Ariel Y. Deutch

Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models

Parkinson disease is a common neurodegenerative disorder that leads to difficulty in effectively translating thought into action. Although it is known that dopaminergic neurons that innervate the striatum die in Parkinson disease, it is not clear how this loss leads to symptoms. Recent work has implicated striatopallidal medium spiny neurons (MSNs) in this process, but how and precisely why these neurons change is not clear. Using multiphoton imaging, we show that dopamine depletion leads to a rapid and profound loss of spines and glutamatergic synapses on striatopallidal MSNs but not on neighboring striatonigral MSNs. This loss of connectivity is triggered by a new mechanism—dysregulation of intraspine Cav1.3 L-type Ca2+ channels. The disconnection of striatopallidal neurons from motor command structures is likely to be a key step in the emergence of pathological activity that is responsible for symptoms in Parkinson disease.

Pharmacological characterization of dopamine systems in the nucleus accumbens core and shell.

Recent anatomical data suggest that the nucleus accumbens can be parcellated into a core region, related to the caudate-putamen, and a shell region, associated with the limbic system. We have used pharmacological methods to characterize the dopamine innervations of the nucleus accumbens core and shell in the rat. Concentrations of both dopamine and serotonin were significantly greater in the nucleus accumbens shell than the nucleus accumbens core. Metabolite: amine ratios suggested that both dopamine and serotonin utilization are greater in the core. However, dopamine turnover (as determined by measuring the rate of decline of dopamine after alpha-methyl-p-tyrosine treatment) was not significantly different in the two accumbal sectors. Dopamine concentrations in the two nucleus accumbens sectors were decreased to an equivalent degree at both 4 and 18 h after reserpine administration. In contrast, serotonin concentrations were decreased to a significantly greater degree in the nucleus accumbens core than nucleus accumbens shell at 4 h, but not 18 h, after reserpine administration. Administration of haloperidol increased dopamine utilization in both nucleus accumbens sectors, but augmented utilization to a significantly greater degree in the nucleus accumbens core. Clozapine increased dopamine utilization to an equivalent degree in both nucleus accumbens regions. Short duration immobilization stress selectively increased dopamine utilization in the nucleus accumbens shell. These data indicate that there are significant differences between the nucleus accumbens core and nucleus accumbens shell in basal dopamine metabolism, and indicate that the core and shell dopamine innervations can be distinguished on the basis of response to both pharmacological and environmental challenges.(ABSTRACT TRUNCATED AT 250 WORDS)

Anatomical substrates of orexin-dopamine interactions: Lateral hypothalamic projections to the ventral tegmental area

Dopaminergic projections to the forebrain arising from the mesencephalic ventral tegmentum modulate information processing in cortical and limbic sites. The lateral hypothalamus is crucial for the coordination of behavioral responses to interoceptive cues. The presence of a hypothalamic input to the ventral tegmental area has been known for some time, but the organization of this pathway has received little attention. Among the neuropeptides found in the hypothalamus are the orexins, which are selectively expressed in the lateral hypothalamus and adjacent perifornical area and are critically involved in homeostatic regulatory processes, including arousal and feeding. We examined the anatomical relationships between orexin and dopamine neurons in rats, with particular attention to characterizing the lateral hypothalamic projection to midbrain dopamine neurons. Iontophoretic deposits of the retrograde tracer FluoroGold into the ventral tegmental area revealed a large number of retrogradely-labeled cells that formed a band extending from the medial perifornical area arching dorsally over the fornix and then ventrolaterally into the lateral hypothalamus; approximately 20% of these cells expressed orexin A-like immunoreactivity. Moreover, axons that were anterogradely labeled from the lateral hypothalamus were seen throughout the ventral tegmental area, and were often in close proximity to the dendrites and somata of dopamine neurons. Dopamine and orexin fibers were found to codistribute in the medial prefrontal cortex; orexin fibers were present in lower density in the medial shell of the nucleus accumbens, and the central and posterior basolateral nuclei of the amygdala. We conclude that the lateral hypothalamic/perifornical projection represents an anatomical substrate by which interoceptive-related signals may influence forebrain dopamine function.

The determinants of stress-induced activation of the prefrontal cortical dopamine system.

Publisher Summary The dopamine (DA) innervation of the prefrontal cortex (PFC) differs from other mesotelencephalic DA terminal field regions in that it responds in a quantitatively different manner to a number of pharmacological and environmental manipulations. The quantitatively different response characteristics of the PFC DA system and the resultant pattern of changes across the mesotelencephalic DA terminal fields presumably reflect differences in the regulatory features of mesencephalic neurons, which give rise to the DA innervations of different forebrain regions. The regulatory controls involved in the normal impulse-dependent release of DA from the nerve terminal range from intrinsic regulatory features to extrinsic regulatory features. This chapter explores the features of mesoprefrontal cortical DA neurons that render their response characteristics to a number of pharmacological and environmental challenges different from those of other mesotelencephalic DA neurons by using stress-induced alterations in mesotelencephalic DA neurons as a model. It also examines both the similarities and differences between DA neurons projecting to the PFC and those innervating other telencephalic sites.

Footshock and conditioned stress increase 3, 4-dihydroxyphenylacetic acid (DOPAC) in the ventral tegmental area but not substantia nigra

The effects of stress on dopamine (DA) metabolism in the mesencephalic DA cell body areas and DA terminal field regions were examined. Both mild footshock stress and exposure to a neutral stimulus previously paired with footshock resulted in a selective increase in the levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the prefrontal cortex as has been previously reported. Footshock stress also resulted in a slight but significant increase in DOPAC levels in the olfactory tubercles. DOPAC levels were selectively increased in the A10 cell body area (ventral tegmental area) but not A9 region (substantia nigra) by both footshock and the conditioned stress paradigm. These data indicate that the cell bodies of origin of the mesocortical dopaminergic system are activated by stress in contrast to those DA neurons innervating the striatum. It appears that mesocortical dopaminergic neurons exhibit different regulatory features than mesolimbic or nigrostriatal neurons.

Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat cortex.

The distribution of 5‐HT2A receptors in rat cortex was evaluated using newly developed antibodies. Each of three antibodies tested identified an identical pattern of 5‐HT2A‐like immunoreactivity (5‐HT2A‐li) in rat cortex with 5‐HT2A‐li showing a widespread distribution. The majority of 5‐HT2A‐li cells displayed a pyramidal morphology. While a minority, some cortical neurons with a bipolar morphology displayed 5‐HT2A‐li as well. Dual‐label fluorescence confocal microscopic studies with a 5‐HT2A antibody and a mouse monoclonal antibody to parvalbumin, a marker of a subset of gamma aminobutyric acid (GABA)ergic interneurons in the cortex, demonstrated that although some cells expressing 5‐HT2A‐li were interneurons, most were not. Synapse 27:79–82, 1997.

Mechanisms of action of atypical antipsychotic drugs: Implications for novel therapeutic strategies for schizophrenia

The mechanisms which contribute to the actions of atypical antipsychotic drugs, such as clozapine and the putative atypical agents remoxipride and raclopride, are reviewed. Examination of available preclinical and clinical data leads to two hypotheses concerning the mode of action of atypical antipsychotic drugs. The first hypothesis is that antagonism of the dopamine D2 receptor is both necessary and sufficient for the atypical profile, but that interaction with subtypes of the D2 receptor differentiates typical from atypical antipsychotic drugs. The second hypothesis has been previously advanced, and suggests that a relatively high ratio of serotonin 5-HT2:dopamine D2 receptor antagonism may subserve the atypical profile. It seems likely that the atypical antipsychotic drug profile may be achieved in more than one way.

Regionally specific effects of atypical antipsychotic drugs on striatal Fos expression: The nucleus accumbens shell as a locus of antipsychotic action.

The mechanisms by which atypical antipsychotic drugs such as clozapine exert therapeutic effects but do not induce extrapyramidal side effects are not clear. We have examined the effects of acute administration of three antipsychotic drugs on Fos protein expression in the striatal complex. The ypical neuroleptic haloperidol was compared with the atypical agent clozapine and the putative atypical antipsychotic drug remoxipride. Haloperidol increased the number of neurons expressing Fos-like immunoreactivity in both the dorsolateral and the medial striatum and increased Fos expression in the nucleus accumbens core and shell. Clozapine increased Fos in the nucleus accumbens shell, but not in the core or two neostriatal sectors. Remoxipride significantly increased the number of Fos-like immunoreactive neurons in the medial but not the dorsolateral striatum, and increased the number of cells expressing Fos protein in the nucleus accumbens shell but not core. The remoxipride-induced increase in the number of medial striatal neurons expressing Fos was entirely attributable to a selective increase in the striatal patch compartment, whereas haloperidol increased Fos protein in neurons of both striatal compartments. These data indicate that typical and atypical antipsychotic drugs exert regionally distinct effects on striatal Fos expression, and suggest that the dorsolateral striatum may be a locus involved in the genesis of extrapyramidal side effects. All three antipsychotic drugs increased Fos expression in the shell of the nucleus accumbens. The shell of the nucleus accumbens may be a site of antipsychotic action.

FETAL NEURONAL GRAFTS IN MONKEYS GIVEN METHYLPHENYLTETRAHYDROPYRIDINE

Fetal substantia nigra cells of two different gestational ages were successfully transplanted into the brains of three methylphenyltetrahydropyridine-treated monkeys with severe parkinsonian motor and behavioural deficits. Functional improvement continued for 10 weeks after cell grafts into the striata of two monkeys with substantial numbers of tyrosine-hydroxylase-positive fetal neurons at necropsy. Behavioural improvement was correlated with increases in cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations after the transplants. A control monkey with inappropriately placed transplanted cells of an earlier gestational age remained severely parkinsonian and died during a similar period. CSF HVA fell slightly in this monkey from the low level seen before the transplants. Fetal dopamine neurons of two different gestational ages appear to survive transplantation in primates and have biochemical and functional effects.

Prefrontal cortical dopamine systems and the elaboration of functional corticostriatal circuits: implications for schizophrenia and Parkinson's disease

The dopaminergic innervation of the prefrontal cortex is able to transsynaptically regulate the activity of subcortical dopamine innervations. Disruption of the prefrontal cortical DA innervation results in the enhanced biochemical responsiveness of the dopamine innervation of the nucleus accumbens. We present recent data indicating that distinct prefrontal cortical dopamine innervations can be functionally dissociated on the basis of responsiveness to stress. The ventral striatal projection target (nucleus accumbens shell) of the prefrontal cortical region that is stress sensitive is also responsive to stress. In this manner interconnected cortico-striato-pallido-mesencephalic loops can be defined on the basis of the biochemical responsive of local dopamine systems to stress and on the basis of responsiveness to antipsychotic drugs. These data suggest the functional derangement of a distinct corticofugal loops in schizophrenia and in certain aspects of Parkinsons disease.