Nigral glutathione deficiency is not specific for idiopathic Parkinson's disease

The consistent findings of decreased levels of the major antioxidant glutathione in substantia nigra of patients with idiopathic Parkinson's disease (PD) has provided most of the basis for the oxidative stress hypothesis of the etiology of PD. To establish whether a nigral glutathione deficiency is unique to PD, as is generally assumed, or is present in other Parkinsonian conditions associated with nigral damage, we compared levels of reduced glutathione (GSH) in postmortem brain of patients with PD to those with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). As compared with the controls, nigral GSH levels were decreased in the PD and PSP patient groups (P < 0.05 for PD [-30%], PSP [-21%]), whereas a similar decrease in the MSA patient group did not reach statistical significance (P = 0.078, MSA [-20%]). GSH levels were normal in all examined normal and degenerating extra-nigral brain areas in PSP and MSA. A trend for decreased levels of uric acid (antioxidant and product of purine catabolism) also was observed in nigra of all patient groups (-19 to -30%). These data suggest that glutathione depletion, possibly consequent to overutilisation in oxidative stress reactions, could play a causal role in nigral degeneration in all nigrostriatal dopamine deficiency disorders, and that antioxidant therapeutic approaches should not be restricted to PD.     

A multicenter trial of ropinirole as adjunct treatment for Parkinson's disease. Ropinirole Study Group

OBJECTIVE: To evaluate the nonergot dopamine agonist ropinirole as an adjunct to L-dopa in a randomized, double-blind trial in PD patients with motor fluctuations. BACKGROUND: L-dopa in the treatment of PD is associated with motor fluctuations, dyskinesia, and other adverse effects. The use of dopamine agonists in the treatment of PD delays recourse to L-dopa and thus delays the possibility of adverse effect onset. METHODS: Ropinirole (n = 95) or placebo (n = 54) was added to L-dopa, and L-dopa was then reduced in a planned manner during the 6-month trial. RESULTS: A significantly greater number of ropinirole patients were able to achieve a 20% or greater reduction in both L-dopa dose and in percent time spent "off" compared with placebo (35.0% versus 13.0%; p = 0.003). The mean daily L-dopa dose was reduced significantly with ropinirole treatment (242 mg versus 51 mg; p < 0.001) as was the percent awake time spent "off" (11.7% versus 5.1%; p = 0.039). There was no difference in the percent of patients who withdrew because of adverse effects (15.8% on ropinirole versus 16.7% on placebo). CONCLUSIONS: Ropinirole permits a reduction in L-dopa dose with enhanced clinical benefit for PD patients with motor fluctuations.     

Vasorelaxant effect of olprinone, an inhibitor of phosphodiesterase 3, on mesenteric small artery and vein of rabbits

An augmented synthesis of tetrahydroisoquinolines, such as salsolinol (SAL) or an increased N-methylation of these compounds has been addressed by various investigators as putative pathophysiologic mechanisms in Parkinson's disease (PD). Aim of this study was (1) to investigate putative relations between plasma levels of dopamine and R- and S-enantiomers of SAL and (2) whether these metabolic precursors of the neurotoxic N-methylated-SAL (NMSAL) are elevated in untreated "de-novo" Parkinsonian patients compared to age- and sex-matched healthy controls. Plasma levels of R- and S-SAL and dopamine did not significantly (R-SAL: p=0.61, S-SAL: p=0.51, dopamine: p=0.84) differ in both groups. Parkinsonian patients' R-SAL plasma levels were inversely related to intensity (p=0.03, r =-0.42) and duration of PD (p=0.03, r=-0.43) in contrast to S-SAL and dopamine. Dopamine levels were not associated to R-SAL (p=0.88, r2=0.0008) and S-SAL (p=0.088, r2=0.12) neither in Parkinsonian patients nor in controls. We conclude, that an upregulation of N-methylation of tetrahydroisoquinolines takes place in PD by enzymes such as neutral N-methyltransferase specific for R-SAL. The activity of this enzyme has been found elevated in parkinsonian lymphocytes. This increased N-methylation by the N-methyltransferase specific for R-SAL leads to the known augmented levels of neurotoxic R-NMSAL in Parkinsonian patients compared to controls in the cenral nervous system especially in the beginning of PD.     

Peripheral and central pharmacokinetics of apomorphine and its effect on dopamine metabolism in humans

Apomorphine is a dopamine receptor agonist increasingly used in the treatment of Parkinson's disease (PD). In the present study, we examined the plasma and ventricular cerebrospinal fluid (CSF) pharmacokinetics of apomorphine as well as its effects on dopamine metabolism in six patients (one woman and five men, mean age 79.5 years) without evidence of PD who underwent 48-h intracranial pressure monitoring for suspected normal pressure hydrocephalus. Maximal plasma apomorphine concentration (25.04 ng/ml) is found 20 min after subcutaneous injection (50 micrograms/kg), and the mean area under the curve is 1,439.37 ng/ml for 120 min. In contrast to plasma values, the maximal ventricular CSF apomorphine concentration (1.08 ng/ml) is found 30 min after injection and the mean area under that curve is 7% of that of plasma (96.69 ng/ml for 120 min). Apomorphine administration causes a significant reduction in ventricular CSF concentrations of dopamine and of its major metabolites sulfoconjugated dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). This effect starts 10 min after the injection of apomorphine, is maximal after 30 min (free dopamine, -30%; sulfoconjugated dopamine, -28%; HVA, -21%; DOPAC, -31%) and is still present, although to a lesser extent (-5 to -10%), 120 min after the injection of apomorphine. This study shows that in humans a dose of apomorphine commonly used in PD causes significant inhibition of dopamine metabolism lasting > 120 min. In addition to their symptomatic effects, dopamine agonists such as apomorphine may play a role in preventing or slowing the neurodegeneration in PD by autoreceptor-mediated inhibition of dopamine metabolism.     

The risky business of dopamine agonists in Parkinson disease and impulse control disorders.

Risk-taking behavior is characterized by pursuit of reward in spite of potential negative consequences. Dopamine neurotransmission along the mesocorticolimbic pathway is a potential modulator of risk behavior. In patients with Parkinson's disease (PD), impulse control disorder (ICD) can result from dopaminergic medication use, particularly dopamine agonists (DAA). Behaviors associated with ICD include hypersexuality as well as compulsive gambling, shopping, and eating, and these behaviors are potentially linked to alterations to risk processing. Using the Balloon Analogue Risk Task, we assessed the role of agonist therapy on risk-taking behavior in PD patients with (n = 22) and without (n = 19) active ICD symptoms. Patients performed the task both “on” and “off” DAA. DAA increased risk-taking in PD patients with active ICD symptoms, but it did not affect risk behavior of PD controls. DAA dose was also important in explaining risk behavior. Both groups similarly reduced their risk-taking in high compared to low risk conditions and following the occurrence of a negative consequence, suggesting that ICD patients do not necessarily differ in their abilities to process and adjust to some aspects of negative consequences. Our findings suggest dopaminergic augmentation of risk-taking behavior as a potential contributing mechanism for the emergence of ICD in PD patients. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Contributions of the dopaminergic system to voluntary and automatic orienting of visuospatial attention

Visuospatial attention can be directed by voluntary or involuntary control independent of eye movement. The involvement of cortical and subcortical neural structures in this covert orienting mechanism has been studied using neuroimaging and electrophysiological techniques. This study was designed to investigate the role of the dopaminergic system in both voluntary and automatic orienting mechanisms of visuospatial attention. We recorded event-related evoked potentials (ERPs) and reaction time (RT) during a cued priming task in both patients with idiopathic Parkinson's disease (PD) and control subjects. Voluntary and automatic shifts in attention were studied by using central and peripheral cues, respectively. In the experiment using a central cue, the RT data showed that when the cue-target interval was long, PD patients' responses were delayed, and cue validity effects were reduced, whereas in the peripheral cue experiment the validity effects persisted across all trials. The ERPs demonstrated reduced sustained negativities preceding the imperative targets in both the central and peripheral cue experiments in PD patients. Furthermore, during the long cue-target interval in the central cue experiment, PD patients showed reduced attention shift-related negativities (ARNs) at the anterior scalp sites, whereas ARNs were generated widely in the peripheral cue experiment. The ERP findings were consistent with the RT data. These findings suggest that the dopaminergic system may contribute to voluntary and sustained control of visuospatial attention as well as to the neural system for response preparation, whereas automatic control of visuospatial attention is relatively independent of the dopamine system.     

Polymorphisms of dopamine receptor and transporter genes and Parkinson's disease

Disturbances of the dopamine system are involved in the pathogenesis of idiopathic Parkinson's disease (PD). Although genetic factors may play a role in the etiology of PD, there is little direct evidence implicating a specific gene. We conducted a study to test the hypothesis that allelic variations of the dopamine receptors (D2, D3, D4) and the dopamine transporter (DAT) contribute to the susceptibility to PD. Association analyses of 70 Japanese PD patients and the same number of age-matched controls did not reveal any association between alleles of the D2, D3 or D4 receptor genes or the DAT gene and PD. Thus, our results suggest that factor(s) other than allelic variations of these key proteins in the dopamine system contribute to the susceptibility to PD.     

123I]beta-CIT and SPECT in essential tremor and Parkinson's disease

Resting and postural tremor may occur in essential tremor (ET) and Parkinson's disease (PD). The aim of the present study was to investigate the cocaine derivative [123I]beta-CIT, which labels striatal dopamine transporters, and SPECT in differentiating these diseases. METHODS: 30 healthy volunteers, 32 patients with ET and 29 patients with idiopathic PD of Hoehn/Yahr stage I were investigated. Specific over nondisplaceable binding ratios (target/cerebellum-1) were calculated for the striatum, the caudate nucleus and the putamen separately as well as a ratio putamen/caudate and the percent deviation of each patient's ratio from age-expected control values. RESULTS: Striatal [123I]beta-CIT binding ratios in ET were within normal ranges and showed only a discrete elevation to age-expected control values (+14.6%). In PD significantly reduced specific binding was evident not only contralaterally to the clinically affected side (putamen: -62%, caudate nucleus: -35%), but also ipsilaterally (putamen: -45%, caudate nucleus: -22%). All investigated parameters differed significantly between PD and controls and ET respectively. CONCLUSION: Imaging striatal dopamine transporters with [123I]beta-CIT and SPECT could clearly distinguish between ET and PD in an early stage of the disease. Findings do not suggest a subclinical involvement of dopaminergic nigrostriatal neurons in ET.     

Adenovirus-mediated gene transfer is augmented in basilar and carotid arteries of heritable hyperlipidemic rabbits

OBJECTIVE: Regional presynaptic dopaminergic function and its regulation by dopamine agonists in different stages of PD can be measured by L-[11C]dopa and PET. In the current investigation, we studied the effects of therapeutic apomorphine on L-[11C]dopa uptake in patients with early and advanced PD. BACKGROUND: With disease progression and chronic dopamine agonist treatment, motor response complications supervene in a majority of PD patients. It is assumed that both presynaptic and postsynaptic changes in the dopaminergic system act to modify dopaminergic efficacy. METHODS: Patients with early and advanced stages of PD were included in the study. All patients were investigated twice with PET and L-[11C]dopa drug free and during a subsequent standardized therapeutic apomorphine infusion. RESULTS: Subregional analysis of the striatum showed differences in the effects of apomorphine infusion on the L-[11C]dopa influx rate in the two patient categories. In patients with early and uncomplicated PD, apomorphine infusion decreased the L-[11C]dopa influx rate. This decrease was most pronounced in the dorsal part of the putamen. In advanced PD patients, apomorphine did not affect the striatal L-[11C]dopa influx rate. CONCLUSIONS: We suggest that in mild and stable PD an upregulated presynaptic inhibitory feedback regulation, particularly in the dorsal putamen, acts to maintain congruity within the dopaminergic system in response to antiparkinsonian medication. However, this inhibitory feedback regulation is diminished with the progression of nigrostriatal degeneration and chronic dopamine agonist treatment.     

Reproductive and productive performance in Chios ewes mated in spring or in autumn

To determine whether specific antibodies are present in PD, we used an enzyme-linked immunosorbant assay (ELISA) that identifies increased immunoglobulin (IgG) levels towards a synthetic substrate prepared by incubating ovalbumin with dopamine and copper sulfate. Altered absorption spectrum and specific chemical detection demonstrated quinone modification of the ovalbumin. This modified protein was demonstrated to react with serial dilutions of PD sera. A threshold dilution of 1:500 was subsequently used to screen sera from patients with PD (n = 21), amyotrophic lateral sclerosis (n = 7), Alzheimer's disease (n = 7) and other neurological disease controls (n = 7). The assay produced a positive result in 7/21 PD patients and 0/21 disease controls (P < 0.02, Kruskal-Wallis test). Further testing of sera from untreated PD patients (n = 6) identified one positive sample. Thus, a subset of Parkinson's disease (PD) patients has immunoglobulin (IgG) to ovalbumin modified by dopamine oxidation. The presence of antibody reactivity to quinone-modified proteins could contribute to or amplify the inflammatory response in PD.     

Bradykinesia and hypokinesia in Parkinson's disease: what's in a name?

Because in the literature bradykinesia and hypokinesia are frequently confounded, we assessed the relation between these two fundamental aspects of altered movement and the influence of disease severity on these measures in 41 patients with Parkinson's disease (PD) and 24 age-matched healthy controls. Bradykinesia was measured with a test microcomputer interfaced with a response-board. Hypokinesia was assessed by activity monitoring at home over a period of 5 successive days. For each subject the choice reaction time and measures reflecting bradykinesia (tap rate, movement time) and hypokinesia (movement index, duration of immobility periods) were calculated. Patients with PD had a normal choice reaction time and a significantly impaired execution of voluntary movement and reduced amount of movement over time. Bradykinesia was clearly present in the less affected patients with PD, and worsened as the disease severity increased. Hypokinesia, however, emerged prominently only in the more affected patients. There was a striking lack of relation between the measures that reflect bradykinesia and hypokinesia. The use of levodopa or dopamine agonists did not confound these findings. Our findings show the very different character and course of two tiers of altered movement in patients with PD and question the causative mechanisms of both motor features in PD. A more precise use of the terms brady- and hypokinesia is a prerequisite for future studies that attempt to provide insight in the causative mechanisms of both motor features.     

PD98059 is an equipotent antagonist of the aryl hydrocarbon receptor and inhibitor of mitogen-activated protein kinase kinase

Striatal dopamine transporter function and dopamine D2 receptor status were evaluated in 15 patients with early untreated Parkinson's disease using single photon emission tomography (SPECT) with 123I-Iodo-2beta-carboxymethoxy-3beta-(4-idiophenyl)tropane (beta-CIT) and 123I-Iodobenzamide (IBZM) as pre- and postsynaptic ligands. Symptoms were unilateral in five patients and bilateral but asymmetric in 10 patients. Patients with bilateral symptoms had significantly lower 18-hour striatal/cerebellar beta-CIT binding ratios (3.59 +/- 0.79) than hemiparkinsonian patients (5.76 +/- 1.48, p < 0.05) reflecting more advanced disease in this subgroup. Patients with bilateral parkinsonism were also found to have a significant side-to-side difference in striatal beta-CIT binding with more marked reduction contralateral to the presenting limb (18-hour striatal/cerebellar ratio: 4.13 +/- 0.78 [ipsilateral] versus 3.59 +/- 0.79 [contralateral], p < 0.05). Dopamine D2 receptor binding as measured by IBZM was significantly elevated contralateral to the affected side in hemiparkinsonian patients (striatal/cerebellar ratio: 2.42 +/- 0.90 [contralateral] versus 2.19 +/- 0.80 [ipsilateral], p < 0.05). This asymmetric upregulation was absent in the patients with bilateral parkinsonism (striatal/cerebellar ratio: 1.85 +/- 0.43 [contralateral to more severely affected side] versus 1.83 +/- 0.34 [ipsilateral], p > 0.05). Our data suggest that postsynaptic dopamine receptor upregulation contralateral to the presenting side occurs in untreated unilateral PD and disappears in untreated bilateral (asymmetric) PD despite a greater loss of dopamine transporter function. Combined beta-CIT and IBZM SPECT studies may be helpful to monitor the progression of nigrostriatal dysfunction in early PD.     

High and low activity alleles of catechol-O-methyltransferase gene: ethnic difference and possible association with Parkinson's disease

Catechol-O-methyltransferase (COMT) is an enzyme that inactivates catecholamines such as adrenaline, noradrenaline, dopamine, and levodopa. Recently an amino acid change (Val-108-Met) of the COMT protein was found to determine high and low activity alleles of the COMT gene. We genotyped 109 Japanese patients with Parkinson's disease (PD) and 153 controls by using polymerase chain reaction (PCR) amplification and digestion by the restriction enzyme NlaIII. The frequency of low activity allele in the controls was 0.29, which was significantly different from that reported in Caucasians (0.50). When comparison was made between patients with PD and controls, homozygosity for the low activity allele was significantly more common among the patients than among the controls (P = 0.017; odds ratio, 2.8, 95% CI 1.2-6.5), suggesting that homozygosity for the low activity allele may increase susceptibility to PD.     

The effects of target and distractor familiarity on visual search in de novo Parkinson's disease patients: Latent inhibition and novel pop-out.

De novo Parkinson's disease (PD) patients identified presence or absence of a unique shape presented with homogeneous distractors. Response time (RT) was examined as a function of prior experience with target and/or distractor assessing latent inhibition (LI; slower RTs to a target that was formerly a distractor against a background of distractors that were formerly targets as compared with a novel target with distractors that were formerly targets) and novel pop-out effects. PD patients were slower than controls in detecting test-phase targets compared with preexposure-phase targets. Female PD patients with right-side motor symptoms had elevated LI compared with female controls and female PD patients with left-side symptoms. Male PD patients with right-side symptoms did not exhibit LI. Results are discussed in terms of the dopamine hypothesis and the reciprocal relationship between PD and schizophrenia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In vivo studies on striatal dopamine D1 and D2 site binding in L-dopa-treated Parkinson's disease patients with and without dyskinesias

Dyskinesias are usually seen in Parkinson's disease (PD) patients after several years of L-dopa therapy. Their presence has been attributed to supersensitivity of striatal D1 and D2 receptors. We have used PET to assess striatal D2 receptor binding in untreated PD patients and striatal D1 and D2 binding in L-dopa-treated PD patients. Untreated patients showed a 14% increase in mean D2 receptor binding in the putamen contralateral to the more affected limbs (p < 0.02). Treated patients were segregated into subgroups according to the presence or absence of dyskinesias. There were no differences in mean caudate and putamen D1 and D2 binding between dyskinetic and nondyskinetic patients, matched for duration of clinical disease. Both dyskinetic and nondyskinetic PD subgroups showed a similar 16% reduction of mean caudate D2 binding (p < 0.01) with normal D2 binding in putamen. Mean caudate and putamen D1 binding potentials of both subgroups were reduced by 10% compared with those of controls, though this trend did not reach significance. Putamen D1 binding, however, showed a negative correlation with duration and L-dopa treatment (p < 0.03). These findings suggest that, while exposure of PD patients to L-dopa may be associated with reductions in caudate D2 and caudate and putamen D1 receptor, dyskinesias are unlikely to result from alterations in striatal dopamine receptor binding.     

Dopamine agonist-induced hypothermia and disruption of prepulse inhibition: evidence for a role of D3 receptors?

The dopamine D3/D2 receptor agonists 7-OH-DPAT, quinpirole, quinelorane, and PD128907, the mixed dopamine agonist apomorphine, the D2 agonist bromocriptine, and the D1/D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition (PPI) in Wistar rats. As dopamine agonist-induced hypothermia has been proposed as a model of D3 receptor function, and dopamine agonists are known to disrupt PPI, drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI. 7-OH-DPAT, quinpirole, quinelorane, PD128907, and apomorphine, reduced body temperature and disrupted PPI with a similar rank order of potency (quinelorane > quinpirole = 7-OH-DPAT > PD128907 = apomorphine). Bromocriptine and SKF38393 were ineffective in both models. In a separate study, the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI. In a final set of studies, the D2/D3 antagonist raclopride blocked both 7-OH-DPAT-induced hypothermia and 7-OH-DPAT-induced PPI disruption. The 5-HT1A antagonist WAY 100,135, and the peripheral D2-like antagonist domperidone had no effect. These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors; however, only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors.     

Conjugates of catecholamines with cysteine and GSH in Parkinson's disease: possible mechanisms of formation involving reactive oxygen species

Oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine (DA) to generate semiquinones/quinones, oxygen radicals, and other reactive oxygen species may play a role in neuronal cell death in Parkinson's disease (PD). In particular, semiquinones/quinones can form conjugates with thiol compounds such as GSH and cysteine. Exposure of L-DOPA, DA, and other catecholamines to a system generating O2.- radical led to O2(.-)-dependent depletion of added GSH (or cysteine), accompanied by the formation of thiol-DA or -DOPA adducts as detected by HPLC. Superoxide could additionally cause destruction of these adducts. Iron or copper ions could also promote conjugate formation between GSH or cysteine and DA and L-DOPA, especially if H2O2 was present. We applied HPLC to measure glutathionyl and cysteinyl conjugates of L-DOPA, DA, and 3,4-dihydroxyphenylacetic acid (DOPAC) in postmortem brain samples from PD patients and normal control subjects. Conjugates were detected in most brain areas examined, but levels were highest in the substantia nigra and putamen. In most regions, adduct levels were lower in PD, but there were significant increases in cysteinyl adducts of L-DOPA, DA, and DOPAC in PD substantia nigra, suggesting that acceleration of L-DOPA/DA oxidation occurs in PD, although we cannot say if this is a primary feature of the disease or if it is related to therapy with L-DOPA. In vitro, conjugate formation could be inhibited by the dithiol dihydrolipoate but not by its oxidised form, lipoic acid.     

Motor response to a dopamine D3 receptor preferring agonist compared to apomorphine in levodopa-primed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys

The profile of dopamine receptor subtype activation contributing to the therapeutic efficacy and motor response complications of levodopa (nonselective pro-agonist) in Parkinson's disease remains unclear. Potent, selective, short-acting dopamine D2 receptor subfamily agonists show good antiparkinsonian efficacy but produce dyskinesias comparable to levodopa. Nonetheless, agonists displaying higher affinity for dopamine receptors other than the D2 subtype may have a better therapeutic index. To clarify this issue, we compared the nonselective dopamine D1/D2 receptor subfamilies agonist apomorphine to the dopamine D3 receptor preferring agonist [R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4 , 3-b]-1,4-oxazin-9-ol] (PD 128,907) in 6 levodopa-primed , 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian monkeys with reproducible dyskinesias. Single s.c. dosing with the lowest fully effective dose of apomorphine (averaging 27.9 +/- 4.5 microg/kg) and PD 128,907 (averaging 41.7 +/- 4.4 microg/kg) yielded equivalent antiparkinsonian efficacy on the behavioral scale and portable activity monitoring used. A comparable significant dose-dependent increase in the response magnitude and duration was seen with two higher doses. The severity of dyskinesia was also similar between the two drugs. When the lower dose for each drug was administered six times at a fixed 90-min interval, both drugs remained efficacious with no significant tolerance observed. The D3 receptor preferring antagonist U-99194A significantly reduced the motor effects of both apomorphine and PD 128,907. Thus, increased D3 receptor tone does not acutely ameliorate dyskinesias in levodopa-primed parkinsonian monkeys. Given the reported lack of affinity of PD 128,907 for central D1 receptors, our data support the concept that the pharmacological activation of D1 receptors is not mandatory for relief of parkinsonism and production of dyskinesia.     

Clinical neurochemistry: developments in dementia research based on brain bank material

Brain tissue obtained at autopsy continues to provide unique opportunities in current dementia research. Not only is tissue analysis still essential for diagnosis, but investigation of neurochemical pathology, at a level of resolution beyond current in vivo imaging, continues to provide new insights into the involvement of neurotransmitter signalling systems. These are relevant to therapy which, with respect to symptoms such as cognitive impairment, psychosis and depression, is currently targeted to specific transmitter (cholinergic, dopaminergic and serotonergic) systems. This paper focuses on dopaminergic, cholinergic and histaminergic parameters in Alzheimer's disease (AD), Dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In the normal striatum the dopamine transporter and D2 receptor exhibit distinct rostral-caudal distributions and D2 binding is affected by genetic polymorphism at the Taq 1A locus. The transporter is reduced in both DLB and PD but not AD, correlating with severity of extrapyramidal dysfunction, and receptor abnormalities are apparent in DLB patients responding adversely to neuroleptics. Striatal nicotine receptors are lost in all 3 disorders, further reduced as a result of neuroleptic medication, and elevated as a result of tobacco use. In the thalamus there are selective reductions in presynaptic cholinergic activity in DLB in the reticular nucleus which relate to symptoms of hallucinations and fluctuating consciousness prevalent in this disorder. In the hippocampus coupling of muscarinic M1 receptors, relevant to response to cholinergic therapy, is impaired in areas most affected by beta-amyloid plaques and intact in less affected areas. Analysis of histamine H2 receptors indicates that, despite presynaptic histamine abnormalities in AD, receptor numbers are normal. Such clinically and therapeutically relevant observations on human brain neurochemistry provide a basis for improving therapeutic strategies and prospects of diagnostic in vivo chemical imaging.     

Novel antipsychotic-like effects on prepulse inhibition of startle produced by a neurotensin agonist

Agonists of the neuropeptide neurotensin have been proposed as potential novel antipsychotics based on their ability to modulate neurotransmission in brain regions associated with schizophrenia. To test this hypothesis, we examined the effects of a neurotensin mimetic with improved metabolic stability in an animal model with strong predictive validity for antipsychotic activity. Subcutaneous injections of PD149163, a reduced amide neurotensin(8-13) mimetic, significantly antagonized the reduction of prepulse inhibition (PPI) of the rat startle reflex produced by amphetamine and by the phencyclidine analog dizocilpine. PD149163 had no significant effect on baseline PPI or on baseline startle amplitude and did not antagonize the reduction of PPI produced by the direct dopamine agonist apomorphine. These findings suggest that PD149163 has novel antipsychotic-like properties that are distinct from known members of both the "typical" and "atypical" families of antipsychotics.