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Schizophrenia: from dopaminergic to glutamatergic interventions
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ScienceDirect Schizophrenia: from dopaminergic to glutamatergic interventions Marc Laruelle Schizophrenia might be considered a neurodevelopmental disease. However, the fundamental process(es) associated with this disease remain(s) uncertain. Many lines of evidence suggest that schizophrenia is associated with excessive stimulation of dopamine D2 receptors in the associative striatum, with a lack of stimulation of dopamine D1 receptors in prefrontal cortex, and with modifications in prefrontal neuronal connectivity involving glutamate transmission at N-methyl aspartate (NMDA) receptors. This article, whilst briefly discussing the current knowledge of the disease, mainly concentrates on the NMDA hypofunction hypothesis. However, there are also potential consequences for a Dopamine imbalance on NMDA function. Thus, it is proposed that schizophrenia has a complex aetiology associated with strongly interconnected aberrations of dopamine and glutamate transmission. Addresses New Medicines Neurosciences Therapeutic Area Head, UCB Pharma, S.A., Belgium
described below. However, data have suggested that schizophrenia is a neurodevelopmental disorder that involves alterations in brain circuits. Psychotic symptoms nearly always emerge during adolescence or early adulthood (i.e. between 18 and 25 years of age). However, this does not mean that earlier in life schizophrenics perform well [4–6]. These longitudinal population studies suggest delayed maturation, especially in the first year of life and that IQ is reduced early and persistently in children that will develop schizophrenia. If indeed schizophrenia is a developmental disease, it may not be possible to develop truly relevant models of schizophrenia in either animals or man. However, Thompson and Levitt [7] have suggested that a lesion early in development may not manifest itself until later in development when compensatory mechanisms may not apply (developmental allostasis). Puberty or its consequences seem to be the defining moment. If true, then circuit and neurotransmitter dysfunctions seen in full blown schizophrenia may be the consequences of the initial lesion.
Corresponding author: Laruelle, Marc ([email protected])
Current Opinion in Pharmacology 2014, 14:97–102 This review comes from a themed issue on Neurosciences Edited by David G Trist and Alan Bye For a complete overview see the Issue and the Editorial 1471-4892/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.coph.2014.01.001
Introduction Schizophrenia is a chronic and severe mental illness with a prevalence of 0.5–1% of the population. Quoting Insel [1] ‘Schizophrenia is a syndrome: a collection of signs and symptoms of unknown aetiology, predominantly defined by observed signs of psychosis. In its most common form, schizophrenia presents with paranoid delusions and auditory hallucinations late in adolescence or in early adulthood. These manifestations of the disorder have changed little over the past century’. In addition, to these ‘positive’ symptoms schizophrenics also exhibit ‘negative’ and ‘cognitive’ symptoms [1]. Negative symptoms include: flattening, speech poverty, apathy, lack of pleasure and withdrawal, whilst cognitive deficits include attention, executive functioning, memory and speed of processing. Some of the symptoms of schizophrenia have been modeled in man using specific pharmacological agents [2,3]. The rationale for the choice of these agents has relied on current hypotheses of the aetiology of schizophrenia, as www.sciencedirect.com
While this aetiology of schizophrenia remains unclear, there is substantial evidence that suggests that there are changes in several neurotransmitter systems in the pathophysiological processes leading to the formation of schizophrenia. Initially, dopamine (DA) and two of its specific receptors in different brain areas received most attention. Subsequently, glutamate (GLU) and one of its receptors (N-methyl aspartate NMDA) have entered the scene [8,9]. Other systems have also been suspected. These include the GABAergic, opioid, cholinergic or serotonergic systems. It has been proposed that positive symptoms observed in schizophrenics are due to a hyperactivity of DA transmission [10]. Evidence for the DA hypothesis has come mainly from two sources: the finding of a correlation between clinical doses of antipsychotic drugs and their efficacy to block DA D2 receptors [8,10] and the fact that DA enhancing molecules are psychotogenic (for review see [2,9]). The classical DA hypothesis has become associated with subcortical regions of the brain such as the striatum and the nucleus accumbens, based on the high concentration of DA terminals and D2 receptors in these structures. Resistance to D2 antagonists by negative and cognitive symptoms of schizophrenia has led to reformiting the DA hypothesis. The use of functional brain imaging has suggested that the prefrontal cortex (PFC) might be responsible for these symptoms (for reviews see [3]). Preclinical studies have shown the importance of Current Opinion in Pharmacology 2014, 14:97–102
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Table 1 A simplified temporal summary of the dopamine (DA) hypothesis of schizophrenia as linked to changed perceptions in the role(s) of three areas of the brain. (VST: Ventral Striatum; AST: Associative Striatum; DLPFC: Dorsolateral Prefrontal Cortex) VST Classical DA Hypothesis (1960–1990) First Modification (1990–2010) Second Modification (2010–?)
Increment in DA (considered to be linked with psychosis) Increment in DA (considered to be linked with psychosis) Normal to decreased DA (hypothesised to be connected with negative symptoms)
prefrontal DA transmission at D1 receptors (the principle DA receptor in the neocortex) (for review see [11]). This has created a hypothesis that a deficit in DA transmission at D1 receptors in the PFC might be involved in the cognitive impairments and negative symptoms of schizophrenia [12,13]. Much evidence supports the idea that schizophrenia might also be associated with a persistent defect in GLU transmission involving NMDA receptors (for reviews see [14–18]). Convergence of both preclinical and clinical data [14,19,20] suggest that dysfunction of DA systems in schizophrenia may be following to a deficit in NMDA receptor function. In addition, it is now understood that DA has a modulatory role on GLU performance. Thus, changes in DA function might in turn affect NMDA activity. In this paper, we briefly review recent imaging evidence on the role in schizophrenia of DA dysfunction and that suggesting this dysfunction is secondary to NMDA dysfunction.
DA and GLU function in schizophrenia Striatal DA function in schizophrenia
Molecular imaging studies have proved to be a powerful tool in increasing our understanding of the structures and mechanisms involved in schizophrenia. Several methodologies have been used to show that during psychotic episodes there is an increased D2 receptor activation [21–28]. For example, increased rates of [18F]DOPA accumulation have been observed in schizophrenics indicating higher DA synthesis. A higher [18F]DOPA uptake was also seen in subjects with ‘prodromal’ symptoms of schizophrenia, an important insight that suggests that increased DA activity in the striatum already precedes the first frank psychotic episode [29]. These data also support the developmental allostasis hypothesis. The amphetamine-induced reduction in [123I]IBZM or [11C]raclopride binding potential (BP) is an indirect measure of the changes in synaptic DA concentration Current Opinion in Pharmacology 2014, 14:97–102
AST
DLPFC
Normal DA
Not considered
Normal DA
Reduced be linked Reduced be linked
Augmentation in DA (considered to be linked with psychosis)
DA (thought to with cognitive impairment) DA (thought to with cognitive impairment)
induced by a challenge [21–25]. Several studies have reported that amphetamine-induced DA increased release in patients with schizophrenia when compared to matched healthy controls [22,26–28]. Recently, some surprising results were found thanks to the improved resolution of imaging cameras. This has allowed DA activity in functional divisions of the striatum to be studied [30–32]. It was thought that DA antagonism in the ventral/limbic striatum (VST) was beneficial, whilst DA antagonism in the dorsal/associative striatum (AST) not only was of no benefit, but also caused extrapyramidal side effects. Contrary to this hypothesis, the results showed that in schizophrenics without treatment have presynaptic DA function increased in the AST instead of the VST. In addition, a decrease of DA activity in the VST was shown to be correlated with the severity of negative symptoms in schizophrenics not treated [33]. As a number of reports have suggested that the AST is the main abnormal area of DA function in schizophrenia, the null hypothesis of dysfunctional DA in schizophrenia requires refinement (Table 1). In 1970s, the DA hypothesis of schizophrenia was expanded to the mesolimbic theory of psychoses [34]. As underlined by Lidsky [35], the striatum was then thought of as being typically involved in motor control. However, the structures innervated by the mesolimbic DA system were better understood to be involved in modulation of drive, affect and memory. These are dimensions that are better related to psychiatric symptoms than the ascribed striatal motor functions. Thus the involvement of the mesolimbic DA system in psychosis was not based on direct empirical evidence. In the 1980s there was the first major reformulation of the DA hypothesis of schizophrenia. This came about through the recognition of enduring cognitive deficits in schizophrenia together with the discovery that prefrontal DA has a critical role in cognitive functions [12,13]. It was hypothesised that prefrontal DA function is reduced in schizophrenia and that in turn this deficit can lead to dysinhibition of the mesolimbic DA system. www.sciencedirect.com
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Improved resolution of PET cameras recently showed that DA activity is augmented in schizophrenia. Surprisingly, this was seen in the AST rather than in the VST and that increased AST DA activity is correlated with the severity of psychosis. These observations suggest that antipsychotics blocking the D2 receptors in the circuit in the AST, but not those in the VST, is correlated with therapeutic effects. Mesolymbic DA activity does not seem to be primarily changed in schizophrenia, and in a number of patients, a deficit in DA activity in the mesolymbic area could add to the severity of negative symptoms. Logic thus suggests that continuous blockade of D2 receptors in the VST could help worsen negative symptoms. These diverse reformulations of the DA hypothesis of schizophrenia are summarized in Table 1. Prefrontal DA function in schizophrenia
It has been suggested, following studies in schizophrenics, that there is a relationship between low cerebrospinal fluid homovanillic acid, a measure of DA activity in the prefrontal cortex, and poor working memory (WM) [36,37]. A postmortem study gives direct support for this hypothesis of a reduction in DA innervation in the dorsolateral prefrontal cortex (DLPFC) [38]. Studies carried out in schizophrenics with the D1 PET ligand [11C]NNC 112 showed an increased [11C]NNC 112 BP in the DLPFC [39,40]. Upregulated [11C]NNC 112 BP was correlated with a poor achievement on a WM assignment. Also in vivo binding has been carried out with [11C]NNC 112 in rodents [41]. Chronic DA depletion increased in vivo binding in the PFC. It is assumed that this is due to an upregulation of D1 receptors. Direct data are still lacking for a DA reduction in DLPFC in patients with schizophrenia. The development of new imaging technologies, presently under way, should facilitate the testing of this hypothesis more directly [30,42].
disruption is produced that also leads to changes in DA transmission similar to that found in schizophrenia (for review see [18]). Thus, both abnormalities in DA transmission in schizophrenia (cortical DA deficit and subcortical DA hyperactivity) might be related to a persistent alteration in NMDA transmission.
Glutamate–dopamine interactions A neuronal circuitry model of GLU–DA interactions
A model described by Carlsson et al. [29,52] hypothesises that GLU can affect DA activity in the substantia nigra (SN) and ventral tegmental area (VTA). A deficiency of NMDA transmission leading to diminished prefrontal activity in schizophrenics might cause a lowering of mesocortical DA transmission making worse cognitive function. If maintained, this lesion of mesolimbic DA transmission is hypothesised to trigger positive symptoms. Imaging studies of GLU–DA interactions
When NMDA antagonists are administered acutely there has been seen hardly any or just small effects on extracellular striatal DA, neither its concentrations or its release either with preclinical microdialysis [19,41] or measurements in human with [11C]raclopride before and during ketamine infusion [53,54]. However, DA release induced by amphetamine is elevated in rats following block by acute administration of NMDA antagonists [20]. Also in humans [20], ketamine (an NMDA antagonist), when given acutely to healthy subjects, the reduction in D2 binding potential caused by amphetamine increased from 5.5 3.5% to 12.8 8.8%. The former was for controls with just amphetamine, 0.25 mg/kg and the latter with ketamine, P = 0.023. Thus, the data support the hypothesis that a lesion in the GLU neuronal circuits that regulate dopaminergic cells is responsible for the abnormal increased release of DA following amphetamine administration in schizophrenics.
NMDA hypofunction in schizophrenia
The idea that schizophrenia might be caused by a persistent lesion in GLU transmission via NMDA receptors has arisen based on evidence generated with NMDA antagonists and agonists for reviews (see [15–19]). Phencyclidine (PCP) or ketamine, both noncompetitive antagonists of the NMDA receptor, creates positive and negative symptoms in schizophrenic and healthy subjects [31,32]. Specific NMDA co-agonists such as glycine [43– 45], D-cycloserine [46–48], and D-serine [49] when added to existing therapy provided a small improvement of symptoms in schizophrenia (for review see [50]). Bitopertin, an inhibitor of the glycine transporter has been shown to ameliorate negative symptoms in a well powered, placebo controlled phase II clinical study [51]. Confirmation of these findings in a large phase III trial is in progress [51]. Finally, when NMDA antagonists are given to animals over a long period a sustained NMDA transmission www.sciencedirect.com
Dopamine–glutamate interactions DA–GLU interaction in the striatum
Stimulation of either D1 or D2 receptors in the striatum has divergent activity on NMDA transmission. From an anatomical point of view, GLU afferents from the cortex and DA projections coincide in the striatum on GABAergic medium spiny neurons. Here DA has strong consequences on GLU transmission (for reviews, see [55– 60]). It has been noted that D2 receptor excitement reduces NMDA-mediated GLU, and D1 receptor activation aids GLU transmission [61,62]. Imaging data (see above) suggest that excess activation of AST D2 receptors in schizophrenia would block the flow of information into cortico-striato-thalamic-cortical loops. This probably will make worse a deficient NMDA transmission. Antipsychotic drugs through their D2 receptor antagonism might be able to restore the reception and Current Opinion in Pharmacology 2014, 14:97–102
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processing of information from the cortical through a restored NMDA functionality. D1 receptor antagonists have been shown not to have antipsychotic activity. Antagonism of D1 receptors would be expected to reduce NMDA functionality. As might be predicted, clinical trials with D1 receptor antagonists in schizophrenics, actually made worse positive symptoms [63–66]. As hypothesised above this might be through NMDA function impairment. Response to D2 receptor antagonists by schizophrenics depends on the level of DA occupancy. When the occupancy is high D2 antagonists act rapidly on positive symptoms [42]. When the occupancy is normal patients respond slowly to D2 receptor antagonists. One can hypothesise that in these slow responders the positive symptoms could be caused by a primary deficiency on NMDA function rather than through a D2 receptorinduced NMDA deficiency. Antipsychotic D2 receptor antagonists could still help slow responding patients by reducing D2 receptor activation to that below normal and by changing the equilibrium D1 receptor/D2 receptor in favour of D1 receptors. However, this approach would be predicted to take longer and be less predictable than in patients where a NMDA deficit is mainly through an excess of D2 receptor activity. DA–GLU interactions in the cortex
In the PFC, D1 receptors can be found on pyramidal cells (both dendritic spines and shafts). They are also located with D2 and D4 on GABAergic interneurons [67,68]. Thus, the excitability of pyramidal cells is modulated by DA, either immediately or indirectly through effects on GABAergic interneurons [52]. DA receptors found on GABAergic interneurons are generally seen as stimulating an inhibition of pyramidal cells through GABA [69–72]. D1 receptor activation is neither ‘excitatory’ nor ‘inhibitory’. It is actually pivotal on the operative status of GABAergic interneurons when the D1 receptors are stimulated [52,73,74]. DA, through its D1 receptors, functions as a ‘sustainer’ in prefrontal circuits. This is through direct activation of the D1 receptors on pyramidal cells which causes a potentiation of reaction of those stimulated and silences those not stimulated. At the same time, DA causes activation of GABAergic interneurons adding to a common repressory tone. Through these processes, DA increases the signal to noise ratio in the PFC [72,71]. It can thus be hypothesised that an insufficiency in stimulation of D1 receptors in the PFC of schizophrenics could be partly responsible for cognitive deficits shown by these patients.
Conclusions Schizophrenia can be considered a neurodevelopmental disease that manifests itself in adolescence or young Current Opinion in Pharmacology 2014, 14:97–102
adulthood through a first psychotic episode. However, there are other domains of schizophrenia, such as cognitive impairment, that might be present prodromal. Imaging data support the concept that there is an association between schizophrenia and an endophenotype consisting of a DA function deficit in the cortex together with an excess of DA activity in the AST. Imaging and animal data support the hypothesis that both of the DA function changes might follow reduced activity of NMDA transmission. Both changes in these DA functionalities might make worse synaptic connectivity and NMDA function. In fact, interactions of GLU on DA and DA on GLU could be highly important for schizophrenia. A lowering of GLU function could produce the DA endophenotype for this disease, and these DA changes could increase the severity of GLU transmission reductions. Thus, both GLU and DA alterations seem to strengthen one another. Whilst it is difficult to pharmacologically model a neurodevelopmental disease, data suggesting that there is increased DA activity in the striatum prodromal and that there are non-psychotic symptoms prodromal. This suggests that augmentation strategies using selective NMDA or D1 function modulators might have an early effect before the first psychotic episode as well as acting on negative and cognitive symptoms in diagnosed schizophrenics.
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ScienceDirect Schizophrenia: from dopaminergic to glutamatergic interventions Marc Laruelle Schizophrenia might be considered a neurodevelopmental disease. However, the fundamental process(es) associated with this disease remain(s) uncertain. Many lines of evidence suggest that schizophrenia is associated with excessive stimulation of dopamine D2 receptors in the associative striatum, with a lack of stimulation of dopamine D1 receptors in prefrontal cortex, and with modifications in prefrontal neuronal connectivity involving glutamate transmission at N-methyl aspartate (NMDA) receptors. This article, whilst briefly discussing the current knowledge of the disease, mainly concentrates on the NMDA hypofunction hypothesis. However, there are also potential consequences for a Dopamine imbalance on NMDA function. Thus, it is proposed that schizophrenia has a complex aetiology associated with strongly interconnected aberrations of dopamine and glutamate transmission. Addresses New Medicines Neurosciences Therapeutic Area Head, UCB Pharma, S.A., Belgium
described below. However, data have suggested that schizophrenia is a neurodevelopmental disorder that involves alterations in brain circuits. Psychotic symptoms nearly always emerge during adolescence or early adulthood (i.e. between 18 and 25 years of age). However, this does not mean that earlier in life schizophrenics perform well [4–6]. These longitudinal population studies suggest delayed maturation, especially in the first year of life and that IQ is reduced early and persistently in children that will develop schizophrenia. If indeed schizophrenia is a developmental disease, it may not be possible to develop truly relevant models of schizophrenia in either animals or man. However, Thompson and Levitt [7] have suggested that a lesion early in development may not manifest itself until later in development when compensatory mechanisms may not apply (developmental allostasis). Puberty or its consequences seem to be the defining moment. If true, then circuit and neurotransmitter dysfunctions seen in full blown schizophrenia may be the consequences of the initial lesion.
Corresponding author: Laruelle, Marc ([email protected])
Current Opinion in Pharmacology 2014, 14:97–102 This review comes from a themed issue on Neurosciences Edited by David G Trist and Alan Bye For a complete overview see the Issue and the Editorial 1471-4892/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.coph.2014.01.001
Introduction Schizophrenia is a chronic and severe mental illness with a prevalence of 0.5–1% of the population. Quoting Insel [1] ‘Schizophrenia is a syndrome: a collection of signs and symptoms of unknown aetiology, predominantly defined by observed signs of psychosis. In its most common form, schizophrenia presents with paranoid delusions and auditory hallucinations late in adolescence or in early adulthood. These manifestations of the disorder have changed little over the past century’. In addition, to these ‘positive’ symptoms schizophrenics also exhibit ‘negative’ and ‘cognitive’ symptoms [1]. Negative symptoms include: flattening, speech poverty, apathy, lack of pleasure and withdrawal, whilst cognitive deficits include attention, executive functioning, memory and speed of processing. Some of the symptoms of schizophrenia have been modeled in man using specific pharmacological agents [2,3]. The rationale for the choice of these agents has relied on current hypotheses of the aetiology of schizophrenia, as www.sciencedirect.com
While this aetiology of schizophrenia remains unclear, there is substantial evidence that suggests that there are changes in several neurotransmitter systems in the pathophysiological processes leading to the formation of schizophrenia. Initially, dopamine (DA) and two of its specific receptors in different brain areas received most attention. Subsequently, glutamate (GLU) and one of its receptors (N-methyl aspartate NMDA) have entered the scene [8,9]. Other systems have also been suspected. These include the GABAergic, opioid, cholinergic or serotonergic systems. It has been proposed that positive symptoms observed in schizophrenics are due to a hyperactivity of DA transmission [10]. Evidence for the DA hypothesis has come mainly from two sources: the finding of a correlation between clinical doses of antipsychotic drugs and their efficacy to block DA D2 receptors [8,10] and the fact that DA enhancing molecules are psychotogenic (for review see [2,9]). The classical DA hypothesis has become associated with subcortical regions of the brain such as the striatum and the nucleus accumbens, based on the high concentration of DA terminals and D2 receptors in these structures. Resistance to D2 antagonists by negative and cognitive symptoms of schizophrenia has led to reformiting the DA hypothesis. The use of functional brain imaging has suggested that the prefrontal cortex (PFC) might be responsible for these symptoms (for reviews see [3]). Preclinical studies have shown the importance of Current Opinion in Pharmacology 2014, 14:97–102
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Table 1 A simplified temporal summary of the dopamine (DA) hypothesis of schizophrenia as linked to changed perceptions in the role(s) of three areas of the brain. (VST: Ventral Striatum; AST: Associative Striatum; DLPFC: Dorsolateral Prefrontal Cortex) VST Classical DA Hypothesis (1960–1990) First Modification (1990–2010) Second Modification (2010–?)
Increment in DA (considered to be linked with psychosis) Increment in DA (considered to be linked with psychosis) Normal to decreased DA (hypothesised to be connected with negative symptoms)
prefrontal DA transmission at D1 receptors (the principle DA receptor in the neocortex) (for review see [11]). This has created a hypothesis that a deficit in DA transmission at D1 receptors in the PFC might be involved in the cognitive impairments and negative symptoms of schizophrenia [12,13]. Much evidence supports the idea that schizophrenia might also be associated with a persistent defect in GLU transmission involving NMDA receptors (for reviews see [14–18]). Convergence of both preclinical and clinical data [14,19,20] suggest that dysfunction of DA systems in schizophrenia may be following to a deficit in NMDA receptor function. In addition, it is now understood that DA has a modulatory role on GLU performance. Thus, changes in DA function might in turn affect NMDA activity. In this paper, we briefly review recent imaging evidence on the role in schizophrenia of DA dysfunction and that suggesting this dysfunction is secondary to NMDA dysfunction.
DA and GLU function in schizophrenia Striatal DA function in schizophrenia
Molecular imaging studies have proved to be a powerful tool in increasing our understanding of the structures and mechanisms involved in schizophrenia. Several methodologies have been used to show that during psychotic episodes there is an increased D2 receptor activation [21–28]. For example, increased rates of [18F]DOPA accumulation have been observed in schizophrenics indicating higher DA synthesis. A higher [18F]DOPA uptake was also seen in subjects with ‘prodromal’ symptoms of schizophrenia, an important insight that suggests that increased DA activity in the striatum already precedes the first frank psychotic episode [29]. These data also support the developmental allostasis hypothesis. The amphetamine-induced reduction in [123I]IBZM or [11C]raclopride binding potential (BP) is an indirect measure of the changes in synaptic DA concentration Current Opinion in Pharmacology 2014, 14:97–102
AST
DLPFC
Normal DA
Not considered
Normal DA
Reduced be linked Reduced be linked
Augmentation in DA (considered to be linked with psychosis)
DA (thought to with cognitive impairment) DA (thought to with cognitive impairment)
induced by a challenge [21–25]. Several studies have reported that amphetamine-induced DA increased release in patients with schizophrenia when compared to matched healthy controls [22,26–28]. Recently, some surprising results were found thanks to the improved resolution of imaging cameras. This has allowed DA activity in functional divisions of the striatum to be studied [30–32]. It was thought that DA antagonism in the ventral/limbic striatum (VST) was beneficial, whilst DA antagonism in the dorsal/associative striatum (AST) not only was of no benefit, but also caused extrapyramidal side effects. Contrary to this hypothesis, the results showed that in schizophrenics without treatment have presynaptic DA function increased in the AST instead of the VST. In addition, a decrease of DA activity in the VST was shown to be correlated with the severity of negative symptoms in schizophrenics not treated [33]. As a number of reports have suggested that the AST is the main abnormal area of DA function in schizophrenia, the null hypothesis of dysfunctional DA in schizophrenia requires refinement (Table 1). In 1970s, the DA hypothesis of schizophrenia was expanded to the mesolimbic theory of psychoses [34]. As underlined by Lidsky [35], the striatum was then thought of as being typically involved in motor control. However, the structures innervated by the mesolimbic DA system were better understood to be involved in modulation of drive, affect and memory. These are dimensions that are better related to psychiatric symptoms than the ascribed striatal motor functions. Thus the involvement of the mesolimbic DA system in psychosis was not based on direct empirical evidence. In the 1980s there was the first major reformulation of the DA hypothesis of schizophrenia. This came about through the recognition of enduring cognitive deficits in schizophrenia together with the discovery that prefrontal DA has a critical role in cognitive functions [12,13]. It was hypothesised that prefrontal DA function is reduced in schizophrenia and that in turn this deficit can lead to dysinhibition of the mesolimbic DA system. www.sciencedirect.com
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Improved resolution of PET cameras recently showed that DA activity is augmented in schizophrenia. Surprisingly, this was seen in the AST rather than in the VST and that increased AST DA activity is correlated with the severity of psychosis. These observations suggest that antipsychotics blocking the D2 receptors in the circuit in the AST, but not those in the VST, is correlated with therapeutic effects. Mesolymbic DA activity does not seem to be primarily changed in schizophrenia, and in a number of patients, a deficit in DA activity in the mesolymbic area could add to the severity of negative symptoms. Logic thus suggests that continuous blockade of D2 receptors in the VST could help worsen negative symptoms. These diverse reformulations of the DA hypothesis of schizophrenia are summarized in Table 1. Prefrontal DA function in schizophrenia
It has been suggested, following studies in schizophrenics, that there is a relationship between low cerebrospinal fluid homovanillic acid, a measure of DA activity in the prefrontal cortex, and poor working memory (WM) [36,37]. A postmortem study gives direct support for this hypothesis of a reduction in DA innervation in the dorsolateral prefrontal cortex (DLPFC) [38]. Studies carried out in schizophrenics with the D1 PET ligand [11C]NNC 112 showed an increased [11C]NNC 112 BP in the DLPFC [39,40]. Upregulated [11C]NNC 112 BP was correlated with a poor achievement on a WM assignment. Also in vivo binding has been carried out with [11C]NNC 112 in rodents [41]. Chronic DA depletion increased in vivo binding in the PFC. It is assumed that this is due to an upregulation of D1 receptors. Direct data are still lacking for a DA reduction in DLPFC in patients with schizophrenia. The development of new imaging technologies, presently under way, should facilitate the testing of this hypothesis more directly [30,42].
disruption is produced that also leads to changes in DA transmission similar to that found in schizophrenia (for review see [18]). Thus, both abnormalities in DA transmission in schizophrenia (cortical DA deficit and subcortical DA hyperactivity) might be related to a persistent alteration in NMDA transmission.
Glutamate–dopamine interactions A neuronal circuitry model of GLU–DA interactions
A model described by Carlsson et al. [29,52] hypothesises that GLU can affect DA activity in the substantia nigra (SN) and ventral tegmental area (VTA). A deficiency of NMDA transmission leading to diminished prefrontal activity in schizophrenics might cause a lowering of mesocortical DA transmission making worse cognitive function. If maintained, this lesion of mesolimbic DA transmission is hypothesised to trigger positive symptoms. Imaging studies of GLU–DA interactions
When NMDA antagonists are administered acutely there has been seen hardly any or just small effects on extracellular striatal DA, neither its concentrations or its release either with preclinical microdialysis [19,41] or measurements in human with [11C]raclopride before and during ketamine infusion [53,54]. However, DA release induced by amphetamine is elevated in rats following block by acute administration of NMDA antagonists [20]. Also in humans [20], ketamine (an NMDA antagonist), when given acutely to healthy subjects, the reduction in D2 binding potential caused by amphetamine increased from 5.5 3.5% to 12.8 8.8%. The former was for controls with just amphetamine, 0.25 mg/kg and the latter with ketamine, P = 0.023. Thus, the data support the hypothesis that a lesion in the GLU neuronal circuits that regulate dopaminergic cells is responsible for the abnormal increased release of DA following amphetamine administration in schizophrenics.
NMDA hypofunction in schizophrenia
The idea that schizophrenia might be caused by a persistent lesion in GLU transmission via NMDA receptors has arisen based on evidence generated with NMDA antagonists and agonists for reviews (see [15–19]). Phencyclidine (PCP) or ketamine, both noncompetitive antagonists of the NMDA receptor, creates positive and negative symptoms in schizophrenic and healthy subjects [31,32]. Specific NMDA co-agonists such as glycine [43– 45], D-cycloserine [46–48], and D-serine [49] when added to existing therapy provided a small improvement of symptoms in schizophrenia (for review see [50]). Bitopertin, an inhibitor of the glycine transporter has been shown to ameliorate negative symptoms in a well powered, placebo controlled phase II clinical study [51]. Confirmation of these findings in a large phase III trial is in progress [51]. Finally, when NMDA antagonists are given to animals over a long period a sustained NMDA transmission www.sciencedirect.com
Dopamine–glutamate interactions DA–GLU interaction in the striatum
Stimulation of either D1 or D2 receptors in the striatum has divergent activity on NMDA transmission. From an anatomical point of view, GLU afferents from the cortex and DA projections coincide in the striatum on GABAergic medium spiny neurons. Here DA has strong consequences on GLU transmission (for reviews, see [55– 60]). It has been noted that D2 receptor excitement reduces NMDA-mediated GLU, and D1 receptor activation aids GLU transmission [61,62]. Imaging data (see above) suggest that excess activation of AST D2 receptors in schizophrenia would block the flow of information into cortico-striato-thalamic-cortical loops. This probably will make worse a deficient NMDA transmission. Antipsychotic drugs through their D2 receptor antagonism might be able to restore the reception and Current Opinion in Pharmacology 2014, 14:97–102
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processing of information from the cortical through a restored NMDA functionality. D1 receptor antagonists have been shown not to have antipsychotic activity. Antagonism of D1 receptors would be expected to reduce NMDA functionality. As might be predicted, clinical trials with D1 receptor antagonists in schizophrenics, actually made worse positive symptoms [63–66]. As hypothesised above this might be through NMDA function impairment. Response to D2 receptor antagonists by schizophrenics depends on the level of DA occupancy. When the occupancy is high D2 antagonists act rapidly on positive symptoms [42]. When the occupancy is normal patients respond slowly to D2 receptor antagonists. One can hypothesise that in these slow responders the positive symptoms could be caused by a primary deficiency on NMDA function rather than through a D2 receptorinduced NMDA deficiency. Antipsychotic D2 receptor antagonists could still help slow responding patients by reducing D2 receptor activation to that below normal and by changing the equilibrium D1 receptor/D2 receptor in favour of D1 receptors. However, this approach would be predicted to take longer and be less predictable than in patients where a NMDA deficit is mainly through an excess of D2 receptor activity. DA–GLU interactions in the cortex
In the PFC, D1 receptors can be found on pyramidal cells (both dendritic spines and shafts). They are also located with D2 and D4 on GABAergic interneurons [67,68]. Thus, the excitability of pyramidal cells is modulated by DA, either immediately or indirectly through effects on GABAergic interneurons [52]. DA receptors found on GABAergic interneurons are generally seen as stimulating an inhibition of pyramidal cells through GABA [69–72]. D1 receptor activation is neither ‘excitatory’ nor ‘inhibitory’. It is actually pivotal on the operative status of GABAergic interneurons when the D1 receptors are stimulated [52,73,74]. DA, through its D1 receptors, functions as a ‘sustainer’ in prefrontal circuits. This is through direct activation of the D1 receptors on pyramidal cells which causes a potentiation of reaction of those stimulated and silences those not stimulated. At the same time, DA causes activation of GABAergic interneurons adding to a common repressory tone. Through these processes, DA increases the signal to noise ratio in the PFC [72,71]. It can thus be hypothesised that an insufficiency in stimulation of D1 receptors in the PFC of schizophrenics could be partly responsible for cognitive deficits shown by these patients.
Conclusions Schizophrenia can be considered a neurodevelopmental disease that manifests itself in adolescence or young Current Opinion in Pharmacology 2014, 14:97–102
adulthood through a first psychotic episode. However, there are other domains of schizophrenia, such as cognitive impairment, that might be present prodromal. Imaging data support the concept that there is an association between schizophrenia and an endophenotype consisting of a DA function deficit in the cortex together with an excess of DA activity in the AST. Imaging and animal data support the hypothesis that both of the DA function changes might follow reduced activity of NMDA transmission. Both changes in these DA functionalities might make worse synaptic connectivity and NMDA function. In fact, interactions of GLU on DA and DA on GLU could be highly important for schizophrenia. A lowering of GLU function could produce the DA endophenotype for this disease, and these DA changes could increase the severity of GLU transmission reductions. Thus, both GLU and DA alterations seem to strengthen one another. Whilst it is difficult to pharmacologically model a neurodevelopmental disease, data suggesting that there is increased DA activity in the striatum prodromal and that there are non-psychotic symptoms prodromal. This suggests that augmentation strategies using selective NMDA or D1 function modulators might have an early effect before the first psychotic episode as well as acting on negative and cognitive symptoms in diagnosed schizophrenics.
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