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Introduction The differentiated cell state has been traditionally considered irreversible and insensitive to epigenetic modifications. Nevertheless, in contrast with this classical view, accumulating evidence indicates that cell identity relies on [...], Direct lineage reprogramming through genetic-based strategies enables the conversion of differentiated somatic cells into functional neurons and distinct neuronal subtypes. Induced dopaminergic (iDA) neurons can be generated by direct conversion of skin fibroblasts; however, their in vivo phenotypic and functional properties remain incompletely understood, leaving their impact on Parkinson's disease (PD) cell therapy and modeling uncertain. Here, we determined that iDA neurons retain a transgene- independent stable phenotype in culture and in animal models. Furthermore, transplanted iDA neurons functionally integrated into host neuronal tissue, exhibiting electrically excitable membranes, synaptic currents, dopamine release, and substantial reduction of motor symptoms in a PD animal model. Neuronal cell replacement approaches will benefit from a system that allows the activity of transplanted neurons to be controlled remotely and enables modulation depending on the physiological needs of the recipient; therefore, we adapted a DREADD (designer receptor exclusively activated by designer drug) technology for remote and real- time control of grafted iDA neuronal activity in living animals. Remote DREADD-dependent iDA neuron activation markedly enhanced the beneficial effects in transplanted PD animals. These data suggest that iDA neurons have therapeutic potential as a cell replacement approach for PD and highlight the applicability of pharmacogenetics for enhancing cellular signaling in reprogrammed cell-based approaches.

Introduction The semantic priming effect refers to the observation that reaction times (i.e., pronunciation or speeded lexical decision) to a target word, such as 'dog' are faster when the word [...], Background: Enhanced automatic spreading of activation in the semantic network has been suggested to underlie formal thought disorder in patients with schizophrenia, but it is not clear how this relates to the dopaminergic dysfunction implicated in the disorder. Previous studies on dopaminergic modulation of priming in healthy volunteers have focused on controlled rather than automatic processes. The present study aimed to examine the effects of both a dopaminergic agonist and a dopaminergic antagonist on semantic priming while minimizing the contribution of controlled processes. Methods: We investigated the effects of levodopa (L-Dopa; 100 mg), haloperidol (2 mg) and placebo on priming in healthy participants within a randomized, double-blind, crossover design. We used a pronunciation priming task with word triplets; the middle word was an ambiguous word, whereas the first word of the triplet served to provide either a congruent, incongruent or unbiased context for the target word. Two stimulus onset asynchronies (SOA) were used: 150 ms and 750 ms. Results: The study involved 34 participants. At an SOA of 150 ms, L-Dopa accelerated responses to incongruent targets and subordinate targets of ambiguous words, whereas haloperidol was associated with faster responses in congruent contexts and dominant targets. At an SOA of 750 ms, haloperidol accelerated responses to subordinate targets. Limitations: Modulations in the relative magnitude of priming according to substance and condition rather than absolute priming were assessed. Conclusion: Effects of L-Dopa on automatic priming processes appear to be different than those on controlled processes. Our results are consistent with those of studies on semantic priming and the effects on antipsychotics in patients with schizophrenia.

The 'One neuron-one neurotransmitter' concept has been challenged frequently during the last three decades, and the coexistence of neurotransmitters in individual neurons is now regarded as a common phenomenon. The functional significance of neurotransmitter coexistence is, however, less well understood: Several studies have shown that a subpopulation of dopamine (DA) neurons in the ventral tegmental area (VTA) expresses the vesicular glutamate transporter 2 (VGLUT2) and has been suggested to use glutamate as a cotransmitter. The VTA dopamine neurons project to limbic structures including the nucleus accumbens, and are involved in mediating the motivational and locomotor activating effects of psychostimulants. To determine the functional role of glutamate cotransmission by these neurons, we deleted VGLUT2 in DA neurons by using a conditional gene-targeting approach in mice. A DAT-Cre/Vglut2Lox mouse line ([Vglut2.sup.f/f;DAT-/Cre] mice) was produced and analyzed by in vivo amperometry as well as by several behavioral paradigms. Although basal motor function was normal in the [Vglut2.sup.f/f;DAT-Cre] mice, their risk-taking behavior was altered. Interestingly, in both home-cage and novel environments, the gene targeted mice showed a greatly blunted locomotor response to the psychostimulant amphetamine, which acts via the midbrain DA system. Our results show that VGLUT2 expression in DA neurons is required for normal emotional reactivity as well as for psychostimulant-mediated behavioral activation. amphetamine | midbrain | neurotransmission | reward | striatum www.pnas.org/cgi/doi/10.1073/pnas.0910986107

Escano CS, Armando I, Wang X, Asico LD, Pascua A, Yang Y, Wang Z, Lau YS, Jose PA. Renal dopaminergic defect in C57Bl/6J mice. Am J Physiol Regul Integr Comp Physiol 297: R1660-R1669, 2009. First published September 2, 2009; doi: 10.1152/ajpregu.00147.2009.--The C57Bl/6J mouse strain, the genetic background of many transgenic and gene knockout models, is salt sensitive and resistant to renal injury. We tested the hypothesis that renal dopaminergic function is defective in C57Bl/6J mice. On normal NaCl (0.8%, 1 wk) diet, anesthetized and conscious (telemetry) blood pressures were similar in C57Bl/6J and SJL/J mice. High NaCl (6%, 1 wk) increased blood pressure ([approximately equal to]30%) in C57Bl/6J but not in SJL/J mice and urinary dopamine to greater extent in SJL/J than in C57B1/6J mice. Absolute and fractional sodium excretions were lower in SJL/J than in C57Bl/6J mice. The blood pressure-natriuresis plot was shifted to the right in C57Bl/6J mice. Renal expressions of [D.sub.1]-like ([D.sub.1]R and [D.sub.5]R) and angiotensin II [AT.sub.1] receptors were similar on normal salt, but high salt increased [D.sub.5]R only in C57B1/6J. GRK4 expression was lower on normal but higher on high salt in C57Bl/6J than in SJL/J mice. Salt increased the excretion of microalbumin and 8-isoprostane (oxidative stress marker) and the degree of renal injury to a greater extent in SJL/J than in C57Bl/6J mice. A [D.sub.1]-like receptor agonist increased sodium excretion whereas a [D.sub.1]-like receptor antagonist decreased sodium excretion in SJL/J but not in C57B1/6J mice. In contrast, parathyroid hormone had a similar natriuretic effect in both strains. These results show that defective [D.sub.1]-like receptor function is a major cause of salt sensitivity in C57B1/6J mice, decreased renal dopamine production might also contribute. The relative resistance to renal injury of C57Bl/6J may be a consequence of decreased production of reactive oxygen species. angiotensin II receptors; dopamine receptors; GRK4; reactive oxygen species doi: 10.1152/ajpregu.00147.2009

A reduction in dopaminergic innervation of the subventricular zone (SVZ) is responsible for the impaired proliferation of its resident precursor cells in this region in Parkinson's disease (PD). Here, we show that this effect involves EGF, but not FGF2. In particular, we demonstrate that dopamine increases the proliferation of SVZ-derived cells by releasing EGF in a PKC-dependent manner in vitro and that activation of the EGF receptor (EGFR) is required for this effect. We also show that dopamine selectively expands the [GFAP.sup.+] multipotent stem cell population in vitro by promoting their self-renewal. Furthermore, in vivo dopamine depletion leads to a decrease in precursor cell proliferation in the SVZ concomitant with a reduction in local EGF production, which is reversed through the administration of the dopamine precursor levodopa (L-DOPA). Finally, we show that [EGFR.sup.+] cells are depleted in the SVZ of human PD patients compared with age-matched controls. We have therefore demonstrated a unique role for EGF as a mediator of dopamine-induced precursor cell proliferation in the SVZ, which has potential implications for future therapies in PD. adult neural progenitor cell | Parkinson's disease | FGF2 | EGF receptor | L-DOPA

In mammalian kidney, dopamine produced in the proximal tubule (PT) acts as an autocrine/paracrine natriuretic hormone that inhibits salt and fluid reabsorption in the PT. In high-salt-treated animals, PT dopamine activity increases and inhibits reabsorption, leading to increased salt and fluid.delivery to the macula densa (MD) and subsequent natriuresis and diuresis. Regulated cyclooxygenase-2 (COX-2) in the MD represents another intrinsic system mediating renal salt and water homeostasis. Renal cortical COX-2 is inversely related to salt intake, and decreased extracellular NaC1 stimulates COX-2 expression in cultured MD/cortical thick ascending limb cells. The current study investigated interactions between renal dopamine and cortical COX-2 systems. In rats fed a control diet, the dopamine precursor L-dihydroxyphenylalanine (L-DOPA) or the DAI receptor agonist SKF-81297 suppressed cortical COX-2 expression. High salt suppressed cortical COX-2 expression, which was attenuated by inhibition of dopamine production with benserazide or the DA1 receptor antagonist, SCH-23390. In contrast, L-DOPA or the dopamine-metabolizing enzyme inhibitor entacapone suppressed low-salt-induced cortical COX-2 expression. Inhibition of PT reabsorption with the carbonic anhydrase inhibitor acetazolamide suppressed cortical COX-2 expression. In contrast, treatment with distally acting diuretics led to elevation of cortical COX-2. These results indicate that dopamine modulates renal cortical COX-2 expression by modifying PT reabsorption. prostaglandin synthase [G.sub.2]/[H.sub.2]; cortex; proximal tubule reabsorption

In many cells, ATP-sensitive [K.sup.+] channels ([K.sub.ATP] channels) couple metabolic state to excitability. In pancreatic beta cells, for example, this coupling regulates insulin release. Although [K.sub.ATP] channels are abundantly expressed in the brain, their physiological role and the factors that regulate them are poorly understood. One potential regulator is [H.sub.2][O.sub.2]. We reported previously that dopamine (DA) release in the striatum is modulated by endogenous [H.sub.2][O.sub.2], generated downstream from glutamatergic [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor activation. Here we investigated whether [H.sub.2][O.sub.2]-sensitive [K.sub.ATP] channels contribute to DA-release modulation by glutamate and [gamma]-aminobutyric acid (GABA). This question is important because DA-glutamate interactions underlie brain functions, including motor control and cognition. Synaptic DA release was evoked by using local electrical stimulation in slices of guinea pig striatum and monitored in real time with carbon-fiber microelectrodes and fast-scan cyclic voltammetry. The [K.sub.ATP]-channel antagonist glibenclamide abolished the H202-dependent increase in DA release usually seen with AMPA-receptor blockade by GYKI-52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride] and the decrease in DA release seen with GABA-type-A-receptor blockade by picrotoxin. In contrast, 5-hydroxydecanoate, a mitochondrial [K.sub.ATP]-channel blocker, was ineffective, as were sulpiride, a D2-receptor antagonist, and tertiapin, a G protein-coupled [K.sup.+]-channel inhibitor. Diazoxide, a sulfonylurea receptor 1 (SUR1)-selective KATp-channel opener, prevented DA modulation by [H.sub.2][O.sub.2], glutamate, and GABA, whereas cromakalim, a SUR2-selective opener, did not. Thus, endogenous [H.sub.2][O.sub.2] activates SUR1-containing KATP channels in the plasma membrane to inhibit DA release. These data not only demonstrate that [K.sub.ATP] channels can modulate CNS transmitter release in response to fast-synaptic transmission but also introduce [H.sub.2][O.sub.2] as a [K.sub.ATP]-channel regulator.

To determine whether reduced caloric intake affects the susceptibility of nigrostriatal dopamine (DA) neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, 1-year-old male C57BL6 mice were offered food ad libitum or were given only 60% of the normal dietary intake. After 3 months, both groups were treated with low cumulative doses of 0, 10, 15, or 20 mg/kg MPTP. One week later, the striata were collected and DA, dihydroxyphenylalanine (DOPAC), and norepinephrine (NE) were measured. Treatment with MPTP had no effect on striatal NE but produced a dose-related depletion of DA and DOPAC in both the ad libitum-fed and the dietary-restricted mice. The MPTP-induced depletions of DA and DOPAC were not ameliorated in the dietary-restricted versus the ad libitum-fed mice. Baseline DA levels and those observed after treatment with the 15-mg/kg dose of MPTP were lower in the dietary-restricted mice compared with the ad libitum-fed mice. Overall, these results suggest that, at least in 1-year-old mice, dietary restriction for 3 months does not protect nigral DA nerve terminals from low toxic dosages of MPTP.

Midbrain dopaminergic neurons maintain low ongoing `tonic' activity interrupted by high frequency bursts associated with behavioral reward. Dopamine released during bursts feeds back onto [D.sub.2] autoreceptors that depress neuronal activity. New findings from Ingram and colleagues suggest that, by contrast, tonic activity excites these neurons by activating an uncoupled [Cl.sup.-] conductance that is mediated by the dopamine uptake transporter. This response extends the range of states regulated by neurotransmitter feedback, and could contribute importantly to understanding amphetamine action.

Byline: Svenja Happe (1), Walter Pirker (2), Gerhard Klosch (2), Cornelia Sauter (2), Josef Zeitlhofer (2) Keywords: Key words [123I][beta]-CIT; Parkinson's disease (PD); periodic leg movements during sleep (PLMS); polysomnography; SPECT Abstract: We used single photon emission computed tomography (SPECT) to study striatal [[.sup.123]I][beta]-CIT binding and polysomnography to study periodic leg movements during sleep (PLMS) in eleven patients with idiopathic Parkinson's disease (PD). The reduced striatal [[.sup.123]I][beta]-CIT binding was significantly correlated with the number of PLMS. We propose that striatal dopaminergic nerve cell loss is involved in the increased number of PLMS in PD patients. Author Affiliation: (1) Department of Clinical Neurophysiology, Robert-Koch-Strasse 40, 37075 Goettingen, Germany. shappe@gwdg.de, DE (2) Department of Clinical Neurology, University of Vienna, Austria, AT Article note: Received: 26 April 2002, Received in revised form: 21 August 2002, Accepted: 29 August 2002 Correspondence to Svenja Happe, MD

The loss of nigral dopaminergic (DA) cells in Parkinson's disease (PD) was discovered in the mid-twentieth century (1), and DA cell replacement was quickly posited as a potential therapeutic strategy. [...], Cell replacement for restoring neuronal populations in Parkinson's disease has been demonstrated as a potential therapeutic strategy over several decades of studies; however, a number of issues regarding sources of replacement neurons and optimization of therapeutic efficacy in vivo have hampered clinical implementation. In this issue of the JCI, Dell'Anno and colleagues evaluated the use of induced dopaminergic (iDA) neurons that were generated by direct fibroblast reprogramming for transplantation and demonstrated that postmitotic iDA neurons stably and functionally integrate into host striatum to produce motor improvements in 6-OHDA rats, a Parkinson's disease model. Furthermore, using designer receptors exclusively activated by designer drugs (DREADDs) in iDA grafts to noninvasively increase dopamine release from grafted neurons, the authors were able to remotely control transplanted neurons and enhance therapeutic efficacy. This initial proof-of-concept study is the first application of DREADD technology to treat neurodegenerative dysfunction, and by using DREADDs as an adjunct to iDA cell therapy, it presents a novel strategy to overcome some current caveats of cell replacement therapy.

Parkinson's disease (PD) is characterized by the progressive loss of substantia nigra dopaminergic neurons and the presence of cytoplasmic inclusions named Lewy bodies. Two missense mutations of the [alpha]-synuclein ([alpha]-syn; A30P and A53T) have been described in several families with an autosomal dominant form of PD. [alpha]-Syn also constitutes one of the main components of Lewy bodies in sporadic cases of PD. To develop an animal model of PD, lentiviral vectors expressing different human or rat forms of [alpha]-syn were injected into the substantia nigra of rats. In contrast to transgenic mice models, a selective loss of nigral dopaminergic neurons associated with a dopaminergic denervation of the striatum was observed in animals expressing either wild-type or mutant forms of human [alpha]-syn. This neuronal degeneration correlates with the appearance of abundant [alpha]-syn-positive inclusions and extensive neuritic pathology detected with both [alpha]-syn and silver staining. Lentiviral-mediated expression of wild-type or mutated forms of human [alpha]-syn recapitulates the essential neuropathological features of PD. Rat [alpha]-syn similarly leads to protein aggregation but without cell loss, suggesting that inclusions are not the primary cause of cell degeneration in PD. Viral-mediated genetic models may contribute to elucidate the mechanism of [alpha]-syn-induced cell death and allow the screening of candidate therapeutic molecules.

We tested the hypothesis that ovarian steroids stimulate breathing through a dopaminergic mechanism in the carotid bodies. In ovariectomized female rats raised at sea level, domperidone, a peripheral [D.sub.2]-receptor antagonist, increased ventilation in normoxia (minute ventilation = +55%) and acute hypoxia (+32%). This effect disappeared after 10 daily injections of ovarian steroids (progesterone + estradiol). At high altitude (3,600 m, Bolivian Institute for High-Altitude Biology-IBBA, La Paz, Bolivia), neutered females had higher carotid body tyrosine hydroxylase activity (the rate-limiting enzyme for catecholamine synthesis: +129%) and dopamine utilization (+150%), lower minute ventilation (-30%) and hypoxic ventilatory response (-57%), and higher hematocrit (+18%) and Hb concentration (+21%) than intact female rats. Consistent signs of arterial pulmonary hypertension (right ventricular hypertrophy) also appeared in ovariectomized females. None of these parameters was affected by gonadectomy in males. Our results show that ovarian steroids stimulate breathing by lowering a peripheral dopaminergic inhibitory drive. This process may partially explain the deacclimatization of post-menopausal women at high altitude. hypoxia; ovarian steroids; chronic mountain sickness

Binding of [Zn.sup.2+] to the endogenous[Zn.sup.2+] binding site in the human dopamine transporter leads to potent inhibition of [[sup.3.H]]dopamine uptake. Here we show that mutation of an intracellular tyrosine to alanine (Y335A) converts this inhibitory [Zn.sup.2+] switch into an activating [Zn.sup.2+] switch, allowing [Zn.sup.2+]-dependent activation of the transporter. The tyrosine is part of a conserved YXX[phi] trafficking motif (X is any residue and [phi] is a residue with a bulky hydrophobic group), but Y335A did not show alterations in surface targeting or protein kinase C-mediated internalization. Despite wild-type levels of surface expression, Y335A displayed a dramatic decrease in [[sup.3.H]]dopamine uptake velocity ([V.sub.max]) to less than 1% of the wild type. In addition, Y335A showed up to 150-fold decreases in the apparent affinity for cocaine, mazindol, and related inhibitors whereas the apparent affinity for several substrates was increased. However, the presence of [Zn.sup.2+] in micromolar concentrations increased the [V.sub.max] up to 24-fold and partially restored the apparent affinities. The capability of [Zn.sup.2+] to restore transport is consistent with a reversible, constitutive shift in the distribution of conformational states in the transport cycle upon mutation of Tyr-335. We propose that this shift is caused by disruption of intramolecular interactions important for stabilizing the transporter in a conformation in which extracellular substrate can bind and initiate transport, and accordingly that Tyr-335 is critical for regulating isomerization between discrete states in the transport cycle.

We previously identified a stromal cell-derived inducing activity (SDIA), which induces differentiation of neural cells, including midbrain tyrosine hydroxylase-positive T[H.sup.+] dopaminergic neurons, from mouse embryonic stem cells. We report here that SDIA induces efficient neural differentiation also in primate embryonic stem cells. Induced neurons contain T[H.sup.+] neurons at a frequency of 35% and produce a significant amount of dopamine. Interestingly, differentiation of T[H.sup.+] neurons from undifferentiated embryonic cells occurs much faster in vitro (10 days) than it does in the embryo ([approximately equal to]5 weeks). In addition, 8% of the colonies contain large patches of Pax[6.sup.+] - pigmented epithelium of the retina. The SDIA method provides an unlimited source of primate cells for the study of pathogenesis, drug development, and transplantation in degenerative diseases such as Parkinson's disease and retinitis pigmentosa.

Parkinson's disease is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. We now report that minocycline, a semisynthetic tetracycline, recently shown to have neuroprotective effects in animal models of stroke/ischemic injury and Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Minocycline treatment also blocked dopamine depletion in the striatum as well as in the nucleus accumbens after MPTP administration. The neuroprotective effect of minocycline is associated with marked reductions in inducible NO synthase (iNOS) and caspase 1 expression. In vitro studies using primary cultures of mesencephalic and cerebellar granule neurons (CGN) and/or glia demonstrate that minocycline inhibits both 1-methyl-4-phenylpyridinium (MP[P.sup.+])-mediated iNOS expression and NO-induced neurotoxicity, but MP[P.sup.+]-induced neurotoxicity is inhibited only in the presence of glia. Further, minocycline also inhibits NO-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in CGN and the p38 MAPK inhibitor, SB203580, blocks NO toxicity of CGN. Our results suggest that minocycline blocks MPTP neurotoxicity in vivo by indirectly inhibiting MPTP/MP[P.sup.+]-induced glial iNOS expression and/or directly inhibiting NO-induced neurotoxicity, most likely by inhibiting the phosphorylation of p38 MAPK. Thus, NO appears to play an important role in MPTP neurotoxicity. Neuroprotective tetracyclines may be effective in preventing or slowing the progression of Parkinson's and other neurodegenerative diseases.

Byline: Naoto Adachi (1), Baiping Lei (1), Gautam Deshpande (1), Frank J. Seyfried (1), Ichiro Shimizu (1), Takumi Nagaro (1), Tatsuru Arai (1) Keywords: Acute renal failure Central nervous system Dopamine Norepinephrine Rats Serotonin Abstract: Objective: Uraemia often provokes various neurological disorders, such as mental changes, malperception, confusion, seizures and coma. Since changes in neurotransmissions induce neurological symptoms, we investigated changes in the monoamine metabolism and motor activity in uraemic rats. Design: Prospective, randomised, controlled animal study. Subjects: Male Wistar rats. Interventions: Acute renal failure was induced by occlusion of bilateral renal arteries for 60 min, and the motor activity and brain monoamine turnover were examined 48 h later. The brain monoamine turnover was evaluated by the depletion of norepinephrine (NE) and dopamine (DA) induced by [alpha]-methyl-p-tyrosine ([alpha]-MT), or the accumulation of 5-hydroxyindoleacetic acid (5-HIAA) induced by probenecid. Measurements and results: Marked damage in renal function was found in animals subjected to renal ischaemia 48 h after the operation. The motor activity of the uraemic rats was impaired. The turnover of DA in the striatum, mesencephalon and hypothalamus was decreased in these rats. The turnover of NE and 5-hydroxytryptamine (5-HT) was unchanged in all regions examined. Conclusions: Suppression of the central DA turnover appears to be involved in the impairment of motor activity in uraemic rats. Author Affiliation: (1) Department of Anaesthesiology and Resuscitology, Ehime University School of Medicine, Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 791--0295, Japan Article History: Received Date: 09/02/2001 Accepted Date: 17/07/2001 Article note: Final revision received: 9 February 2001 Electronic Publication

The rate of fibrillization of mouse alpha-synuclein in the presence and absence of WT or 53T has been studied. Fibrillization inhibition and accumulation of prefibrillar oligomers was seen in mixtures of human and mouse alpha-synuclein. In early-onset familial Parkinson's disease (PD) two mutants of human alpha-synuclein, a small highly conserved presynaptic protein abundant in some brain regions, have been found to relate. Oligomeric forms of the mutants, one of which is A53T, accumulate faster and/or last longer than oligomeric, human wild-type alpha synuclein, WT. It was shown that the murine protein, similar to WT, is natively unfolded and forms amyloid fibrils faster than WT or A53T. A link between oligomerization and cell death may exist. Results relate to interpretation of phenotypes of transgenic PD animal models and testing cause/effect between fibrillization and neurodegeneration.

Experiments were conducted to investigate the pharmacologic properties of the dopamine receptor subtype that attenuates the angiotensin-II-induced arginine vasopressin (AVP) secretion in hypothalamo-neurohypophysial explants. Increases basal AVP release were attributed to dopamine, while the angiotensin-II-induced AVP secretion was localized at the AT1 receptor. The findings identify a D1 receptor as the precursor of AVP increases.

The mesolimbic dopamine system has recently been implicated in the long-term aversive consequences of withdrawal from major drugs of abuse. In the present study we sought to determine whether mesolimbic dopamine neurons are involved in the neurobiologic mechanisms underlying withdrawal from chronic cannabinoid exposure. Rats were treated chronically with the major psychoactive ingredient of hashish and marijuana, [[Delta].sup.9]-tetrahydrocannabinol ([[Delta].sup.9]-THC). Administration of the cannabinoid antagonist SR 141716A precipitated an intense behavioral withdrawal syndrome, whereas abrupt [[Delta].sup.9]-THC suspension failed to produce overt signs of abstinence. In contrast, both groups showed a reduction in dopamine cells activity as indicated by extracellular single unit recordings from antidromically identified mesoaccumbens dopamine neurons. The administration of [[Delta].sup.9]-THC to spontaneously withdrawn rats restored neuronal activity. Conversely, SR 141716A produced a further decrease of spontaneous activity in cannabinoid-treated although it was ineffective in control rats. These data indicate that withdrawal from chronic cannabinoid administration is associated with reduced dopaminergic transmission in the limbic system, similar to that observed with other addictive drugs; these changes in neuronal plasticity may play a role in drug craving and relapse into drug addiction.

An investigation was conducted to determine the signals that indicate the fates and initial positions of dopaminergic and serotonergic neurons which appear in the dorso-ventral and anterior-posterior axes of the neural tube. Induction sites for dopaminergic neurons are created by the intersections of Shh and FGF8. Results revealed that cell patterning in the neural plates involves multistep process for the regionalization of the tissue which is executed in multiple local organizing centers.

In rats with unilateral lesions of the nigro-striatal dopamine pathway with 6-hydroxydopamine, the motor stimulating effects of levodopa, an indirect dopamine receptor agonist, evidenced by contraversive rotations, become enhanced upon repeated intermittent administration. However, the mechanisms of this behavioral sensitization are essentially unknown. We show that development of sensitization is accompanied by a progressive appearance of D3 receptor mRNA and binding sites, visualized by in situ hybridization and 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin autoradiography, respectively, occurring in the denervated caudate putamen, a brain area from which this receptor subtype is normally absent. Development and decay of these two processes occur with closely parallel time courses, whereas there were no marked changes in [D.sub.1] or [D.sub.2] receptor mRNAs. [D.sub.3] receptor induction by levodopa is mediated by repeated [D.sub.1] receptor stimulation, since it is prevented by the antagonist SCH 33390 and mimicked by the agonist SKF 38393, but not by two [D.sub.2] receptor agonists. The enhanced behavioral response to levodopa is mediated by the newly synthesized [D.sub.3] receptor, since it is antagonized by nafadotride, a preferential [D.sub.3] receptor antagonist, in low dosage, which has no such effect before [D.sub.3] receptor induction. [D.sub.3] receptor induction and behavioral sensitization are also accompanied by a sustained enhancement of prodynorphin mRNA level and a progressively decreasing expression of the preprotachykinin gene. We propose that imbalance between dynorphin and substance P release from the same striatonigral motor efferent pathway, related to [D.sub.3] receptor induction, is responsible for behavioral sensitization.

Rank correlations on latent inhibition learning among internal scorers versus external scorers on Rotter's I-E locus of control scale were compared between trial numbers and speed of correct reactions in a left- and in a right-hemispheric discrimination task. On the basis of previous research and theorizing reviewed by De Brabander, Boone, and Gerits (1992) we expected latent inhibition effects to show mainly on the left-hemisphere task and more clearly among internal scorers on Rotter's I-E locus of control scale. The findings seem to confirm our expectations.

Background. Marked decreases in cardiac responses to [Beta]-adrenergic stimuli have been found in cellular, animal, and human models of physiologic aging. As another probe of receptor-regulated cardiovascular changes with aging, responses to dopamine were studied. Responses were studied with and without depletion of myocardial catecholamines to eliminate effects secondary to myocardial catecholamine release. Methods. Responses of heart rate (A-A intervals), atrioventricular conduction (AV intervals and AV Wenckebach block cycle length) to 0-50 [[micro]molar] dopamine were studied in Langendorff perfused hearts from 10 mature (6.2 [+ or -] 0.8 mo, mean [+ or -] SD) and 9 senescent (23.6 [+ or -] 0.7 mo) Fischer 344 rats and in hearts from 10 mature (5.3 [+ or -] 0.4 mo) and 8 senescent (23.9 [+ or -] 0.8) Fischer 344 rats after myocardial catecholamine depletion by reserpine (0.25 mg/kg i.p. x 5 days). Results. Dopamine decreased A-A (p < .0001) and AV conduction intervals (p < .0001) and increased peak developed pressure (p < .0001) and dP/dt (p < .001) in hearts from nonreserpine treated mature and senescent rats. Greater decreases in A-A intervals and AV conduction were seen in senescent compared to mature hearts (p < .0001). Contractile responses were greater in mature hearts (p < .001). After reserpine, A-A interval and paced AV conduction dose vs response relationships shifted rightward (p < .0001), but peak responses and age-related differences in responses were not significantly affected. In contrast, increases in peak developed pressure were greatly reduced in mature hearts (p < .0001) and age-related differences in contractile responses to dopamine were eliminated in hearts from reserpine-treated rats. Conclusions. (a) A-A interval and AV conduction responses to dopamine were greater in senescent hearts even after catecholamine depletion, suggesting age-related differences in sinus and AV nodal responses to direct dopaminergic stimuli exist. (b) Age-related differences in contractile responses to dopamine were eliminated by reserpine suggesting basal age-related differences in response were secondary to age-related differences in responses to myocardial catecholamine release.

Specific antagonists of central dopaminergic receptors constitute the major class of antipsychotic drugs (APD). Two principal effects of APD are used as criteria for the pre-clinical screening of their antipsychotic action: (i) inhibition of basal and depolarization-induced activity of mesolimbic dopaminergic neurons; (ii) antagonism of the locomotor effects of dopaminergic agonists. Given that glucocorticoid hormones in animals increase dopamine release and dopamine-mediated behaviors and that high levels of glucocorticoids can induce psychotic symptoms in humans, these experiments examined whether inhibition of endogenous glucocorticoids might have APD-like effects on mesolimbic dopaminergic transmission in rats. It is shown that suppression of glucocorticoid secretion by adrenalectomy profoundly decreased (by greater than 50%): (i) basal dopaminergic release and the release of dopamine induced by a depolarizing stimulus such as morphine (2 mg/kg, s.c.), as measured in the nucleus accumbens of freely moving animals by microdialysis; (ii) the locomotor activity induced by the direct dopaminergic agonist apomorphine. The effects of adrenalectomy were glucocorticoid specific given that they were reversed by the administration of glucocorticoids at doses within the physiological range. Despite its profound diminution of dopaminergic neurotransmission, adrenalectomy neither modified the number of mesencephalic dopaminergic neurons nor induced gliosis in the mesencephalon or in the nucleus accumbens, as shown by tyrosine hydroxylase and glial fibrillary acidic protein immunostaining. In conclusion, these findings suggest that blockade of central effects of glucocorticoids might open new therapeutic strategies of behavioral disturbances.

An increase in the activity of mesencephalic dopaminergic neurons has been implicated in the appearance of pathological behaviors such as psychosis and drug abuse. Several observations suggest that glucocorticoids might contribute to such an increase in dopaminergic activity. The present experiments therefore analyzed the effects of corticosterone, the major glucocorticoid in the rat, both on dopamine release in the nucleus accumbens of freely moving animals by means of microdialysis, and on locomotor activity, a behavior dependent on accumbens dopamine. Given that glucocorticoids have certain state-dependent neuronal effects, their action on dopamine was studied in situations differing in dopaminergic tonus, including during the light and dark phases of the circadian cycle, during eating, and in groups of animals differing in their locomotor reactivity to novelty. Dopaminergic activity is increased in the dark period, further increased during food-intake, and is higher in rats defined as high responders to novelty than in low responders. Corticosterone, peripherally administered in a dose that approximates stress-induced plasma concentrations, increased extra-cellular concentrations of dopamine, and this increase was augmented in the dark phase, during eating, and in high responder rats. Corticosterone had little or no effects in the light phase and in low responder rats. Corticosterone also stimulated locomotor activity, an effect that paralleled the release of dopamine and was abolished by neurochemical (6-hydroxydopamine) depletion of accumbens dopamine. In conclusion, glucocorticoids have state-dependent stimulant effects on mesencephalic dopaminergic transmission, and an interaction between these two factors might be involved in the appearance of behavioral disturbances.

The striatum is viewed as a structure performing fast neurotransmitter-mediated operations through somato-topically organized projections to medium-size spiny neurons. This view is contrasted with another view that depicts the striatum as a site of diffuse modulatory influences mediated by cholinergic interneurons and by dopamine and N-methyl-D-aspartate receptors. These two operational and organizational modes both contribute, through their mutual interaction, to the function of basal ganglia. Detailed knowledge of the neural mechanisms by which such interactions take place and are expressed into behaviour, can provide new insight into the physiopathology and new clues for therapy of disorders of basal ganglia.

The interaction between adenyl cyclase and dopamine1 receptors was studied in spontaneously hypertensive rats (SHR) and compared with normotensive controls. A defective dopamine1 receptor-G protein coupling mechanism in proximal convoluted tubules (PCT) of the SHR was identified. This defect was assumed to be exclusive to the PCT because it was not observed in the renal collecting duct or in the striatum.