolic reactions like phosphorylation or dephosphorylation, synthesis of different cytoplasmic and nuclear proteins, activation of the different membrane channels and different G protein-coupled receptor sensitization.

Signal transduction of the dopamine receptors may result in phospholipase C activity or regulation of the arachidonic acid secretion, as well. Besides, dopamine receptors regulate Na-K ATPase and Na/H exchanger activity.

Activation of D2S isoform of D2 receptors coupling with Rho family of the G proteins results in stimulation of phospholipase D. Phospholipase D catalyzes the hydrolysis of the phosphatidylcholine to phosphatidic acid. Phosphatidic acid is an active signal molecule that plays pivotal role in cell growth, cell differentiation and regulation of cell metabolism.

Gβγ subunits of both D2S and D2L receptor isoforms are effective in the activity of protein kinase C, Mitogen-Activated Protein Kinase (MAPK), extracellular signal regulated kinase pathway (ERK) related cell growth, differentiation and apoptosis. Activation of MAPK and ERK pathways by dopamine agonists through D2 receptors provides apoptosis and cell death in tumor cells in the hypophysis.

Dopamine receptors are regulated by DRIPs [44]. Dopamine receptor interacting proteins provide movement of the receptors, emerging of the dopaminergic signals in the neurons and regulation of the receptor signals. Neurons having D1 and D2 receptors are controlled by different DRIPs.

1.5 Regulation of dopaminergic secretion

There are two basic transmission types called as intrasynaptic and extrasynaptic for dopamine in the CNS. In striatum, intrasynaptic dopamine secretion stimulates the postsynaptic dopamine receptors and extrasynaptic dopamine stimulates presynaptic D2-like autoreceptors. In extrastriatal regions, such as the prefrontal cortex, dopamine shows its extrasynaptic effect by diffusion through the gap junctions and by activating D1 receptors [45].

Dopamine regulates its self-dynamic activity through D2/D3 receptors through a (-) feedback mechanism of action. In addition, diffusion, intrasynaptic enzyme degradation through Monoamine Oxidase (MAO) and Catechol O-Methyltransferase (COMT) and transportation through presynaptic DAT all play a role in regulating dopamine levels in neurosynaptic junctions. DAT is a protein in the dopaminergic neurons and a specific marker showing dopaminergic neurons in immunohistochemically experiments [45]. There is the highest amount of DAT in the putamen, nucleus caudate and ventral striatum, meaning highest density of the dopaminergic neurons [46].

There are two types of secretion of dopamine from dopaminergic neurons. After an action potential from a presynaptic neuron, a dopamine secretion called as burst or phasic dopamine response with fast and high amplitude occurs in the first type of secretion. Mostly this type of response is associated with the dopaminergic behavior. Low-level extrasynaptic dopamine concentration called as tonic dopamine response occurs in the second type of secretion. In this response, dopamine level is too low to activate intrasynaptic dopamine receptors, but at a level to activate extrasynaptic autoreceptors. This response provides the (-) feedback suppression of high amount of phasic dopamine secretion.

Synthesize of dopamine is also regulated by other neurotransmitters. Afferent neurons synthesizing GABA from striatonigral and local circuits regulate secretion of dopaminergic neurons. N-methyl-D-aspartate (NMDA) receptor activity induced by glutamate administration results in slow Excitatory Postsynaptic Potentials (EPSP) in dopaminergic neurons in substantia nigra and VTA [45, 47].

Abnormalities in the dopaminergic system in the brain are related to diseases such as schizophrenia, Parkinson's disease (PD), addiction, depression and attention deficit hyperactivity disorder.

1.6 Cognitive effects of changes in dopaminergic neurotransmission on dopamine receptors

1.6.1 Importance of the nigrostriatal dopaminergic system on motor functions

Bilateral lesions primarily affecting the substantia nigra can result in slowness of movement and are correlated with bradykinesia in PD. The movement time in monkeys after 6-OHDA-induced lesion of the dopaminergic neurons and reaction time in a conditioned motor task in the rat administered to 6-OHDA were reported to increase. Such deficit has led to assume the importance of dopaminergic nerve terminals of dorsolateral part of the striatum on motor functions. Administration of D2 dopaminergic receptor antagonists were reported to cause similar results. However, DA and DA agonists were reported to decrease the reaction time. In Parkinsonian patients and Parkinsonian rodents constituted by lesion of the nigrostriatal dopaminergic system, increased reaction time has been reported. Besides, similar results also shown in conditioned motor task experiments in primates where 6-OHDA administration in substantia nigra or the neurotoxin MPTP were used. These results show the pivotal role of the nigrostriatal projections on the early stages of the motor control [48].

Forward locomotion is mostly controlled by the D1–3 receptors in ventral striatum. Activation of presynaptic D2 autoreceptors leads to a decrease in dopamine release, resulting in decreased locomotor activity. However, activation of postsynaptic D2 receptor activity slightly increases the locomotor activity. D3 receptors in nucleus accumbens have inhibitory role on locomotor activity. D3 agonists increase this effect while D3 antagonists decrease it [49].

1.6.2 Importance of mesocorticolimbic system on adaptation and memory

The administration of 6OHDA and lesioning of the different brain structures innervated by the mesocorticolimbic dopaminergic neurons are reported to show specific behavioral deficits. Lesions in VTA resulted in the inability to switch from one behavior to another, affecting the motivation and adaptation to behavior. Lesions of the dopaminergic terminals at septal level, the level of amygdala, hippocampus and habenula of the limbic system resulted in impaired performances in behavior tests like memory tests in maze paradigm [48].

Studies have reported that both D1 and D2 receptors are associated with intracranial self-stimulation behavior in the prefrontal cortex and nucleus accumbens of rats. D1 and D2 agonists stimulate this behavior, while antagonists inhibit it. Furthermore, D2-like receptors are reported to increase to seek further cocaine reinforcement in an animal model for cocaine seeking behavior. However, D1-like receptors decrease this behavior and thus agonists of these receptors may be a partner in the therapy of cocaine addiction. Both D1 and D2 receptors in the hippocampus of rat and prefrontal cortex in monkey have roles on learning and memory in pharmacological behavior experiments like performance measurement in working memory tasks [49].

D3 and D4 receptors are expressed mostly in the limbic and cortical regions but lesser amount in the dorsal striatum and may be useful in new antipsychotic drug discovery thanks to the lower incidence of extrapyramidal side effects [49].

2. Dopamine receptors and schizophrenia

The main reason of schizophrenia is the increase in dopaminergic neurotransmission in the brain. This increase may stem from either increased dopamine concentration in neurosynaptic junction between presynaptic and postsynaptic neurons or increased activity of the postsynaptic dopamine receptors like D2 [50]. Secretion of dopamine is changed abnormally and behavioral psychotic symptoms emerge in the patients with schizophrenia.

Schizophrenic patients are behaviorally more responsive to drugs such as amphetamine and methylphenidate increasing the amount of dopamine in neurosynaptic junction compared to healthy subjects. On used in these patients, these drugs trigger the psychotic symptoms. The main reason of this response is not only increased release of dopamine from presynaptic neuron, but also the increased amount of D2 receptors in the postsynaptic neurons. Both of these two main factors increase the dopaminergic neurotransmission and this neurotransmission is a basic source of delusion and hallucinations in schizophrenia. Even if presynaptic dopamine release is normal, D2 receptors are increased by an average of 5.8% in antipsychotic-free schizophrenia patients [50]. Increased psychotic response to psychostimulant drugs may stem from more D2 receptors in schizophrenia. It was reported that 75% of schizophrenia patients and 25% of healthy control subjects experienced new symptoms of psychosis after usage of the psychostimulants like amphetamine and methylphenidate [50].

2.1 Development and progression of schizophrenia

The consistency between acts and results provides the learning. Learning according to the amount of pleasure after act is an important way to learn. The mesolimbic dopaminergic pathways are related to motivation, providing a link between affect and action. These pathways provide connection between mood and act. Dopaminergic inputs to nucleus accumbens provide knowledge about importance and awareness of events occurring throughout the world. This knowledge contains rewarding and punisher stimuli and their foreseeability and novelty [51, 52].

The phasic firings in dopaminergic neurons, associated with the broad transient increase in synaptic dopamine release, stimulate postsynaptic signals encoding reward prediction or incentive awareness [53]. The abnormal functioning of this process in schizophrenia leads to abnormal perceptions of excessive novelty [54], awareness and thus to psychotic delusions [55].

In patients with schizophrenia, rate of habituation to the acoustic startle is decreased, and they exhibit higher scores of neuroticism compared to healthy control [56]. Attenuated acoustic startle response means to Prepulse Inhibition (PPI) is associated with central dopaminergic dysfunction. In PPI, startling stimulus is immediately preceded by a weaker, non-startling tone. Prepulse inhibition correlates with some schizophreniform cognitive dysfunctions like prolong maternal separations and variations in maternal care [57].

Recent studies indicate a significant increase in the levels of tyrosine hydroxylase, rate limiting enzyme involved in DA synthesis, suggesting increased production of DA in the midbrain. Studies using Positron Emission Tomography imaging (PET) showed abnormally high subcortical synaptic DA release after using DA stimulants like amphetamine, which induced psychotic symptoms in healthy individuals indicating that there is a presynaptic hyperdopaminergic abnormality in schizophrenia, and the antipsychotic drugs used to treat the disorder act by blocking DA receptors. However, it is also reported that glutamate, g-aminobutyric acid (GABA), acetylcholine and serotonin alterations, related to cognitive behavioral and social dysfunction, are involved in the pathophysiology of schizophrenia [58].

2.2 Psychosis and dopaminergic neurotransmission

Dopaminergic neurons in VTA and substantia nigra secret excess amount of the dopamine in patients with schizophrenia. These neurons provide the mesolimbic dopaminergic activity. This system projects into the medial and anterior portions of the limbic system composed of hippocampus, amygdala, prefrontal cortex and anterior caudate nucleus. These regions control the behavior. Increased phasic activity of subcortical dopaminergic neurotransmission on cortical regions results in behavioral impairments in patients with schizophrenia [59].

In the pathogenesis of schizophrenia, an abnormal dopaminergic neurotransmission occurs after genetic and environmental risk factors. Changes in the brain connections under the environmental effects like stress may lead to formation of psychosis, loss of brain mass and neurodegeneration in the formation of schizophrenia [60, 61]. The volume of the hippocampus in dominant hemisphere is decreased in patients with schizophrenia. However, an in vivo imaging study showed that main abnormality of the dopamine function in schizophrenia is also in the dorsal striatum related to the nigrostriatal pathway as well as the ventral (limbic) striatum related to the mesolimbic pathway [62].

During physiological conditions, sensation and explication of the novelty is provided by dopaminergic system. However, high activity in some brain regions of dopaminergic system results in an abnormal novelty sensation [63] and awareness [64]. These symptoms of schizophrenia can be reversed by antipsychotic drugs [63].

Main signs of the psychosis are delusions and hallucinations. Before the open psychosis, patients experience a prodromal period. During this period, dopaminergic neurons fire in a context independent manner. That condition results in a new novelty perception in patients. At this moment, perception is clearer and patients notice the things that they are not interested in before. Patients experience changed perceptions in the prodromal period.

Changes in mood and behavior, confusion and wonder increase day by day and transform to meaningful delusions. Abnormality of the dopaminergic system is the main source of the delusions. Personal and cultural history of the patient determine the basis of the delusion [55]. Decreased ability to use context information occurs in this late period [65]. After these pathological processes, delusions change abnormally the behavior of the patient. Patients or relatives of the patients request psychiatric examination in this active period. Usage of antipsychotics starts at this time.

Antipsychotics block the effect of the dopamine in CNS and decrease the abnormal perceptions. However, these drugs affect locomotor functions of the dopaminergic systems, as well. This effect emerges as disruption of the locomotor activity and prevents continuity of antipsychotic treatment [55].

3. Dopamine receptors and Parkinson’s disease

PD is a common neurodegenerative disorder and affects 2–3% of the people, older than 65 years of age, throughout the world. Neuropathological markers of the PD are the aggregates of the α-synuclein as intracellular inclusion body and nigrostriatal dopaminergic neuronal loss [66].

Aging is an important risk factor for PD. While PD affects the 1% of the population older than 60 years, prevalence increases up to 5% in population older than 85 years [67].

The corticostriatal projections from the primary motor cortex, supplementary motor area, cingulate motor cortex and premotor cortex, which terminate on the dendrites of striatal medium spiny neurons, comprise the motor circuit of the dopaminergic system related to PD. Substantia nigra pars reticulata and globus pallidus internus are main dopaminergic output nuclei of the basal ganglia projecting into the ventrolateral thalamus and brainstem. Striatal projections on these output nuclei are composed of direct and indirect pathway. The direct pathway is between medium spiny neurons and GABAergic neurons in the globus pallidus internus and substantia nigra pars reticulata. This is a monosynaptic connection between these spiny neurons having D1 receptors and GABAergic neurons in these output nuclei. Projections from medium spiny neurons expressing D2 receptors to the globus pallidus externus constitute the indirect pathway. In a form of glutamatergic relay in the subthalamic nucleus, these projections arrive at globus pallidus internus, as well. Together with these two pathways, GABAergic output activity is regulated by dopaminergic projections from striatum. Changes in these relays result in PD.

Defect in the nigrostriatal dopaminergic activity results in different effects on direct and indirect pathways. In this condition, activity of direct pathway related to D1 receptor is reduced and activity of indirect pathway related to D2 receptor is increased. Hence firing rate of GABAergic neurons in basal ganglia strongly increases, inhibiting thalamocortical and brainstem areas [66].

3.1 Risk factors of Parkinson’s disease

The number of the dopaminergic neurons in the substantia nigra decreases at a rate of 9.8% every 10 years during the aging process. Besides, the volume of these neurons decreases at a rate of 4.4% every 10 years [68]. The cognitive impairment of normal aging decreases the stimulation of the dopaminergic transmission from substantia nigra to other brain regions.

Family history of PD, family history of tremor, preceding constipation, prior mood disorder, exposure to pesticides, previous head injury, rural living, beta-blocker use and agricultural occupation were strongly and positively associated with PD. However, interestingly, smoking, coffee drinking, prior hypertension, use of NSAIDs, use of calcium channel blocker and alcohol consumption were associated negatively with PD [69]. Negative correlation between PD and smoking may result from the neuroprotective effect of nicotine [70, 71].

3.2 Physiopathology of Parkinson’s disease

Dopaminergic dysfunction in basal ganglia is related to movement disorders such as PD, dystonia, chorea and tics [72]. PD is characterized with neurodegeneration in the dopamine producing neurons in the substantia nigra controlling motor functions of body. Dopaminergic degeneration mainly results from loss of the dopaminergic neurons in substantia nigra pars compacta. During neurodegeneration, some microscopic changes such as Lewy body and intracytoplasmic inclusion bodies composed of fibrillary α-synuclein occur [73]. After loss of dopaminergic neurons at a rate of 60–80%, symptoms can be detectable in patients with PD [74].

A part of the dopaminergic neuronal degeneration is the formation of the intracellular alpha-synuclein (SNCA) aggregates [75]. Involvement of miRNA is related to SNCA accumulation [76]. miRNAs control SNCA expression. miR-7 and miR-153 post-transcriptionally regulate SNCA and suppress SNCA expression. An advantage of the suppression of SNCA thanks to miR-7 and miR-153 is to protect cells from oxidative stress [77, 78].

Among pathologic reasons of the PD, there are mitochondrial dysfunction, oxidative stress, disruption of ubiquitin-proteasome system, neuro inflammation induced by microglia, excitotoxicity by glutamate receptor activation, iron deposition and familial PD [79].

Dysfunction of mitochondrial complex I has high importance in the formation of PD [80]. It was reported that dopaminergic neurons in substantia nigra died and PD occurred in genetically engineered mice lacking a gene (NDUFS2) encoding complex I subunit [81]. Mitochondrial complex I activity is significantly decreased in substantia nigra of patients with PD and mitochondrial DNA damage occurs in a high level [79]. Besides, excess amount of Reactive Oxygen Species (ROS) production, ATP consumption, mtDNA deletion, caspase secretion may occur in the table of mitochondrial dysfunction [82]. In a recent electrophysiological study, it was reported that lack of gene for mitochondrial transcription factor A in a Mitopark mice model resulted in loss of dopaminergic neurons of SN and provided a genetic model of PD. These neurons in SN exhibited age-dependent declines in electrophysiological parameters like disrupted pace maker firing regularity, decreased ion channel conductance and smaller D2 receptor-mediated outward currents [83]. These findings emphasize the importance of the mitochondrial dysfunction in the progression of PD.

Increased oxidative stress activates the Ubiquitin-Proteasome System (UPS). Hence, damaged and misfolded proteins are accumulated, leading to dopaminergic degeneration together with UPS [73]. Ubiquitin-proteasome system (UPS) is one of the degradation pathways for misfolded proteins in PD [79, 84]. Mutant Parkin, PINK1 and DJ-1 proteins disrupt the function of UPS and form an ubiquitin E3 ligase complex resulting in unfolded protein degradation [85]. The E3 ligase complex typically plays a vital role in controlling cell trafficking, DNA repair and signaling, which affect survival of dopaminergic neurons [86].

Neuroinflammation is among the specific compound of the PD [87]. Main actor of this inflammatory pattern is microglia [88]. After a genetic or environmental effect, α-synuclein protein is secreted from dying dopaminergic neurons and triggers the chemotaxis and activation of the microglia [89]. It was reported that the number of dopaminergic neurons of the substantia nigra is decreased in mice because of excess activation of the microglia in patients with PD [90]. Similarly, it was also reported that anti-inflammatory drugs decrease the loss of the dopaminergic neurons and symptoms of the disease in a mouse model of PD [91].

Excess stimulation of the ionotropic receptors of the glutamate results in the damage and death of the dopaminergic cells [92], resulted from the increase in the intracellular Ca⁺² concentration, change in the mitochondrial membrane potential [93] and disorder of the production of the ROS and reactive nitrogen species [94]. After the hyperactivation of NMDA receptors, Ca⁺² influx as a secondary messenger triggers dopaminergic neurodegeneration [95]. Effects of NMDA receptor activity in a dopaminergic neuron spread into other neighbor neurons by diffusion of Ca⁺² through the gap junctions between dopaminergic neurons. If there are no gap junctions between cells, neurodegeneration is limited [96].

Iron accumulation is seen in patients with PD [97]. During aging, the concentration of the iron increases in the substantia nigra, putamen, globus pallidus and caudate nucleus that are basic dopamine synthesizing regions in the brain [79]. Accumulation of iron in the brain results from the increase in the permeability in Blood Brain Barrier (BBB) [98], increase in pro-inflammation [99] and gene mutations of the proteins related to iron transport, bind and metabolism [100].

Accumulation of α-synuclein is common in familial PD [101]. Parkin gene mutation is seen in familial autosomal recessive PD [102]. While prevalence of this mutation in all familial PD is 50%, it is seen at a rate of 20% in idiopathic PD [103].

3.3 Treatment of Parkinson’s disease

In PD, dopamine synthesis is decreased in some specific brain regions like substantia nigra and striatum. DA receptor agonists are generally used to treat PD, which act by stimulating both presynaptic and postsynaptic dopaminergic receptors. DA deficiency in PD is substituted by a chemical precursor l-DOPA, which is the most effective drug to treat various symptoms. l-DOPA passes through the BBB and transforms to dopamine. l-DOPA has pivotal role in PD therapy strategy. However, changes in the concentration in body fluids of this drug result in some adverse effects like motor fluctuations. Intestinal gel infusions of l-DOPA provide continuous dopaminergic receptor stimulation thanks to more stable concentrations of drug and thus, prevents drug-induced dyskinesia [104].

The only drug used in the treatment of PD is not the l-DOPA. Dopaminomimetic drugs affect the striatal neurons via dopamine receptors. Dopaminomimetics directly activate the D2 receptor family. Ergot alkaloid bromocriptine and other dopaminomimetics have important role in PD therapy for motor symptoms [105, 106].

In terms of motor fluctuations and adverse effects of anti-Parkinson drugs, dopamine agonists are more attractive choices than l-DOPA [105, 107]. Dopamine agonists have less striatal dopamine receptor stimulation than l-DOPA and this provides reduced risk for motor complications during drug administration in initial PD monotherapy [106]. Besides, some dopaminomimetics like rotigotine are possible to be administrated as transdermal patch, providing constant drug concentration in cerebrospinal fluid [66].

However, dopamine agonists have some adverse effects including drowsiness and impulse dyscontrol resulted from D3 receptor activity in the ventral striatum causing to the stimulation of the brain reward system. Besides, dopamine agonists have more reduced effect size in PD compared to l-DOPA [108]. However, apomorphine has equal effect size to l-DOPA and affects both D1 and D2 receptors [109]. Continuous subcutaneous apomorphine administration prevents the motor response fluctuations and dyskinesia resulting from l-DOPA usage [110].

Current literature reports that metabolic stress could be the most important reason for the degeneration of DA neurons. A few selective voltage-gated ion channels, such as Ca⁺² channels and ATP pumps under metabolic stress, fail to maintain membrane potential, thereby causing an imbalance in ion concentrations. These fluctuations in turn affect the neuronal network and cause dopaminergic neuron degeneration [111]. Because the symptoms cannot be identified at an earlier state of onset of disease, providing treatment on time is difficult for PD patients. To find early symptoms and protect dopaminergic neurons from degradation is the biggest challenge to date. Some studies show that supplementing PD patients with vitamin E or C at optimal doses is a potential treatment, because vitamin E and C produce large amounts of anti-oxidants, which can relieve a cell from metabolic stress by inhibiting the production of free radicals and reactive oxygen [112].

Dopamine receptor agonists are generally used to treat PD, which act by stimulating both presynaptic and postsynaptic dopaminergic receptors. DA deficiency in PD is substituted by a chemical precursor l-DOPA, which is the most effective drug to treat various symptoms.

4. Dopamine receptors and addiction

Dopamine is responsible for reward and addiction as well as control of coordinated movement, metabolism and hormonal secretion in CNS [113]. Addictive drugs generally largely and rapidly increase the extracellular concentration of dopamine in the nucleus accumbens [114]. Besides, addictive drug-evoked neurosynaptic plasticity results in behavioral responses in addicted patients [115]. Plasticity in the mesolimbic system triggers the compulsive behavior for seeking addictive matters after enough usage of addictive drugs [116]. These drugs trigger long-lasting synaptic adaptations in the mesolimbic reward system causing the additional pathological behaviors, as well [117].

Cannabinoids increase the dopamine levels in VTA through cannabinoid type 1 receptors. Cues related to cannabis smoking elicit phasic dopamine secretions and induce drug seeking behaviors like craving [118].

Cocaine controls the movement, cognition, motivation and reward in the CNS by blocking the reuptake of dopamine and thereby extracellular concentration of dopamine increases especially in the nucleus accumbens [119]. While psychostimulants like ecstasy, amphetamine and cocaine decrease dopamine reuptake, nicotine can directly increase the spike of dopaminergic neurons and thereby, the secretion of dopamine. Opioids, cannabinoids, γ-hydroxybutyrate and benzodiazepines inhibit the VTA GABAergic neurons [120]. This leads to a reduction in inhibition of dopaminergic neurons, resulting in increased dopamine secretion [120].

Cocaine shows its effects by phosphorylating ERK in the nucleus accumbens, providing D1 receptor-dependent synaptic potentiation [121] and behavioral adaptation [122] as well as increasing the mesolimbic dopamine level. ERK has important roles in gene regulation and drug addiction through chromatin remodeling and activation of gene transcription factors [121].

Addictive drugs elicit synaptic plasticity in dopaminergic neurons of VTA, leading to an increase in dopamine concentration in the mesolimbic reward system [122]. Cocaine provides insertion of GluA2-lacking AMPA receptors at glutamatergic synapse in dopaminergic neurons [122].

Addictive drugs cause a transient and significant increase in the extracellular concentration of dopamine in nucleus accumbens located in the ventral striatum in limbic system of the brain [123]. Increases in dopamine level in the ventral striatum triggered by addictive drugs like nicotine and alcohol provide euphoria during exposure [124].

After addicts notice the drug cues, mesolimbic projections on striatum are hyper-responsive to these cues and addicted patients desire to take drugs causing incentive salience and motivation for compulsive behaviors to take drugs. Hence these conditions result in relapse [125].

Reward and punishment stimuli bring search and avoidance responses, set by burst firing of dopaminergic neurons through long-term potentiation mechanism. Relationship between dopaminergic stimuli, glutamatergic inputs and GABAergic outputs enables learning and the ability to seek out rewarding behaviors and aversive ones [126]. Animals that lack of ability to synthesize dopamine cannot realize conditional reflexes or appetitive behavior. These animals have only unconditional and unlearned reflexes. To learn reward and punishment stimuli is mostly associated with phasic firing of dopaminergic neurons in the brain, establishing long-term memories. Independent firing of dopaminergic neurons motivates responses to reward and punishment cues. Interest in habitual rewards decreases because of reduction in the dopamine receptors resulted from habitual chronic usage of addictive drugs [127].

Decreased dopamine release from striatum to other brain regions within the reward circuitry may be a part of the deprivation neurophysiology in addicted chronic drug users. An altered feedback regulation of the reward circuit by prefrontal and amygdala pathways may also be responsible for disruption mechanism. Prefrontal regions and amygdala are involved in some behaviors related to addiction and deprivation like impulsivity, relapse and craving in chronic drug abusers that dopaminergic dysfunction occurs [123].

4.1 Treatment of addiction

Medications for addiction may be agonists, antagonists and anti-craving drugs. Methadone activates opiate receptors and prevents cravings for opiates and euphoria induced by usage of opiates [114, 128]. Naltrexone is a complete mu-receptor antagonist and it prevents relapse and euphoria resulted from abusing any opiate [129]. Buprenorphine is a partial mu-agonist and prevents cravings and euphoria because of usage of any opiate [114].

If D2 receptor activity in ventral striatum is increased in the reward system, self-administration of cocaine or alcohol can be reduced [130]. Similarly, impulsivity and compulsive pattern of self-administration in methamphetamine abuse is related to changed D2 receptor activity [131]. In addition, a potential strategy to address behavioral problems resulting from addiction and deprivation is to use transcranial magnetic stimulation or deep brain stimulation to eliminate cocaine-induced synaptic plasticity [132].

4.1.1 Dopamine and other neuropsychiatric diseases

Dopaminergic projections from VTA to hippocampus provide the formation of new memories. The ability to learn new information is lost when dopaminergic neurotransmission in this pathway is decreased. Hence, risk of dementia related diseases like Alzheimer’s disease increases.

Pharmacological and imaging studies show that increase in dopamine neurotransmission, elevations in D2 and D3 receptors level in striatum and activation of reward circuit result in mania. However increased dopamine transporter level in striatum results in the decrease in the dopaminergic transmission and depressive attacks in bipolar affective disorder [133].

Attention Deficit Hyperactivity Disorder (ADHD) is diagnosed by lack of concentration, short attention span and physical restlessness. Patients with ADHD were reported at least one gene defect such as DRD2, DRD4 or dopamine transporter genes, resulting in decrease in the dopaminergic neurotransmission in the brain [134].

4.1.2 Future treatment strategies on drug design for neurodegenerative disorders

With the advent of computer-based technology, it is possible to find a solution and bring better treatment procedures for complex disorders. Computer-Aided Drug Design (CADD) may be useful to provide more rapidly the discovery of the drugs, more effective for neurodegenerative disorders such as PD and Alzheimer’s disease [135]. CADD could emerge as an effective tool to minimize time and cost of the new lead molecules for extensively studying the DA receptors and other protein targets involved in dopaminergic signaling, and this gives a clear-cut idea of targets, which aids in designing New Chemical Entities (NCEs). After the discovery of NCE, it must be tested in terms of its safety and efficacy for humans as it is in the traditional drugs as well.

Dysfunctions of the dopamine neurotransmission in neuropsychiatric diseases are mostly related to presynaptic or postsynaptic dopamine receptors and can be reversed or stopped by targeting these receptors and their intracellular pathways. New researches must be focused on at this area to find more effective and cheaper solutions to treat these diseases.