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The dopamine hypothesis of schizophrenia posits that increased subcortical dopamine underpins psychosis. In vivo imaging studies indicate an increased presynaptic dopamine synthesis capacity in striatal terminals and cell bodies in the midbrain in schizophrenia; however, measures of the dopamine-synthesising enzyme, tyrosine hydroxylase (TH), have not identified consistent changes. We hypothesise that dopamine dysregulation in schizophrenia could result from changes in expression of dopamine synthesis enzymes, receptors, transporters or catabolic enzymes. Gene expression of 12 dopamine-related molecules was examined in post-mortem midbrain (28 antipsychotic-treated schizophrenia cases/29 controls) using quantitative PCR. TH and the synaptic dopamine transporter (DAT) proteins were examined in post-mortem midbrain (26 antipsychotic-treated schizophrenia cases per 27 controls) using immunoblotting. TH and aromatic acid decarboxylase (AADC) mRNA and TH protein were unchanged in the midbrain in schizophrenia compared with controls. Dopamine receptor D2 short, vesicular monoamine transporter (VMAT2) and DAT mRNAs were significantly decreased in schizophrenia, with no change in DRD3 mRNA, DRD3nf mRNA and DAT protein between diagnostic groups. However, DAT protein was significantly increased in putatively treatment-resistant cases of schizophrenia compared to putatively treatment-responsive cases. Midbrain monoamine oxidase A (MAOA) mRNA was increased, whereas MAOB and catechol-O-methyl transferase mRNAs were unchanged in schizophrenia. We conclude that, whereas some mRNA changes are consistent with increased dopamine action (decreased DAT mRNA), others suggest reduced dopamine action (increased MAOA mRNA) in the midbrain in schizophrenia. Here, we identify a molecular signature of dopamine dysregulation in the midbrain in schizophrenia that mainly includes gene expression changes of molecules involved in dopamine synthesis and in regulating the time course of dopamine action.

Iron accumulation is a cardinal feature of degenerating regions in the Parkinson's disease brain. As a potent pro-oxidant, redox-active iron may be a key player in upstream mechanisms that precipitate cell death in this disorder. Although an elevation in brain iron levels is a normal feature of ageing, the increase is greater in Parkinson's disease; on the other hand, the effects of the disease are most marked in the nigrostriatal dopaminergic system. In this Update, we explain that neurodegeneration in the affected regions may result from the potent redox couple formed by iron and dopamine itself, and discuss the clinical implications of this molecular trait in this dynamic and rapidly moving area of Parkinson's disease research.

Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase), breakdown (catechol-O-methyl transferase; monoamine oxygenase), transport [vesicular monoamine transporter (VMAT), dopamine transporter (DAT)] and receptors (DRD1-D5)] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen receptor-driven events as estradiol had minimal effect. We conclude that nigrostriatal responsivity to dopamine may be modulated by testosterone acting via androgen receptors to alter gene expression of molecules involved in dopamine signaling during adolescence.

Background: Parkinson's disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons., Methodology/principal Findings: Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO) mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT) was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR) of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD) was absent in corticostriatal slices from old transgenic mice., Conclusions/significance: Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches.

Neuromelanin is a dark-coloured pigment which forms in the dopamine neurons of the human midbrain. Here we describe the age-related development and regulation of neuromelanin within these dopamine neurons. 10 microm sections from formalin-fixed midbrain from 29 people spanning the ages of 24 weeks to 95 years old were either stained with a basic Nissl substance stain (0.5% cresyl violet), or processed unstained. After locating the substantia nigra using the stained sections, digital photos were taken of individual ventral substantia nigra neurons in the unstained sections, and the cellular area occupied by pigment, and optical density were measured using computer software. These measurements demonstrated three developmental phases. Neuromelanin was not present at birth and initiation of pigmentation began at approximately 3 years of age, followed by a period of increasing pigment granule number and increasing pigment granule colouration until age 20. In middle and later life the colour of the pigment granules continued to darken but was not associated with any substantial growth in pigment volume. The identification of three phases and changes in the rate of neuromelanin production over time suggests the regulation of neuromelanin production and turnover, possibly through enzymatic processes.

Neuromelanin (NM) is a dark polymer pigment produced in specific populations of catecholaminergic neurons in the brain. It appears in greatest quantities in the human brain, in lesser amounts in some other non-human primates, but is absent from the brain in many lower species. Interest in this pigment has seen a resurgence in recent years because of a hypothesised link between neuromelanin and the especial vulnerability of neuromelanin-containing neurons to cell death in Parkinson's disease (PD). Little is known regarding the biology of neuromelanin. As neuromelanin appears to have characteristics in common with the better studied peripheral melanin pigments this review compares what is known about neuromelanin with melanins found in other body tissues. Unlike peripheral melanins, which are produced in specialised cells called melanocytes and may be transferred to other cell types, neuromelanin granules are believed to be stored in the cell in which they are produced. Neuromelanin granules display a unique, more heterogeneous appearance compared with peripheral melanins. Unlike melanin, neuromelanin is traditionally thought to result from a non-enzymatic synthesis pathway with no known pathway for neuromelanin catabolism. More recent data, however, is indicative of some regulation of neuromelanin synthesis and turnover. By analogy with peripheral melanins, neuromelanin may function in vivo to attenuate the effects of damaging stimuli. Among several possible mechanisms suggested, the ability of neuromelanin to interact with transition metals, especially iron, and to mediate intracellular oxidative mechanisms has received particular attention. Recent data from neuromelanin in the Parkinson's disease brain suggests that this proposed function may be compromised, thus rendering pigmented neurons vulnerable to oxidative damage in this disorder.

Many dopamine agonists used in the treatment of Parkinson's disease are suggested to be potentially neuroprotective. On the basis of its structure, the dopamine agonist lisuride may share this characteristic. In the current study discrete asymptomatic lesions were produced by the injection of iron-laden neuromelanin into the rat substantia nigra and the animals treated with lisuride to determine the protective potential of this substance. Two treatment regimes were utilised. In the neuroprotective protocol, animals were treated with 0.1 mg.kg(-1) lisuride twice daily 3 days prior to, and 7 days following, the iron lesion. In the neurorescue protocol, the animals received 0.1 mg.kg(-1) lisuride twice daily for 1 week beginning on the fourth day post surgery. Eight weeks post surgery, tyrosine hydroxylase-positive neurons surrounding the injection site (33% of total nigral volume) were counted. Dopamine neuron number in iron-lesioned animals was reduced to 50% of that in vehicle-injected animals. The absence of motoric disturbances or a striatal dopamine deficit in these animals suggests a subclinical dopaminergic lesion. Dopamine neuron number in the quantified area in sham-injected animals receiving lisuride or iron-lesioned animals receiving lisuride in both the neuroprotection and neurorescue groups were not significantly reduced. These results suggest that lisuride can protect neurons against iron-induced cell death and might thus be neuroprotective in Parkinson's disease.

Neuromelanin (NM) is a granular, dark brown pigment produced in some but not all of the dopaminergic neurons of the human substantia nigra (SN). In Parkinson's disease (PD) the pigmented dopaminergic neurons of the SN degenerate, suggesting that this process is related to the presence of NM. As yet it is unknown whether NM in the parkinsonian brain differs from that found in healthy tissue and thus may fulfil a different role within this tissue. The function of NM within the pigmented neurons is unknown but other melanins are believed to play a protective role via attenuation of free radical damage. Experimental evidence suggests that NM may also exhibit this characteristic, possibly by direct inactivation of free radical species or via its ability to chelate transition metals, such as iron. NM has the ability to bind a variety of metals, seven per cent of isolated NM is reported to consist of Fe, Cu, Zn and Cr. Iron is of particular interest as this metal is highly concentrated within the SN. Up to 20 per cent of the total iron contained in the SN from normal subjects is bound within NM. Further, it was demonstrated that NM contains a protein component and that iron is bound to NM in the ferric form. Increased tissue iron found in the parkinsonian SN may saturate iron-chelating sites on NM, and a looser association between iron and NM may result in an increased, rather than decreased, production of free radical species. It is hypothesized that this redox-active iron could be released and involved in a Fenton-like reaction leading to an increased production of oxidative radicals. The resultant radical-mediated cytotoxicity may contribute to cellular damage observed in PD.

Neuromelanin (NM) is a complex polymer pigment found primarily in the dopaminergic neurons of the human substantia nigra. The structure of NM is only partially characterized, and its synthesis pathway remains unknown. We used nuclear magnetic and infrared spectroscopy to examine the structure of human NM isolated from the substantia nigra compared with synthetic dopamine melanins. Biochemical analyses were used to investigate proteinaceous and dopaminergic components in these samples. Following acid hydrolysis of NM samples, small amounts of DOPA, dopamine, and a variety of amino acids were measured. These findings suggest a peptide component in NM structure. NM also appears to contain a variety of unidentified structural components possibly derived from the oxidation of dopamine. Human NM differs structurally from synthetic dopamine melanin, but both human and synthetic NM include an aromatic backbone. It is interesting that both human NM and synthetic melanin also contain a large proportion of aliphatic structures. Our results suggest that NM is a more complex pigment than synthetic dopamine melanin formed via dopamine autoxidation alone.