Melchitzky, D. S. & Lewis, D. A. Tyrosine hydroxylase- and dopamine transporter-immunoreactive axons in the primate cerebellum. Evidence for a lobular- and laminar-specific dopamine innervation. Neuropsychopharmacology 22, 466-472

Departments of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 06/2000; 22(5):466-72. DOI: 10.1016/S0893-133X(99)00139-6
Source: PubMed

ABSTRACT The cerebellum seems to play a critical role in many motor and cognitive functions, including those that are disturbed in schizophrenia. Although dopamine is known to influence the motor or cognitive functions mediated by other brain regions and to play a role in the pathophysiology of schizophrenia, the cerebellum has not been thought to be a target of dopamine-containing axons. However, given recent reports of dopamine receptors in the cerebellum, we sought to determine whether axons immunoreactive for the proteins involved in dopamine synthesis and reuptake are present in the cerebellum of macaque monkeys. We found that axons immunoreactive for the dopamine membrane transporter, a specific marker of dopamine axons, were present in high density, but only in certain lobules of the cerebellar vermis. In addition, these axons were found principally in the granule cell layer, where they densely arborized immediately subjacent to the Purkinje cells. Similarly, axons labeled for tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, were also present in high density in the granule cell layer of the same lobules of the vermis. In contrast, axons immunoreactive for dopamine beta-hydroxylase, a marker of noradrenergic axons, exhibited a different and more widespread pattern of innervation. These findings are consistent with a dopamine innervation of the primate cerebellum that is both lobular- and laminar-specific, and they suggest that dopamine may play a role in certain cerebellar functions.

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    • "Schroederetal.,2009;Muriachetal.,2010). Dopamineauto-oxidation(Numaetal.,2008)hasbeen typicallyacceptedascocaine-inducedROSsource.However, dopamineisnotthemainneurotransmitterincerebellum, particularlypresentinvermis(MelchitzkyandLewis,2000). Therefore,theobservedantioxidantdefensedecreasecouldbe duetootherorigins.Cocaine-inducedvasoconstrictionmay decreasescerebellarbloodflow,leadingtohypoxiaincreasing ROS(Kaufmanetal.,1998;GottschalkandKosten,2002;Pae "
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    ABSTRACT: Different mechanisms have been suggested for cocaine neurotoxicity, including oxidative stress alterations. Nuclear factor kappa B (NF-κB), considered a sensor of oxidative stress and inflammation, is involved in drug toxicity and addiction. NF-κB is a key mediator for immune responses that induces microglial/macrophage activation under inflammatory processes and neuronal injury/degeneration. Although cerebellum is commonly associated to motor control, muscular tone, and balance. Its relation with addiction is getting relevance, being associated to compulsive and perseverative behaviors. Some reports indicate that cerebellar microglial activation induced by cannabis or ethanol, promote cerebellar alterations and these alterations could be associated to addictive-related behaviors. After considering the effects of some drugs on cerebellum, the aim of the present work analyzes pro-inflammatory changes after cocaine exposure. Rats received daily 15 mg/kg cocaine i.p., for 18 days. Reduced and oxidized forms of glutathione (GSH) and oxidized glutathione (GSSG), glutathione peroxidase (GPx) activity and glutamate were determined in cerebellar homogenates. NF-κB activity, CD68, and GFAP expression were determined. Cerebellar GPx activity and GSH/GSSG ratio are significantly decreased after cocaine exposure. A significant increase of glutamate concentration is also observed. Interestingly, increased NF-κB activity is also accompanied by an increased expression of the lysosomal mononuclear phagocytic marker ED1 without GFAP alterations. Current trends in addiction biology are focusing on the role of cerebellum on addictive behaviors. Cocaine-induced cerebellar changes described herein fit with previosus data showing cerebellar alterations on addict subjects and support the proposed role of cerebelum in addiction.
    Frontiers in Cellular Neuroscience 08/2015; 9:279. DOI:10.3389/fncel.2015.00279 · 4.29 Impact Factor
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    • "Animal studies revealed that there is a small but well-defined dopaminergic system in the cerebellum, which expresses all types of dopamine receptors and whose properties are similar to the striatal dopaminergic system (84). It receives inputs from the SNc and VTA that terminate in the granule and Purkinje cell layers (85–88). This system is important for the optimal development and functioning of both the cerebellum and the basal ganglia. "
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    ABSTRACT: The exact mechanisms that generate levodopa-induced dyskinesias (LID) during chronic levodopa therapy for Parkinson’s disease (PD) are not yet fully established. The most widely accepted theories incriminate the non-physiological synthesis, release and reuptake of dopamine generated by exogenously administered levodopa in the striatum, and the aberrant plasticity in the corticostriatal loops. However, normal motor performance requires the correct recruitment of motor maps. This depends on a high level of synergy within the primary motor cortex (M1) as well as between M1 and other cortical and subcortical areas, for which dopamine is necessary. The plastic mechanisms within M1 which are crucial for the maintenance of this synergy are disrupted both during “OFF” and dyskinetic states in PD. When tested without levodopa, dyskinetic patients show loss of treatment benefits on long-term potentiation and long-term depression-like plasticity of the intracortical circuits. When tested with the regular pulsatile levodopa doses, they show further impairment of the M1 plasticity, such as inability to depotentiate an already facilitated synapse and paradoxical facilitation in response to afferent input aimed at synaptic inhibition. Dyskinetic patients have also severe impairment of the associative, sensorimotor plasticity of M1 attributed to deficient cerebellar modulation of sensory afferents to M1. Here we review the anatomical and functional studies, including the recently described bidirectional connections between the cerebellum and the basal ganglia that support a key role of the cerebellum in the generation of LID. This model stipulates that aberrant neuronal synchrony in PD with LID may propagate from the sub thalamic nucleus to the cerebellum and “lock” the cerebellar cortex in a hyperactive state. This could affect critical cerebellar functions such as the dynamic and discrete modulation of M1 plasticity and the matching of motor commands with sensory information
    Frontiers in Neurology 08/2014; 5(00157). DOI:10.3389/fneur.2014.00157
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    • "Both cerebellar–striatal and cerebellar–prefrontal connectivity are bidirectional, forming reciprocal prefrontal–midbrain–cerebellar loops. Importantly, dopamine– glutamate interactions have also been described in the cerebellum [9] [10] [13] [15] [19] [20]. Recently, we have shown that conditioned preference towards an odour associated with cocaine was directly correlated with cFOS expression in cells at the dorsal region of the granule cell layer of the cerebellar vermis [21]. "
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