How do d2 receptors work

Criterion consisted of the mouse making head entries during 20 dipper presentations in one session. In the second training session, criterion was achieved when mice made head entries during 30 of 30 dipper presentations. For lever press training, lever presses were reinforced on a continuous reinforcement CRF schedule. The session ended when the mouse earned 60 reinforcements, or one hour elapsed, whichever occurred first.

Sessions were repeated daily until mice achieved 60 reinforcements. In FI training, lever presses were reinforced until after a fixed interval timed relative to the lever extension had elapsed. Mice underwent operant training 4 weeks after surgery followed by PR. In PR, a reward was obtained after the mice made the required number of lever presses. The criterion was set at two lever presses for the first trial and the requirement doubled with each successive trial.

Breakpoint was defined as the last criterion successfully completed. Mean values from 3 PR sessions were analyzed. Each mouse received one infusion of saline and one of CNO, 3 days apart.

Investigators were blind to genotype of mice during the experiment, and the order of the infusions was counterbalanced between groups, matched for age and sex.

Mice had two intervening RR5 sessions in the days between each PR test. For this task, we used random ratio RR schedules, which involve a constant probability of reinforcement for each lever press and assess effort in instrumental responding One animal was excluded from the data analysis because of lever pressing extinction. Voltage- and current-clamp whole-cell recordings were performed using standard techniques at room temperature.

Electrodes were pulled from 1. Spiking frequency Hz was determined from the initial pair of action potentials Peak amplitudes of oIPSCs were measured from averages of five individual traces.

Ten trials using a 5-ms blue light pulse 0. From this starting point, the VP was sampled in four locations 0. The starting locations were counterbalanced across animals and groups. Prior to PR test, a Doric Lenses snap-in microscope was attached to the imaging cannula under brief isoflurane anesthesia.

Ten minutes after full recovery, mice were placed in operant chamber to begin PR session. This period was chosen because it generally showed the highest press rates, generated more than 1 reward, and showed no difference in responding between groups.

Image stacks collected using the microendoscope imaging system were registered using Doric Neuroscience Studio Image Analysis software. Brains were harvested, post-fixed overnight and washed in PBS. Sample sizes were determined by performing statistical power analyses based on effect sizes observed in preliminary data or on similar work in the literature. Statistical analyses were performed using Graphpad Prism 5. Log-rank tests were used to analyze survival curves.

Behavioral and electrophysiological findings were successfully replicated with mice from different litters, ages, or sexes, and in several instances, across independent cohorts or related mouse strains. In addition, evoked electrophysiology responses were replicated using different stimulus intensities in vitro and in vivo, and data was collected from several animals.

Custom code used to generate results that are reported in the paper will be made available upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Cooper, A. Neuropharmacology 41 , 62—71 Tecuapetla, F. The review summarizes the recent advances in the field, addressing the relevance of emerging new targets in schizophrenia in particular in relation to the dopamine — glutamate NMDA systems interactions.

The dopaminergic system undergoes a delayed maturation in the brain, suggesting important stabilizing and integrating functions on neural circuits Grace, ; Ohira, Schizophrenia SCZ is associated with dopamine DA neurotransmission alterations during puberty and adult life causing deficits in motivation, cognition and sensory functions Simpson and Kellendonk, ; Abi-Dargham, ; Grace and Gomes, ; Sonnenschein and Grace, DA release measures in SCZ clinical studies and in preclinical models have clearly documented a fronto-cortical DA hypoactivity and a striatal mainly dorsal DA hyperactivity, associated with the occurrence of different SCZ symptoms Terrillion et al.

The limited SCZ genetic links to dopamine receptors DR and the main glutamatergic alterations observed in SCZ imaging studies are among the most compelling reasons for this debate Coyle et al.

This clearly does not question the well documented therapeutic benefit of DR antagonists as antipsychotics, but challenges two decades of efforts to develop new and improved SCZ therapies. This review aims at providing a summary of the most recent advances in DR control in SCZ with focus on DR—glutamate NMDA interactions across the genetic, intracellula,r and synaptic aspects of the disease.

Rampino et al. Table 1 Summary of most recent evidence of dopaminergic alterations in schizophrenia. The degradation of DA is under the control of a methylation enzyme, COMT highly expressed in prefrontal cortex and presynaptic monoamine oxidases. The by-product of this oxidation, H 2 O 2 is funneled into the mitochondrial transport chain to support further DA release Chen and Jonas, DA release occurs in a rather diffuse manner and ultrastructural studies show DA neuron axonal arborization and intricate projections covering large areas.

DA transmission is tightly controlled at presynaptic level, while only varicosity elements define the postsynaptic sites with a variety of inputs cholinergic, glutamatergic in close proximity. DA neurons are specialized to receive high volumes of afferent signals and transform this information into a modulatory tone through a large projection area. It is estimated that one DA neuron provides input to several thousand neurons in the striatum and vice-versa, any given individual striatal neuron is influenced by DA released from more than one hundred DA projections.

The DA neuronal system is often described in terms of DA release tonic or phasic and several models have tried to explain how multiple functions can be effectively impacted by different temporal DA release patterns Eshel et al.

DA neurons are intrinsic pacemakers, with a slow 2—4 Hz rhythmic activity associated with a tonic feed-forward control on DA receptor activation. DA neurons can also fire in rapid bursts in response to relevant salient stimuli.

This transient increase in firing rate induces a temporally precise rise in DA concentrations that can be synchronized in within local circuits. The lack of canonical synaptic release sites and the low probability of release for DA containing vesicles allow a scaling of neurotransmitter release as a function firing frequencies Lebowitz and Khoshbouei, The DA system is therefore also sensitive to a local presynaptic modulation from other neurotransmitters like acetylcholine or endocannabinoids Xu et al.

DA release is in fact directly modulated at the presynaptic terminals by a Rho-dependent internalization of DAT. Large postexperience DA stimulation phases are important during learning procedures and in motivational drive, reward processes Lak et al.

Most likely both D1 and D2 receptors subtypes are differentially engaged when in presence of DA burst firing at least in cortical and striatal regions Hunger et al. Experimental evidence points at presynaptic alterations in DA nerve terminals in the striatal region and in prefrontal cortex in SCZ Chuhma et al. Recent data managed to shed further light on the synaptic proteins involved in DA release, and how these are linked to SCZ by genetic studies.

For instance both the somato-dendritic and axonal release of DA are controlled by RIM protein isoforms in the active zone and by the Rab3 counterpart via D2L receptors Robinson et al. Glutamatergic effects on the DA release machinery are most likely indirect and sustained by GABAergic interneurons at least in cortical regions Molinaro et al. DR are integral membrane receptors coupled to G proteins Beaulieu and Gainetdinov, ; Thal et al.

There is some difference in the affinity of DA for D1-like receptors and D2-like receptors, mostly reported on the basis of receptor-ligand binding studies in recombinant systems Supplementary Material: Table 1. D2-like receptors have a to fold greater affinity for DA than the D1-like family, suggesting that the balance of D2-like vs.

D1-like receptor signaling can change depending on extracellular DA concentrations. A general view supports the specific engagement of D1 receptors in cortical regions when in presence of burst firing Dreyer et al.

Differences in DR affinity may not be however the only relevant factor when discussing DR engagement in physiological conditions. The timescale of DR engagement minutes and the relative DR abundance in complex circuits need to also be taken into account Hunger et al. The role of DR in different neuronal populations in striatum can be an example of this complexity. D2-MSNs can therefore respond to a broader range of stimuli Marcott et al.

These cholinergic neurons express the receptor D5 D1-like responsible for an excitatory response after a bursts of DA release and D2-like receptors which trigger an hyperpolarization a pause in the cholinergic signaling sequence when activated. In the nucleus accumbens nAcc finally D1 and D2-like receptors work in cooperativity heterodimers in the same neuronal population and still a local complex coding of response to DA release fluctuations can support motivation and decisional processes Hamid et al.

So transcriptional - translational control can be considered a specific part of the DRs activation cascade. D5 research did not produce convincing evidence so far of robust SCZ association Hwang et al. When discussing D1 in the context of SCZ, the most important aspects are certainly related to the prefrontal cortex PFCx regions and the cognitive deficits observed during the disease Arnsten et al.

Both proteins are important to trigger neuroplasticity effects Jiang et al. D1 may be present in heterologous glutamatergic pre-synapsis possibly in heterocomplexes D3? Both receptors can inhibit intracellular cAMP via Gi. The D2 receptor establishes a complex with DISC-1 that facilitates GSK3 mediated signaling and inhibits D2 agonist mediated receptor internalization, further enhancing the final D2 mediated effects Su et al.

Antipsychotics seem to be able to uncouple this complex Zheng et al. The D2S is dominant in the cell bodies and projection axons of the dopaminergic cells in mesencephalon, while the D2L is a mainly postsynaptic receptor strongly expressed by neurons in the striatum and nAcc, brain structures targeted by DA terminals.

This pathway represents a main stimulus for dendritic formation in striato-pallidal MSN Shioda et al. D2S auto-receptors on dendrites and soma are known to inhibits cell firing, activate DA reuptake and inhibit DA synthesis.

Other studies have verified that these alterations are sensitive to stress Sallis et al. The distribution of TAAR1 is predominantly intracellular thus being uniquely positioned to regulate aminergic activity possibly including DAT function Asif-Malik et al. Some D3 intracellular pathways are similar to those observed for D2 Guitart et al. The D3 receptor can however be sequestered in an inactive state at the membrane level rather than internalized Zhang et al. The D3 receptor is able to interact with nicotinic receptors for instance alpha 4 containing nicotinic receptors in particular in VTA Bontempi et al.

PICK1 instead seems to be able to control surface D3 levels. D3 effects can be increased in presence of NMDA receptor hypofunction. See Figure 1 for DR and signal transduction at synaptic level. Highlights on the elements associated with SCZ alterations are depicted in red. Glutamatergic cortical input - presynaptic terminals are in magenta. Cholinergic interneurons are in yellow.

Other projections are in gray. DR dimerization involves transmembrane domains 5 and 6. This interaction can be a transient process, stabilized in presence of agonists like dopamine or quinpirole Kasai et al.

The balance of D2 homodimers to monomers has been also associated to amphetamine sensitization in animals, a further element related to SCZ Weidenauer et al. This is why the generation of bivalent DR ligands has been attempted by several groups Carli et al. They can all be potentially relevant for the effects of antipsychotic agents and for the generation of new ligands with unique pharmacological properties Hubner et al. In this case the presence of a membrane cluster in hippocampal neurons has been convincingly demonstrated during the past decade Ladepeche et al.

D1 activation is associated with increased NMDA trafficking to the synaptic surface and vice-versa. The proposed model shows D1 receptors dynamically retained in clusters in the vicinity of glutamate synapses where they interact with NMDAR.

DR activation disrupts this interaction and favors the lateral redistribution of both receptors. D1Rs moves to extra-synaptic areas, whereas NMDA receptor reaches the glutamatergic postsynaptic density. A region contained in the intracellular C-terminus of the D1 receptor is involved in this interaction with the NMDA receptor Grea et al.

D1 and D2 are localized to different endocytic vesicles after internalization. D1 is recycled back to the cell surface in a process controlled by the VPS35 complex Wang et al.

A specific presynaptic control on D2S membrane density is exerted by the L1 close homolog adhesion factor also a risk gene for SCZ Kotarska et al. The overall complexity of the control of D2 receptor internalization vs D3 is possibly justified by the major biological role of D2 surface density adjustments, required in different circuits depending on DA content.

A specific example is the D2 vs D3 relative control by Dysbindin 1 Leggio et al. Dysbindin variants are known to modify the cognitive response to antipsychotics. Other types of control on DR density are exerted at source at the transcriptional level.

A recent analysis of proteasome alterations in SCZ points at spliceosome nuclear protein and calmodulin related pathways. Development mechanisms are directly impacting on DR expression. The expression control can also be exerted more dynamically on the D1 intracellular signal transducers by nuclear receptors like Nr4A1 Nurr77 Cirnaru et al.

Another nuclear factor involved in shaping dopaminergic terminals is Nurr1, highly relevant for the D2 receptor network and its circadian cycling Chung et al. See Table 1 supplementary material for a summary. Axon navigation is directed by extracellular axon guidance cues, which induce molecular changes in the axonal growth cones in response to extracellular levels of DA via D1 in complex.

The current understanding of the role of DR in SCZ is in full expansion, thanks to developmental brain studies and the advancements of imaging techniques. DR expression is segregated across neuronal populations and associated with temporal and coupling differences in activation properties.

Some developmental and connectivity aspects of DR distribution are maintained across species and useful for the definition of SCZ as a developmental disease across circuits Sonnenschein and Grace, Connectivity measures across different SCZ studies are not always easy to compare, but some key elements are constant across patient groups, detection modalities and data interpretation: the involvement of striatal-thalamic and PFCx connections in SCZ Zhao et al.

Imaging, functional and circadian studies are also in general agreement on the presence of main alterations in the PFCx of SCZ patients, in particular dorso-lateral and cingulate regions Seney et al.

PFCx circuits are central to cognitive functions and linked to the different aspects of cognitive deficits and positive symptoms as observed in SCZ. Dopaminergic ascending terminals reaching these neurons are also hypofunctional Rao et al. Dopamine release enables the PFCx to compute and generate spatio-temporally diverse and specialized outputs, but these are not a linear function of the DA release input. Thus, it is quite complex to establish the functional correlates for cortical functions.

Rapid, transient changes in DA transmission in PFCx are observed in response to task events, such as cues and rewards whereas prolonged responses are relevant to emotional states and motivation Lohani et al.

D1 receptors are enriched in pyramidal cells in both layers 5 thin-tufted layer and 6 projecting in turn to contralateral cortex, striatum, and claustrum. D1 is important for the correct migration of the dopaminergic terminals which increase throughout adolescence across species. Developmental studies in netrin-1 receptor DCC deficient mice demonstrate a role for DA in adolescent brain axon growth. DCC controls in fact the extent of this protracted growth by determining where and when DA acts.

Pyramidal neuron morphology studies and cognitive performances show that the lack of DCC causes dopaminergic deficit across PFCx and morphological changes in pyramidal neurons Reynolds et al. This process can be influenced by stress. The DA deficit in PFCx regions following this hypothesis may be then of developmental origin and caused by morphological alterations affecting DA terminals, pyramidal cells and interneurons.

D2 are enriched within subcortically projecting L5 pyramidal neurons thick-tufted pyramidal cells, with projections to thalamus and pons, but not contralateral cortex Yu et al. These neurons exhibit a prominent hyperpolarization-activated cationic current. In this population, pharmacological activation of D2 elicits a profound after depolarization that only occurs when NMDA receptors are coactivated.

The D2 network controls the connection to the hippocampal system Tomasella et al. Species related differences in this circuitry could be large, so human data are needed for the correct interpretation of the results Gonzalez-Burgos et al.

The cortical D2 mediated effects of the most common antipsychotics antagonists and partial agonists have been extensively evaluated. This is mostly because these agents cannot rescue the cognitive impairment associated with schizophrenia, with possibly few exceptions amisulpride or 5-HT1A partial agonists Park et al. D3 are expressed by a distinct population of prefrontal neurons and they also represent the main auto-receptor controlling DA release in prefrontal cortex. D3 expression defines an additional class of L5 pyramidal cells that largely lack D1 or D2 coexpression.

L5 D3-expressing neurons are similar to D1-expressing cells in their synaptic connectivity, with projections to contralateral cortex. D3-expressing neurons could be distinguished from D1- or D2-expressing neurons by dendritic morphology, intrinsic electro-physiological properties and by the manner in which DA regulates neuronal function. In these neurons in fact D3 selectively regulates the dynamics of voltage-gated calcium channels localized to the site of action potential initiation in the axon initial segment, with a marked suppression in the generation of high-frequency action potential bursts.

D3 regulates Ca V 3. The D3 plays therefore a unique role in the regulation of pyramidal cell excitability Clarkson et al. The D3 receptor function has received attention because it could be a discriminant of the clinical effect of different antipsychotics Girgis et al. In fact, D3 are associated to a cortical circuit important for all the different SCZ symptoms. The recent paper from Meier et al. Treatment response to antipsychotics may be predicted looking at the effect on hippocampal- cortical connections and again these changes could be in part D3 related Guma et al.

The observed hippocampal alterations in some SCZ patients psychotic also support the presence of hippocampal immaturity at least in a subgroup of SCZ patients Alvarez et al. There is therefore a renewed interest for the hippocampal models in SCZ, because it is possible to study developmental changes which are closer to those observed in man and because it is easier to obtain NMDA receptor hypofunction Alvarez et al.

In this animal model both cortical hypo- and striatal hyperdopaminergic phenotypes can be observed Nakao et al. The reason s behind these extensive dopaminergic changes across areas are still not fully understood, but SCZ genetic data related to ancillary proteins for the NMDA receptor function also support this hypothesis.

Very recent work has also given renewed attention to circuit s involving PFCx areas like DL or the orbitofrontal and cerebellum in relation to some aspects of negative symptoms in SCZ Walton et al. It is possibly too early to include a conclusive map of DR expression in within these pathways. The DISC-1 developmental mouse model could however help to analyze these circuit s , considering the main impairment observed in sociability measures Sultana and Lee, The main role of the striatum is the integration of cortical and thalamic glutamatergic projections Hunnicutt et al.

The striatum is at the center of a DA-sensitive basal ganglia circuit associated with psychosis, SCZ related motor dysfunctions and reward deficits. All data confirm the presence of presynaptic DA sensitization and elevated DA synthesis and release capacity Brugger et al.

Higher striatal DA synthesis and higher DA release correlated with worsening of psychotic symptoms in SCZ patients and were also supported by neuromelanin observation Weinstein et al.

There have been extensive efforts to describe the neuroanatomy of striatum, and the cellular distribution of DR Soares-Cunha et al. Substantia nigra DA projections mainly reach the dorsal striatum Uchigashima et al. The two types of neurons are finely intermingled across the whole striatum Ren et al.

They are usually described as enkephalin receptor positive neurons, they express specifically the subunit GluA3 of the AMPA receptor and project broadly to nuclei containing DA neurons cell bodies, to the nAcc and the ento-peduncular nucleus among others Perreault et al. The cross talk of interneurons at this level is a main filter on the cortical input. Clearly, different DR contribute to the final effect, depending on receptor distribution across different types of interneurons Burke et al.

Converging evidences suggest a critical role of the dopaminergic system in adapting synaptic plasticity of glutamatergic inputs synaptic spines. Early in development, the DA system has fundamental roles in forebrain differentiation and circuit formation Brignani and Pasterkamp, , but DA tone also has clear effects on glutamatergic spine density at adult stage. The recent and seminal work of the group of Prof. Groc, using single molecule-based imaging shows that NMDA antibodies present in some SCZ patients with psychotic symptoms are specifically changing the surface dynamics and nanoscale organization of synaptic NMDA and its anchoring partner the EphrinB2 receptor in synaptic spines in hippocampal neurons, ultimately preventing LTP potentiation Jezequel et al.

As expected this causes a small reduction of the D1 surface expression in the same cellular system Grea et al. It would be equally important to study these NMDA-antibody related changes in the context of the striatal circuits in particular on MSN D1 mediated signal and during development. The D1 receptor in dorsal striatum has been also involved in the sensorimotor gating alterations observed in SCZ but these mechanisms needs to be verified in man and with selective agents given the main differences in anatomical connectivity Aguilar et al.

There are main differences in the DA input across the different striatal regions. This is particularly true for the D2 receptor function across dorsal striatum and nAcc.

Gi Marcott et al. The striatal D2 related control on reward is a key aspect of the effects of antipsychotics. Psychotic symptoms have been in fact linked to salience changes in the reward system circuit and blocking D2 controls psychotic symptoms including a normalization on reward disturbances Han et al.

A direct relationship between D2 receptor blockade, normalization of reward processing and symptom improvement was recently further supported by a small study in antipsychotic-naive first-episode SCZ patients Wulff et al.

The cellular basis of the role of striatal D1 vs. D2 in reward and learning have been further clarified by the work of Iino et al. D2 antagonism is still recognized as a main stay of SCZ therapy and the D2 receptor is considered to be directly or indirectly responsible for the efficacy of the majority of typical and atypical antipsychotics.

It is becoming therefore apparent that D2 receptor function is heterogeneous and possibly strictly dependent on the neuronal type expressing the receptor in different cortical and sub-cortical regions.

Considering the role of D2 receptor in the control of emotional, cognitive and sensory functions alterations in SCZ it is therefore important to revisit the molecular aspects of this receptor and possibly even the pharmacology of the different antipsychotics Quintana and Beaulieu, This complex may represent an interesting new pharmacological target in SCZ.

The D2S receptor is involved whenever SCZ treatment resistance is discussed or phenomena of presynaptic D2 receptor supra-sensitivity induced by antipsychotics Amato et al. Motivational deficits in SCZ are most likely associated with cortico-striatal circuits involving the VTA, and the ventral striatum Aberg et al. Clinical observation keep suggesting some involvement of ventral striatum in the control of motivation, emotions and social behavior as relevant for negative symptoms in SCZ with regular debates on the matter Fareri et al.

Interestingly, D3 receptor expression is enriched in midbrain ventral striatum including nAcc Slifstein et al. Cholinergic interneurons in the ventral striatum, particularly those in the insula major of Calleja are highly enriched in D3 receptor, making these cells extremely sensitive to DA from VTA projections.

Calleja islands are also a site related to adult neurogenesis in ventral striatum across species: these neurons are D3, Erb4 and neuroregulin1 positive. Historical perspectives on SCZ drugs generally highlight the DA receptor D 2 antagonism as main mechanism of action Madras, , but the pharmacology of antipsychotics is much more complex and requires a specific discussion on DR selectivity and serotonin receptor poly-pharmacology Butini et al. Important discoveries were made in the DA field during the past decade, in particular in relation to the pharmacology of DR ligands.

DR heterodimers have been described in different brain regions and used to explain the complex biological effects associated with DR activation Borroto-Escuela et al.

Exciting data from crystallographic studies have supported a wave of drug discovery projects looking for new antipsychotics Chien et al. Several recent contributions are available on this matter Vyas et al. D2L or cAMP independent intracellular pathways, looking for agents with less motor side effects. These agents are not per se D2 selective since they also interact with the D3 receptor and might require the presence of an heteromeric complex with the receptor A2a for the final effect.

There is therefore a need for a different look at DR ligands pharmacology in vitro. We should possibly reconsider aspects like receptor internalization or intracellular recycling also for the main active metabolites or when comparing antagonists and partial agonists De Vries et al.

See Table 2 Supplementary Material for chemical series of DR ligands and representative compounds described in section 3. The most interesting finding in the field of DR is certainly the crystal structure of D2, D3. Homology models are also extremely helpful for D1 and D5 with some main limitation for specific domains with reduced identity Bueschbell et al. Molecular docking studies for the D1 receptor were able to demonstrate the presence of allosteric sites that were further targeted to obtain highly selective positive allosteric modulators with high potency, weak agonist properties and able to increase DA response cAMP Bruns et al.

The mode of interaction of biased agonists is different since they fail to trigger D1 receptor desensitization in vitro. The rapid advance of the pharmacology of D1 receptors bringing new drugs to the clinic is a clear demonstration of the therapeutic impact of research on DR-ligand interactions Hall et al.

Thus no main difference was expected. In reality the results show differences in D2 inactive conformation that suggest different receptor inactive states Lane et al. The re-assessment of the D2 interaction profile of different classes of D2 antagonists is also on the way Zieba et al. The case of D3 is complementing this picture given the variety of new ligands currently available.

Subtype-selective compounds have been sought for more than two decades with difficulties achieving sufficient selectivity and central exposure. Clinical PET data have recently provided encouraging results with cariprazine and F Slifstein et al.

More recent D3 over D2 new ligands have been obtained exploiting the presence of a secondary allosteric D3 pocket to generate bitopic ligands with long molecular bridges. This strategy has allowed a powerful expansion in chemical possibilities even while maintaining the capacity to generate agents with biased activities Rossi et al.

Shorter D3 ligands will necessarily reside instead only in within the orthosteric pocket. There is a second interesting aspect in the pharmacology of D3 bitopic ligands. Considering the excess D2 homodimers detected in schizophrenia Wang et al. A molecular model of the homodimer has been also generated for D2 to provide docking information relative to bivalent ligands with different pharmacological properties for example orthosteric and allosteric agents Kaczor et al.

Other DR heterodimers were also considered as selective targets for this type of ligands Carli et al. There are classic aspects of receptor pharmacology like constitutive activity or equilibria across receptor conformations which are quite difficult to address with DR, in particular when considering heterocomplexes. It should be however possible to better distinguish antagonists from partial agonists and systematically discuss on and off rates vs.

Species specific differences are also seldom acknowledged. Several groups have generated a variety of synthetic ligands concurring to build similar molecular models including dynamic aspects of DR receptor activation over time. Destabilization of D3 inactive state s and flexibility of the ligands are among the elements that the most recent model available is proposing Ferraro et al. Molecular recognition steps, changes in hydration of the ligand binding pocket and ligand dependent receptor configuration changes are also important considerations for D2 and D3 in particular when docking flexible ligands and establishing comparisons Pal et al.

Native system pharmacology studies are due to confirm the relevance of the observed in vitro differences. It would be indeed interesting to obtain a database of consistent functional information for all the ligands generated to further advance in the direction of new therapeutics. A re-evaluation of known DR ligands in the clinic on the basis of the latest available molecular model would be useful to help DR drug developers to build a more integrated view on the efforts, the tools and the information available and needed to move forward.

This article reviews current knowledge on DR subtypes in SCZ, anatomical distribution, and new pharmacological tools that can help dissect out subtype-specific functions. The aspects of DR research described hereby are strictly related to SCZ or risk genes associated with it.

What appears is that the current molecular understanding of Glutamate NMDA - DA interactions in SCZ has improved, but it is still insufficient in particular in brain areas like the ventral striatum and in relation to negative symptoms.

A better understanding of the circuit s will possibly further reduce boundaries between cognitive and negative SCZ symptoms domains Robison et al. This may also help drug discovery to address the complexity of DR heterocomplexes in native systems using multiple intracellular markers and benefiting from the available more selective DR tools.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Aberg, K. Interplay between midbrain and dorsal anterior cingulate regions arbitrates lingering reward effects on memory encoding. Abi-Dargham, A. Aguilar, B. Inhibition of the substantia nigra pars reticulata produces divergent effects on sensorimotor gating in rats and monkeys.

Alvarez, R. Amato, D. Psychiatry 10, Anastasiades, P. Cortex 29 7 , — Arango-Lievano, M. Cell Biol. Aringhieri, S. Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences. Arnsten, A. Psychiatry 81 1 , 67— The nervous system contains two basic types of receptors. Fast receptor systems, such as the GABAA receptor and the nicotinic receptor at the neuromuscular junction, involve the direct binding of a neurotransmitter to a ligand-gated channel, which opens or closes the channel.

Slower G-protein-linked receptor systems, as seen in the dopaminergic system, work through second-messenger systems, such as cyclic adenosine monophosphate cAMP , and have a longer duration of action. G-proteins derive their name from the conformational change induced in guanine nucleotides by the neurotransmitter-receptor complex. All of the dopamine receptors are similar in structure, and they mediate their effects through G-proteins.

The prototypic makeup of all dopamine receptors consists of a protein composed of approximately amino acids. These receptor proteins span the cell membrane and have extracellular, intramembrane and intracellular components.

Each receptor contains seven hydrophobic, membrane-spanning segments. Small changes in the primary amino acid sequence of the protein-receptors results in secondary structural changes that differentiate the dopamine subtypes.

Intracellularly, dopamine receptors interact with either stimulatory or inhibitory G-proteins. This interaction stimulates or inhibits adenylate cyclase, an enzyme that can catalyze the production of cAMP, one of the most important second messengers in the cell. The cAMP then exerts several biochemical changes such as activating genes and influencing the opening and closing of calcium and potassium channels. D1 or D1A. The D1 receptor is the most abundant dopamine receptor in the brain. This receptor is linked to stimulatory G-proteins that activate adenylate cyclase.

The D1 receptors are found in high concentration in the substantia nigra pars reticulata, caudate, putamen, nucleus accumbens, olfactory tubercle, and frontal and temporal cortex. To date, the role of the D1-like receptors in psychiatric disorders is unclear. Some evidence suggests that these receptors affect behavior indirectly through their regulatory effects on the D2-like receptors. Recent research suggests that the stimulation of D1 receptors has a synergistic effect on the D2 receptor motor response to dopamine.

This information has led to the development of D1 and D2 agonists, such as pergolide Permax for the treatment of Parkinson's disease. The unique pharmacological profile of clozapine Clozaril may, in part, be secondary to clozapine's mild affinity for the D1 receptor, which is not found in many of the classical neuroleptics. D1B or D5. The D5 receptors also are linked to stimulatory G-proteins and activate the enzyme adenylate cyclase.

The higher affinity for dopamine suggests that D5 receptors may be involved in maintaining dopaminergic tone and arousal. The D5 receptor has been anatomically localized to the cortex, hippocampus and limbic system. The dopamine D2 receptors are linked to inhibitory G-proteins and initiate their action by inhibiting the enzyme adenylate cyclase. The D2 receptors are localized both presynaptically and postsynaptically.

Researchers have identified two molecular forms of the D2 receptor, referred to as D2-long and D2-short because of their differing size. The two isomers of D2 are pharmacologically identical except for minor differences in their affinity for specific G-proteins. These receptors exhibit high affinity for a number of drugs, such as apomorphine, bromocriptine Parlodel and dopamine Intropin , that act as agonists.

Their anatomical distribution includes the striatum, substantia nigra and the pituitary gland. Antipsychotic action and extrapyramidal side effects of classical neuroleptics are a function of dopamine D2-like receptor blockade.

The potency of a neuroleptic is defined by its ability to block D2 receptors. This ability to block the D2 receptor is not uniform throughout the dopaminergic system. For example, clozapine has a moderate affinity for the D2 receptor in the striatum but a much higher affinity for the D2 receptor in the olfactory tubercle, a structure closely tied to the limbic system.

The dopamine D3 receptor appears to be pharmacologically very similar but distinct from the D2 receptor. The D3 receptor may have a two- to five-times lower affinity for classical neuroleptics, making it unlikely to be the main site of neuroleptic action.

The D3 receptor has not been found to affect adenylate cyclase and appears to be a presynaptic receptor. Its anatomical distribution includes the olfactory tubercle, nucleus accumbens, striatum, substantia nigra and hypothalamus.

The presynaptic location and high affinity for dopamine exhibited by these receptors suggests that they may play an autoreceptor role, monitoring the amount of synaptic dopamine. The dopamine D4 receptor appears pharmacologically similar to D2 and D3 receptors but has a times-greater affinity for the atypical antipsychotic clozapine, suggesting that D4 receptors may be the main site of clozapine's antipsychotic action. The anatomical distribution of this receptor includes the frontal cortex, medulla, hypothalamus and lower levels located in the basal ganglia.

Clinicians are beginning to realize the possible benefits from gaining a more complete understanding of the dopaminergic system. Advances in molecular genetics, combined with positron emission tomography PET and single photon emission computed tomography SPECT scanning capable of performing receptor-ligand imaging, have provided a new, more direct access into brain functioning.

There has been considerable debate over what role the dopamine receptors play in the pathophysiology of schizophrenia. In , Wong and coworkers reported a significant increase in D2 receptors in the caudate of drug-naive schizophrenic patients compared with controls. Subsequently, Farde and associates, using a different ligand, found no difference in the D2 receptor density. In , Seeman and colleagues reported that the discrepancy in the findings noted above was not secondary to an increase in D2 receptors, as initially reported by Wong, but actually may be secondary to a six-fold increase in the density of D4 receptors in schizophrenic patients versus controls.

Recently, a modified dopamine hypothesis of schizophrenia has been introduced. It suggests some schizophrenic patients have a hypodopaminergic state in the prefrontal cortex, resulting in negative symptoms, which could lead to hyperdopaminergia in the mesolimbic system and striatum, resulting in positive symptoms.

High-level dopamine receptor blockade occurs within 24 hours after initiation of neuroleptic treatment, yet the antipsychotic effects take days to achieve.