Striatal Dopaminergic Neurotransmission Research Articles

Increased striatal dopamine transporter density in moderately severe old restless legs syndrome patients

Dopamine dysregulation in restless legs syndrome (RLS) may be varied by the severity of RLS, which could contribute to the conflicting results from previous functional neuroimaging studies on the central dopaminergic neurotransmission of RLS. The aim of this study was to observe whether reduced striatal dopaminergic neurotransmission is associated with moderate to moderately severe RLS. Thirteen elderly patients with RLS and 12 normal elderly controls were enrolled in the study. All the subjects were dopaminergic-drug naïve and twelve patients with RLS had the severity of moderate to moderately severe degree based on the International Restless Legs Syndrome Study Group (IRLSSG) Severity Scale. We compared dopamine transporter density (DAT) availability and D2 receptor density in the striatum between patients with RLS and controls using [(123)I]2β-carbomethoxy-3β-(4-iodophenyl)tropane single-photon emission computed tomography (SPECT) and [(123)I]iodobenzamide SPECT. Dopamine transporter density of patients with RLS was increased in the caudate (P = 0.037), posterior putamen (P = 0.041), and entire striatum (P = 0.046) compared with that of normal controls. DAT density was higher in the anterior putamen of patients with RLS than controls, although statistically not significant (P = 0.079). There was no difference in the D2 receptor density between patients with RLS and normal controls in the whole striatum or any of subregions. Dysregulation rather than simple upregulation or downregulation of central dopaminergic neurotransmission may underlie the pathogenesis of RLS, and decreased dopaminergic neurotransmission may cause moderate to moderately severe RLS in the elderly.

Striatal Presynaptic Dopamine in Schizophrenia, Part I: Meta-Analysis of Dopamine Active Transporter (DAT) Density

Striatal dopaminergic neurotransmission has been postulated to be fundamental to the emergence of key symptoms of schizophrenia, such as psychotic symptoms, and is targeted by currently available dopaminergic drugs. A specific marker of the integrity of presynaptic dopamine neurons in the striatum, the density of striatal dopamine terminals, can be quantified through molecular neuroimaging of the dopamine active transporter (DAT). However, the currently available results using this approach in schizophrenia are inconsistent. Thirteen Single Photon Emission Tomography or Positron Emission Tomography (PET) studies investigating DAT density in the striatum of schizophrenic patients and matched controls were included in a quantitative meta-analysis. Binding potentials in the striatum, caudate, and putamen, as well as demographic, clinical, and methodological variables, were extracted from each publication. Hedges' g was used as a measure of effect size. The overall database contained 202 subjects with schizophrenia and 147 controls, well matched with respect to sociodemographic variables. Striatal DAT density was not significantly different between patients and controls. Similar negative findings were regionally confirmed in the putamen and caudate. There was no moderating effect for external factors. Our meta-analysis uncovered no evidence indicating altered density of striatal dopamine terminals in schizophrenia. Moreover, striatal DAT density did not seem to be influenced by antipsychotic medication or illness duration. Our data suggest that altered integrity of striatal dopaminergic synapses is not critical for the emergence of schizophrenia or its treatment. These findings should be useful in further refining dopaminergic hypotheses of schizophrenia.

History of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability

Cannabis use in adolescence is emerging as a risk factor for the development of psychosis. In animal studies, Δ9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, modulates striatal dopaminergic neurotransmission. Alterations in human striatal dopaminergic function have also been reported both in psychosis and in stimulant use. We sought to examine whether striatal dopamine D(2)/D(3) receptor availability was altered in volunteers with a history of cannabis use using a database of previously acquired [(11)C]-raclopride positron emission tomography (PET) scans. Ten [(11)C]-raclopride scans from volunteers with a history of cannabis use were compared to ten control scans using a functional striatal subdivision region of interest (ROI) analysis. No significant differences in either overall striatal BP(ND) values or BP(ND) values in any functional striatal subdivision were found between the two groups. There was also no correlation between lifetime frequency of cannabis use and BP(ND) values. Limbic striatal BP(ND) values were ten percent lower in current nicotine cigarette smokers. These findings suggest that, unlike other drugs of abuse, a history of cannabis use is not associated with alterations in striatal dopamine D(2)/D(3) receptor availability.

Optimizing functional imaging protocols for assessing the outcome of fetal cell transplantation in Parkinson's disease

Clinical trials aiming to assess the safety and efficacy of fetal cell transplantation in Parkinson's disease rely on the hypothesis that the grafted tissue will survive and grow, restore striatal dopaminergic neurotransmission, improve the connectivity between striatum, thalamus and cortex and, thereby, produce long-lasting clinical improvement while avoiding the development of adverse effects. Although transplantation of human fetal ventral mesencephalic tissue has been reported as one of the most effective reparative therapies in Parkinson's disease patients to date, different studies have shown inconsistent results causing a paucity of new trials over the last decade. However, during this period, functional imaging alongside other scientific developments from clinical observations and animal work has significantly aided in understanding the mechanisms responsible for the success or failure of grafting human fetal tissue. Recent advances in functional imaging including both positron emission tomography and functional magnetic resonance imaging could be proven useful in vivo tools for the development and assessment of new clinically competitive trials. In this commentary we discuss how an optimized functional imaging protocol could assist new clinical trials using fetal cell transplantation in Parkinson's disease.

Dopaminergic Genes Predict Individual Differences in Susceptibility to Confirmation Bias

The striatum is critical for the incremental learning of values associated with behavioral actions. The prefrontal cortex (PFC) represents abstract rules and explicit contingencies to support rapid behavioral adaptation in the absence of cumulative experience. Here we test two alternative models of the interaction between these systems, and individual differences thereof, when human subjects are instructed with prior information about reward contingencies that may or may not be accurate. Behaviorally, subjects are overly influenced by prior instructions, at the expense of learning true reinforcement statistics. Computational analysis found that this pattern of data is best accounted for by a confirmation bias mechanism in which prior beliefs--putatively represented in PFC--influence the learning that occurs in the striatum such that reinforcement statistics are distorted. We assessed genetic variants affecting prefrontal and striatal dopaminergic neurotransmission. A polymorphism in the COMT gene (rs4680), associated with prefrontal dopaminergic function, was predictive of the degree to which participants persisted in responding in accordance with prior instructions even as evidence against their veracity accumulated. Polymorphisms in genes associated with striatal dopamine function (DARPP-32, rs907094, and DRD2, rs6277) were predictive of learning from positive and negative outcomes. Notably, these same variants were predictive of the degree to which such learning was overly inflated or neglected when outcomes are consistent or inconsistent with prior instructions. These findings indicate dissociable neurocomputational and genetic mechanisms by which initial biases are strengthened by experience.

EFFECT OF DEXAMETHASONE ON STRIATAL NEUROTRANSMISSIONS IN THE RATS SUBJECTED TO PARKINSON’S DISEASE ANIMAL MODEL

Objective(s) The aim of this study was to evaluate the effects of dexamethasone on striatal dopaminergic, glutamatergic and gamma amino butyric acid (GABA) ergic neurotransmission in normal and parkinsonian rats. Materials and Methods Dexamethasone (0.15, 0.30, 0.60 and 0.8 mg/kg) was administered to normal or parkinsonian rats (i.p.) followed by the analysis of the striatal neurotransmitters concentrations. Additionally, the effect of dexamethasone on the damaged Substantia nigra pars compata (SNc) neurons has been investigated. Results Dexamethasone resulted in decreased level of striatum glutamatergic-GABAergic and enhanced dopaminergic neurotransmission in normal and parkinsonian rats. In addition, acute treatment with dexamethasone did not improve the lesion at all. Conclusion These findings suggest the new therapeutic mechanism of action for dexamethasone in Parkinson’s disease animal model.

Availability of brain serotonin transporters in patients with restless legs syndrome

Selective serotonin reuptake inhibitors have been associated with the risk of restless legs syndrome (RLS), suggesting that dysregulation of serotonergic neurotransmission may provoke or exacerbate RLS. We compared the availability of serotonin transporter (SERT) between 16 drug-naïve patients with RLS and 16 healthy controls. SERT was measured in the pons and medulla via [(123)I]-2beta-carbomethoxy-3beta-(4-iodophenyl) tropane (beta-CIT) SPECT. A ratio of specific to nonspecific brain uptake (V(3)'') was used for all comparisons. RLS was diagnosed according to the criteria proposed by the National Institute of Health, and its severity was measured using the International RLS Study Group (IRLSSG) Severity Scale. The availability of SERT was similar in the RLS group and the control group with regards to the pons (1.24 +/- 0.31 vs 1.24 +/- 0.25, p > 0.1) and the medulla (0.99 +/- 0.25 vs 1.00 +/- 0.23, p > 0.1). However, IRLSSG Severity Scale scores increased with decrease of SERT availability in both the pons (beta = -0.50, t = -3.19, p = 0.009) and the medulla (beta = -0.42, t = -2.44, p = 0.03). Although serotonin transporter (SERT) availability in pons and medulla was similar in the restless legs syndrome (RLS) group and the control group, the severity of RLS symptoms increased as the availability of SERT decreased. These data partially support the hypothesis that an increase of serotonergic neurotransmission in the brainstem may exacerbate RLS, possibly via dual modulations on striatal dopaminergic neurotransmission and on the activities of spinal motor and sensory neurons.

Activation of calcium/calmodulin-dependent protein kinase IIα in the striatum by the heteromeric D1-D2 dopamine receptor complex

Synaptic plasticity in the striatum is a key mechanism that underlies processes such as reward related incentive learning and behavioral habit formation resulting from drugs of abuse. Key aspects of these functions are dependent on dopamine transmission as well as activation of calcium/calmodulin-dependent protein kinase IIα (CaMKIIα). In this study, we examined the ability of a recently identified heteromeric complex composed of D1 and D2 dopamine receptors coupled to Gq/11 to activate striatal CaMKIIα. Using the dopaminergic agonist SKF83959, which selectively activates the D1-D2 complex, we demonstrated phosphorylation of CaMKIIα at threonine 286, both in heterologous cells and in the murine striatum in vivo. Phosphorylation of CaMKIIα by activation of the receptor complex required concurrent agonism of both D1 and D2 receptors and was independent of receptor pathways that modulated adenylyl cyclase. The identification of this novel mechanism by which dopamine may modulate synaptic plasticity has implications for our understanding of striatal-mediated reward and motor function, as well as neuronal disorders in which striatal dopaminergic neurotransmission is involved.

Substantia nigra echogenicity: A structural correlate of functional impairment of the dopaminergic striatal projection in Parkinson's disease

Transcranial sonography (TCS) reveals abnormal spatial extension of substantia nigra (SN) echogenicity in a high proportion of patients with Parkinson's disease (PD). It has been proposed that this abnormality represents a structural trait that is mechanistically distinct from degeneration of dopaminergic nigrostriatal projection neurons. We sought to clarify the relationship between sonographic abnormalities of SN and dysfunction of striatal dopaminergic neurotransmission. We studied 50 patients with PD. The spatial extension of the echogenic SN area was compared with the activity of presynaptic striatal dopamine reuptake transporters, assessed in the same patients by I-123-2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane (beta-CIT) single-photon emission computed tomography (SPECT). Extension of echogenic SN area correlated (inversely) with striatal activity of presynaptic dopamine reuptake transporter in PD patients (R = -0.417; P = 0.003) and with the equivalent levodopa dose (R = 0.380; P = 0.006; linear regression analysis). Findings support the hypothesis that in PD abnormal extension of echogenic SN area provides a direct structural marker of degeneration of SN neurons. Therefore, in PD, TCS and beta-CIT assess pathophysiologically related phenomena.

Steroidal anti inflammatory drug betamethasone significantly alters level of striatal dopamine in a rat model of Parkinson’s disease

AbstractMany scientific efforts have been well done to investigate the effects of anti inflammatory agents on the degenerative brain diseases such as Parkinson’s (PD) or Alzheimer’s disease and their affiliated sings. Previously we showed the effectiveness of steroids on rigidity of PD and in the study for further mechanistic investigation of that observation the microdialysis technique was employed to determine the striatal dopamine changes in parkinsonian rats after administration of betamethasone (0.12, 0.24 mg/kg) respectively. Our findings showed us the significant increase in the striatal dopaminergic neurotransmission (P<0.05) after administration of betamethasone comparing to the controls. These observations suggest a new mechanism for betamethasone on striatum dopaminergic neurotransmission leading us to gather further evidence about effectiveness of betamethasone in PD.

Dopaminergic but Not Glutamatergic Neurotransmission Is Increased in the Striatum after Selective Cyclooxygenase‐2 Inhibition in Normal and Hemiparkinsonian Rats

In the present work, we studied the effect of the selective cyclooxygenase-2 (COX-2) inhibitors, compound 11 g, celecoxib and selective COX-1 inhibitor SC-560 (intraperitoneally and acutely) on striatal glutamatergic and dopaminergic neurotransmission in normal and substantia nigra pars compacta (SNc)-lesioned rats using the microdialysis technique. We also investigated the effect of acute COX inhibition on the damaged SNc neurons. Our results indicate a significant increase in dopaminergic neurotransmission and a decrease in glutamatergic neurotransmission (P<0.05) only after selective COX-2 inhibition in the striatum of normal and hemiparkinsonian rats. Nonetheless, neither COX-1 nor COX-2 inhibitors showed any improvement in the damaged SNc neurons.

Characterization of the striatal dopaminergic neurotransmission in MEN2B mice with elevated cerebral tissue dopamine

The Ret receptor tyrosine kinase is the common signaling receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands. The Met918Thr mutation leads to constitutive activation of Ret and is responsible for dominantly inherited cancer syndrome MEN2B. Previously, we found that the mice carrying the mutation (MEN2B mice) have profoundly increased tissue dopamine (DA) concentrations in the striatum as well as increased striatal levels of tyrosine hydroxylase (TH) and dopamine transporter. The aim of this study was to characterize the striatal dopaminergic neurotransmission in MEN2B mice and to clarify the mechanisms by which they compensate their over-production of DA. We found that tyrosine hydroxylase activity and DA synthesis are increased in MEN2B mice. Augmented effects of alpha-methyl-para-tyrosine (alphaMT, an inhibitor of TH) and tetrabenazine (VMAT2 blocker) on DA levels suggest that also storage of DA is increased in MEN2B mice. There was no difference in the basal extracellular DA concentrations or potassium-evoked DA release between the genotypes. The effects of cocaine and haloperidol were also similar between the genotypes as assessed by in vivo microdialysis. However, with in vivo voltammetry we found increase in stimulated DA release in MEN2B mice and detailed analysis of DA overflow showed that uptake of DA was also enhanced in MEN2B mice. Thus, our data show that enhanced synthesis of DA leading to increased storage and releasable pools in pre-synaptic terminals in MEN2B mice apparently also leads to increased DA release, which in turn is compensated by higher dopamine transporter activity.

Ratio of dopamine synthesis capacity to D2 receptor availability in ventral striatum correlates with central processing of affective stimuli

Dopaminergic neurotransmission in the ventral striatum may interact with limbic processing of affective stimuli, whereas dorsal striatal dopaminergic neurotransmission can affect habitual processing of emotionally salient stimuli in the pre-frontal cortex. We investigated the dopaminergic neurotransmission in the ventral and dorsal striatum with respect to central processing of affective stimuli in healthy subjects. Subjects were investigated with positron emission tomography and [(18)F]DOPA for measurements of dopamine synthesis capacity and [(18)F]DMFP for estimation of dopamine D2 receptor binding potential. Functional magnetic resonance imaging was used to assess the blood-oxygen-level-dependent (BOLD) response to affective pictures, which was correlated with the ratio of [(18)F]DOPA net influx constant K(app)(in)/[(18)F]DMFP-binding potential (BP_ND) in the ventral and dorsal striatum. The magnitude of the ratio in the ventral striatum was positively correlated with BOLD signal increases elicited by negative versus neutral pictures in the right medial frontal gyrus (BA10), right inferior parietal lobe and left post-central gyrus. In the dorsal striatum, the ratio was positively correlated with BOLD signal activation elicited by negative versus neutral stimuli in the left post-central gyrus. The BOLD signal elicited by positive versus neutral stimuli in the superior parietal gyrus was positively correlated with the dorsal and ventral striatal ratio. The correlations of the ratio in the ventral and dorsal striatum with processing of affective stimuli in the named cortical regions support the hypothesis that dopamine transmission in functional divisions of the striatum modulates processing of affective stimuli in specific cortical areas.

Subacute H2O2, but not poly(IC), upregulates dopamine D2 receptors in retinoic acid differentiated SH‐SY5Y neuroblastoma

Abnormalities of striatal dopaminergic neurotransmission play a significant role in the pathophysiology of central nervous system disorders such as movement disorders, addictions and schizophrenia. The striatum appears to be exposed to intrinsically high levels of oxidative stress (OS). Little is known, however, on the effect of OS on the regulation of the dopamine D2 receptor (DRD2), a key component of striatal dopaminergic neurotransmission. We report here on the effects of H2O2 (a canonical oxidant and non conventional messenger) and polyinosinic-polycytidylic acid (poly(IC) which elicits schizophrenia-like behaviors in newborn rodents and disrupts dopaminergic system development), on DRD2 levels in retinoic acid differentiated SH-SY5Y neuroblastoma. H2O2 elicited a significant increase in DRD2 mRNA and protein levels. Conversely, poly(IC) did not regulate DRD2 levels, although SH-SY5Y cells were confirmed to express TLR3 receptors. Under our conditions, H2O2, but not poly(IC), increased NFkappaB activation (as assessed by p65 nuclear translocation), which paralleled their effects on DRD2 levels regulation.

Evaluation of neuronal phosphoproteins as effectors of caffeine and mediators of striatal adenosine A 2A receptor signaling

Adenosine A 2A receptors are predominantly expressed in the dendrites of enkephalin-positive γ-aminobutyric acidergic medium spiny neurons in the striatum. Evidence indicates that these receptors modulate striatal dopaminergic neurotransmission and regulate motor control, vigilance, alertness, and arousal. Although the physiological and behavioral correlates of adenosine A 2A receptor signaling have been extensively studied using a combination of pharmacological and genetic tools, relatively little is known about the signal transduction pathways that mediate the diverse biological functions attributed to this adenosine receptor subtype. Using a candidate approach based on the coupling of these receptors to adenylate cyclase-activating G proteins, a number of membranal, cytosolic, and nuclear phosphoproteins regulated by PKA were evaluated as potential mediators of adenosine A 2A receptor signaling in the striatum. Specifically, the adenosine A 2A receptor agonist, CGS 21680, was used to determine whether the phosphorylation state of each of the following PKA targets is responsive to adenosine A 2A receptor stimulation in this tissue: Ser40 of tyrosine hydroxylase, Ser9 of synapsin, Ser897 of the NR1 subunit of the N-methyl- d-aspartate-type glutamate receptor, Ser845 of the GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptor, Ser94 of spinophilin, Thr34 of the dopamine- and cAMP-regulated phosphoprotein, M r 32,000, Ser133 of the cAMP-response element-binding protein, Thr286 of Ca 2+/calmodulin-dependent protein kinase II, and Thr202/Tyr204 and Thr183/Tyr185 of the p44 and p42 isoforms, respectively, of mitogen-activated protein kinase. Although the substrates studied differed considerably in their responsiveness to selective adenosine A 2A receptor activation, the phosphorylation state of all postsynaptic PKA targets was up-regulated in a time- and dose-dependent manner by treatment with CGS 21680, whereas presynaptic PKA substrates were unresponsive to this agent, consistent with the postsynaptic localization of adenosine A 2A receptors. Finally, the phosphorylation state of these proteins was further assessed in vivo by systemic administration of caffeine.

Striatal dopamine release after prefrontal repetitive transcranial magnetic stimulation in major depression: Preliminary results of a dynamic [ 123I] IBZM SPECT study

Though there is considerable evidence that prefrontal repetitive transcranial magnetic stimulation (rTMS) exerts antidepressant effects, the neurobiological action of rTMS in patients with depression is poorly understood. Preclinical studies in animals and humans have demonstrated that prefrontal rTMS can induce dopamine release in mesostriatal and mesolimbic regions. We therefore investigated whether rTMS also modulates striatal dopaminergic neurotransmission in depressed patients using a dynamic [ 123I] iodobenzamide (IBZM) single photon emission computed tomography (SPECT) approach. Five patients with a major depressive episode (DSM-IV) underwent an acute 10 Hz rTMS challenge with 3000 stimuli over the left dorsolateral prefrontal cortex during an [ 123I] IBZM-SPECT bolus and constant infusion protocol. In four subjects the protocol was repeated after a three week rTMS standard treatment. Striatal IBZM binding to dopamine D 2 receptors was assessed with a region-of-interest (ROI) technique. The change in striatal IBZM binding after the rTMS challenge was regarded as measure of change in endogenous striatal dopamine. Data of nine SPECT investigations showed a significant reduction by 9.6 ± 6.2% in IBZM binding to striatal dopamine D 2 receptors after rTMS challenge compared to baseline ( p = 0.01, Wilcoxon test). In this preliminary study, the reduction of IBZM binding observed after rTMS challenge is suggestive of a release in endogenous dopamine induced by prefrontal rTMS. In future, this approach can be used to differentiate specific and non-specific reward-related effects of rTMS on dopaminergic neurotransmission.

Adenosine receptor‐mediated modulation of dopamine release in the nucleus accumbens depends on glutamate neurotransmission and N‐methyl‐d‐aspartate receptor stimulation

Adenosine, by acting on adenosine A(1) and A(2A) receptors, exerts opposite modulatory roles on striatal extracellular levels of glutamate and dopamine, with activation of A(1) inhibiting and activation of A(2A) receptors stimulating glutamate and dopamine release. Adenosine-mediated modulation of striatal dopaminergic neurotransmission could be secondary to changes in glutamate neurotransmission, in view of evidence for a preferential colocalization of A(1) and A(2A) receptors in glutamatergic nerve terminals. By using in vivo microdialysis techniques, local perfusion of NMDA (3, 10 microm), the selective A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680; 3, 10 microm), the selective A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 300, 1000 microm), or the non-selective A(1)-A(2A) receptor antagonist in vitro caffeine (300, 1000 microm) elicited significant increases in extracellular levels of dopamine in the shell of the nucleus accumbens (NAc). Significant glutamate release was also observed with local perfusion of CGS 21680, CPT and caffeine, but not NMDA. Co-perfusion with the competitive NMDA receptor antagonist dl-2-amino-5-phosphonovaleric acid (APV; 100 microm) counteracted dopamine release induced by NMDA, CGS 21680, CPT and caffeine. Co-perfusion with the selective A(2A) receptor antagonist MSX-3 (1 microm) counteracted dopamine and glutamate release induced by CGS 21680, CPT and caffeine and did not modify dopamine release induced by NMDA. These results indicate that modulation of dopamine release in the shell of the NAc by A(1) and A(2A) receptors is mostly secondary to their opposite modulatory role on glutamatergic neurotransmission and depends on stimulation of NMDA receptors. Furthermore, these results underscore the role of A(1) vs. A(2A) receptor antagonism in the central effects of caffeine.

Abnormalities of dopaminergic neurotransmission in SCA2: a combined 123I-betaCIT and 123I-IBZM SPECT study.

Extrapyramidal features may occur in spinocerebellar ataxias consistent with neuropathological evidence of nigrostriatal involvement. Recently, striatal dopaminergic neurotransmission was found to be abnormal in the uncommon parkinsonian presentation of spinocerebellar ataxia type 2 (SCA2). We have investigated, therefore, striatal dopamine transporter and D2 receptor function in a series of 9 patients with the more common ataxic presentation of SCA2 using single photon emission computed tomography and beta-CIT as well as IBZM. Age-matched healthy subjects and patients with Parkinson's disease (PD) served as controls. All except 1 SCA2 patient exhibited slowness of limb movements without rigidity or rest tremor. In addition, cervical dystonia was present in 5 and dystonic head tremor in 2 SCA2 patients. Striatocerebellar (S/C) ratios of beta-CIT binding were significantly reduced in SCA2 patients compared to control subjects, and they were within the range of PD patients. S/C ratios of IBZM binding were significantly reduced in SCA2 patients compared to control subjects. We conclude that dopaminergic neurotransmission is impaired in the ataxic presentation of SCA2, with a prominent loss of striatal dopamine transporter function. Both slowness of limb movements as well as dystonia in the ataxic SCA2 phenotype may reflect dysfunction not only at cerebellar but also at basal ganglia level.

Molecular brain imaging and the neurobiology and genetics of schizophrenia.

It has been hypothesized that schizophrenia is related to dysfunction in temporolimbic-prefrontal neuronal networks, which is acquired early in an individual's development. After puberty, relatively reduced prefrontal control of striatal dopaminergic neurotransmission may lead to unmodulated striatal dopamine (DA) activity, and the positive symptoms of acute psychosis. Brain imaging studies support the notion of prefrontal dysfunction in schizophrenia and correlated upregulation of presynaptic striatal DA activity. Recent molecular brain imaging studies have combined genetic assessments with a multimodal neuroimaging approach to further refine our understanding of the pathophysiologic architecture of the disorder. We review the literature on functional brain imaging in schizophrenia and discuss genotype effects on core psychotic symptoms. A promising research strategy is the identification of genetic and environmental factors that contribute to intermediate phenotypes such as working memory deficits in schizophrenia. Molecular brain imaging can help to unravel the complex interactions between genes and environment and its association with neuronal network dysfunction in schizophrenia.

Multiple muscarinic acetylcholine receptor subtypes modulate striatal dopamine release, as studied with M1-M5 muscarinic receptor knock-out mice.

A proper balance between striatal muscarinic cholinergic and dopaminergic neurotransmission is required for coordinated locomotor control. Activation of striatal muscarinic acetylcholine receptors (mAChRs) is known to modulate striatal dopamine release. To identify the mAChR subtype(s) involved in this activity, we used genetically altered mice that lacked functional M1-M5 mAChRs [knock-out (KO) mice]. In superfused striatal slices from wild-type mice, the non-subtype-selective muscarinic agonist oxotremorine led to concentration-dependent increases in potassium-stimulated [3H]dopamine release (by up to 60%). The lack of M1 or M2 receptors had no significant effect on the magnitude of these responses. Strikingly, oxotremorine-mediated potentiation of stimulated striatal [3H]dopamine release was abolished in M4 receptor KO mice, significantly increased in M3 receptor-deficient mice, and significantly reduced (but not abolished) in M5 receptor KO mice. Additional release studies performed in the presence of tetrodotoxin suggested that the dopamine release-stimulating M4 receptors are probably located on neuronal cell bodies, but that the release-facilitating M5 and the release-inhibiting M3 receptors are likely to be located on nerve terminals. Studies with the GABA(A) receptor blocker bicuculline methochloride suggested that M3 and M4 receptors mediate their dopamine release-modulatory effects via facilitation or inhibition, respectively, of striatal GABA release. These results provide unambiguous evidence that multiple mAChR subtypes are involved in the regulation of striatal dopamine release. These findings should contribute to a better understanding of the important functional roles that the muscarinic cholinergic system plays in striatal function.