Sif 00 Prelim (Bc-D)

SiF 04 Chap 4 (bc-t) 7/6/06 3:55 pm Page 19 4 The neurochemistry of schizophrenia Our knowledge of the neurochemical abnormalities associated with schizophrenia has grown substantially over the past decade or so. Five decades ago, the accidental discovery of chlorpromazine’s antipsychotic action led, eventually, to a better understanding of the neuronal nature of schizophrenia. More recently, modern techniques for in vivo imaging of neurotransmitter receptors have advanced our understanding still further. Nonetheless, the true and complete neurochemical nature of schizophrenia is still to be elucidated and drug efficacy remains somewhat limited, with no major advance since the introduction of clozapine, a drug first synthesised in the 1950s. In fact, our knowledge of the neurochemistry of schizophrenia is such that we cannot say with certainty whether we know almost nothing or almost everything – it is not clear whether or not we are 1 year or a 100 years away from a major therapeutic breakthrough. In this chapter, we examine neurochemical candidates in schizophrenia and summarise knowledge of their suspected or established involvement in the disorder. Dopamine Dopamine is synthesised in neurones from extracellular tyrosine via dihydrophenylalanine. Intracellular dopamine levels are controlled by the enzyme monoamine oxidase. After release, dopamine may be taken back up into the presynaptic neurone or metabolised by catechol-o- methyl transferase. In the brain, dopamine interacts with a range of postsynaptic dopamine receptors (D1–D5; Figure 4.1). There are four major dopaminergic pathways: 1. the nigrostriatal pathway, controlling motor activities 2. the mesolimbic pathways, controlling reward, pleasure and many behaviours 3. the mesocortical pathway, which has uncertain function but contributes to cognition and volition 4. the tuberoinfundibular pathway, controlling production of prolactin SiF 04 Chap 4 (bc-t) 7/6/06 3:55 pm Page 20 20 The neurochemistry of schizophrenia Dopamine receptors D1 family D2 family D1 D5 D2 D3 D4 Figure 4.1 Dopamine receptor classification. As is well known, the dopamine theory of schizophrenia has its origin in early observation of the pharmacological actions of antipsychotics such as reserpine [1] and chlorpromazine [2]. The theory is further supported by the neurochemically unique correlation between in vitro activity at dopamine receptors and clinical dose [3] and the observed pro-psychotic effects of dopamine agonists such as amfetamine [4]. It became accepted that schizophrenia was a condition associated with, or caused by, dopamine overactivity. Over the last decade or so, the dopamine theory of schizophrenia has suffered numerous blows to its status as accepted fact. Some rather confusing and contradictory evidence comes from neuroimaging studies (Box 4.1). In the 1980s an in vivo positron emission tomography (PET) study of antipsychotic-naive patients using the ligand [11C] N-methylspiperone [5] suggested an increase in dopamine (D2, D3, D4) receptor numbers in schizophrenia, so supporting the dopamine theory of schizophrenia. However, later, studies using a more specific ligand, [11C] raclopride, found no increase in D2 or D3 receptors [6]. In addition to this, neuroimaging studies in patients receiving antipsychotics were able to show, first, that antipsychotics sometimes failed to be effective despite high dopamine receptor binding and, second, that the supremely effective antipsychotic clozapine was able to induce response despite low D2 receptor occupancy [7, 8]. Recent research has also attempted to determine which type or types of dopamine receptor might be involved in the neurochemistry of schizophrenia. D1 receptors are concentrated in the caudate putamen, the nucleus accumbens and the olfactory tubercle but are highly abundant, being found in cortical and limbic regions. There is limited evidence that D1 SiF 04 Chap 4 (bc-t) 7/6/06 3:55 pm Page 21 Dopamine 21 Box 4.1 Neuroimaging Neuroimaging involves the use of radiolabelled receptor-binding compounds (ligands) to identify the location and number of specific neurochemical receptors. The technique is suitable for in vitro and in vivo studies but the latter are generally more illuminating. The radiolabelled compound is usually a specific antagonist of a certain receptor or receptor 11 type. Examples include [ C] N-methylspiperone (D2, D3, D4 receptors); 11 11 123 [ C] raclopride (D2, D3); [ C] SCH 23390 (D1); [ I] epidepride (D2, D3); 123 [ I]-iodobenzamide and R 91150 (5HT2a). There are two major experimental methods: PET and single photon emission tomography (SPET). Both are able to image receptor location, receptor density and numbers of free (unbound) receptors. Both have two potential sources of error: (1) specificity of ligands for receptor types and (2) the competition for receptor sites between the ligand, endogenous neurotransmitter and any drug present. Ligands are therefore specially selected for their specificity and their receptor affinity so that specific, free receptors can be imaged (the ligand should not, for example, displace the drug under investigation from receptor sites). receptor numbers are reduced in schizophrenia but this is not conclusive [8]. Some PET studies have detected reduced D1 density [9]; others have not [10]. Newly developed ligands such as [11C] NNC 112 may help clarify the situation [11]. A reduction in D1 receptor density is an intriguing possibility, which, counterintuitively, supports the dopamine hypothesis. It is possible that antipsychotics (which in general block D2 receptors but not D1) may induce increased dopamine turnover which may compensate for the pathological reduction in D1 numbers and perhaps restore the balance in D1/D2 stimulation [8]. This explanation stands whether D1 receptors are primarily postsynaptic or presynaptic autoreceptors. It is noteworthy that a specific D1 antagonist SCH39166 seems to cause deterioration of psychotic symptoms [12], while clozapine appears to be a D1 receptor agonist [13]. D2 receptors are the most abundant dopamine receptors in the brain with widespread distribution but particular concentration in the basal ganglia (striatum, putamen). Measurements of D2 receptor numbers in schizophrenia have provided conflicting results, largely as a consequence of the use of antipsychotics which share a propensity for D2 antagonism and inevitably affect D2 receptor density. In vivo neuroimaging studies in drug-naive subjects generally suggest increased D2 SiF 04 Chap 4 (bc-t) 7/6/06 3:55 pm Page 22 22 The neurochemistry of schizophrenia receptor density in the striatum with perhaps decreased receptor numbers in the anterior cingulate cortex [14]. Those with schizophrenia also seem to show an exaggerated response to amfetamine – striatal dopamine release is significantly greater than in normal controls [15]. D2 receptor antagonism remains the most plausible and well- supported method by which antipsychotics exert their effects [7, 8]. Neuroimaging studies confirm the D2 receptor-blocking action of all antipsychotics but these studies are limited by their lack of specificity for different dopamine receptor subtypes and their restricted capacity for imaging receptor density in areas of the brain with few receptors (e.g. extrastriatal structures). Improved techniques may eventually be illuminating, as may genetic studies, which have already proposed an association between a polymorphism of a D2 receptor gene and a diag- nosis of schizophrenia [16]. Investigation into the role of D3 receptors in schizophrenia has been severely hampered by the absence of a specific D3 ligand [8]. D3 receptors appear to be predominantly found in limbic areas of the brain – the sites of emotional processing. As such, they are potential candidates for involvement in the symptoms of schizophrenia and for targets for antipsychotic action. D3 receptor densities may be increased in the brains of those with schizophrenia [17], although the evidence for this is slim. Knowledge of the role of D3 receptors is likely to develop more quickly now that specific ligands such as [125I]7-hydroxy-PIPAT have begun to be used [17–19]. Genetic studies may also be productive: it has been suggested that D3 receptor messenger RNA is increased in white blood cells of those with schizophrenia [20]. In the 1990s there was considerable excitement over the role of D4 receptors. This excitement and resultant flurry of activity followed the apparent discovery of a sixfold increase in D4 receptor numbers in schizophrenia [21]. Clozapine was also noted to be a potent D4 receptor antagonist [22]. However, the D4 receptor theory of schizophrenia was short-lived: other workers failed to replicate original findings [8] and the D4 antagonist fananserin was found to have no antipsychotic effects [23]. The role of dopamine D5 receptors in schizophrenia is unclear and their function is unknown. Studies examining associations between genetic mutations of the D5 gene and schizophrenia have produced contradictory results [24, 25] (Dopamine focus 4.1). SiF 04 Chap 4 (bc-t) 7/6/06 3:55 pm Page 23 Serotonin 23 DOPAMINE FOCUS 4.1 Dopamine activity in schizophrenia Brain region Dopamine activity Associated symptoms Broca’s area ↑ Auditory hallucinations Superior temporal gyrus ↑ Auditory hallucinations Cingulate gyrus ↑ Passivity experiences Hippocampus ↑ Positive symptoms Prefrontal cortex ↓ Negative symptoms Anterior cingulate ↓ Thought disorder Attention deficit Serotonin Serotonin or 5-hydroxytryptamine (5HT) has been suspected

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