Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism

Introduction: Methylphenidate (MP) is a widely used psychostimulant prescribed for Attention Deficit Hyperactivity Disorder, and is also used illicitly by healthy individuals. Chronic exposure to MP has been shown to affect physiology, behavior, and neurochemistry. Methods: The present study examined its effect on the endocannabinoid system. Adolescent rats had daily oral access to either water (control), low dose MP (4/10 mg/kg), or high dose MP (30/60 mg/kg). After 13 weeks of exposure, half of the rats in each group were euthanized, however the remaining rats underwent a four-week long abstinence period. Cannabinoid receptor 1 binding (CB1) was measured with in vitro autoradiography using [3H] SR141716A. Results: Rats who underwent a 4-week abstinence period after exposure to chronic HD MP showed increased binding compared to rats with no abstinence period in several cortical and basal ganglia regions of the brain. In contrast to this, rats who underwent a 4-week abstinence period after exposure to chronic LD MP showed lower binding compared to rats with no abstinence period in mainly the basal ganglia regions and in the hindlimb region of the somatosensory cortex. Following 4 weeks of drug abstinence, rats who were previously given HD MP showed higher [ 3H] SR141716A binding than rats given LD MP in many of the cortical and basal ganglia regions examined. These results highlight biphasic effects of MP treatment on cannabinoid receptor levels. Abstinence from HD MP seemed to increase CB1 receptor levels while abstinence from LD MP seemed to decrease CB1 levels. Conclusion: Given the prolific expression of cannabinoid receptors throughout the brain, many types of behaviors may be affected as a result of MP abstinence. Further research will be needed to help identify these behavioral changes.

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Pharmacological Targeting of the Transcription Factor Nrf2 at the Basal Ganglia Provides Disease Modifying Therapy for Experimental Parkinsonism

Antioxidants and Redox Signaling ◽

10.1089/ars.2010.3731 ◽

2011 ◽

Vol 14 (12) ◽

pp. 2347-2360 ◽

Cited By ~ 175

Author(s):

Agnieszka Jazwa ◽

Ana I. Rojo ◽

Nadia G. Innamorato ◽

Marlen Hesse ◽

Javier Fernández-Ruiz ◽

...

Keyword(s):

Transcription Factor ◽

Basal Ganglia ◽

Experimental Parkinsonism ◽

Disease Modifying Therapy ◽

Disease Modifying

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Activation of Nigral and Pallidal Dopamine D1-Like Receptors Modulates Basal Ganglia Outflow in Monkeys

Journal of Neurophysiology ◽

10.1152/jn.00171.2007 ◽

2007 ◽

Vol 98 (3) ◽

pp. 1489-1500 ◽

Cited By ~ 45

Author(s):

Michele A. Kliem ◽

Nigel T. Maidment ◽

Larry C. Ackerson ◽

Sugong Chen ◽

Yoland Smith ◽

...

Keyword(s):

Basal Ganglia ◽

Rhesus Monkeys ◽

Receptor Agonist ◽

Gaba Release ◽

Aminobutyric Acid ◽

Substantia Nigra Pars Reticulata ◽

Axon Terminals ◽

Discharge Rates ◽

Dopaminergic Tone ◽

Output Neurons

Studies of the effects of dopamine in the basal ganglia have focused on the striatum, whereas the functions of dopamine released in the internal pallidal segment (GPi) or in the substantia nigra pars reticulata (SNr) have received less attention. Anatomic and biochemical investigations have demonstrated the presence of dopamine D1-like receptors (D1LRs) in GPi and SNr, which are primarily located on axons and axon terminals of the GABAergic striatopallidal and striatonigral afferents. Our experiments assessed the effects of D1LR ligands in GPi and SNr on local γ-aminobutyric acid (GABA) levels and neuronal activity in these nuclei in rhesus monkeys. Microinjections of the D1LR receptor agonist SKF82958 into GPi and SNr significantly reduced discharge rates in GPi and SNr, whereas injections of the D1LR antagonist SCH23390 increased firing in the majority of GPi neurons. D1LR activation also increased bursting and oscillations in neuronal discharge in the 3- to 15-Hz band in both structures, whereas D1LR blockade had the opposite effects in GPi. Microdialysis measurements of GABA concentrations in GPi and SNr showed that the D1LR agonist increased the level of the transmitter. Both findings are compatible with the hypothesis that D1LR activation leads to GABA release from striatopallidal or striatonigral afferents, which may secondarily reduce firing of basal ganglia output neurons. The antagonist experiments suggest that a dopaminergic “tone” exists in GPi. Our results support the finding that D1LR activation may have powerful effects on GPi and SNr neurons and may mediate some of the effects of dopamine replacement therapies in Parkinson's disease.

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Dopaminergic modulation of basal ganglia output through coupled excitation–inhibition

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1611146114 ◽

2017 ◽

Vol 114 (22) ◽

pp. 5713-5718 ◽

Cited By ~ 14

Author(s):

Agata Budzillo ◽

Alison Duffy ◽

Kimberly E. Miller ◽

Adrienne L. Fairhall ◽

David J. Perkel

Keyword(s):

Basal Ganglia ◽

Dynamic Change ◽

Vocal Learning ◽

Synaptic Connections ◽

Biophysical Mechanism ◽

Output Neurons ◽

Neural Variability ◽

Vocal Variability ◽

Selection Of

Learning and maintenance of skilled movements require exploration of motor space and selection of appropriate actions. Vocal learning and social context-dependent plasticity in songbirds depend on a basal ganglia circuit, which actively generates vocal variability. Dopamine in the basal ganglia reduces trial-to-trial neural variability when the bird engages in courtship song. Here, we present evidence for a unique, tonically active, excitatory interneuron in the songbird basal ganglia that makes strong synaptic connections onto output pallidal neurons, often linked in time with inhibitory events. Dopamine receptor activity modulates the coupling of these excitatory and inhibitory events in vitro, which results in a dynamic change in the synchrony of a modeled population of basal ganglia output neurons receiving excitatory and inhibitory inputs. The excitatory interneuron thus serves as one biophysical mechanism for the introduction or modulation of neural variability in this circuit.

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Inhibition of Striatal Soluble Guanylyl Cyclase-cGMP Signaling Reverses Basal Ganglia Dysfunction and Akinesia in Experimental Parkinsonism

PLoS ONE ◽

10.1371/journal.pone.0027187 ◽

2011 ◽

Vol 6 (11) ◽

pp. e27187 ◽

Cited By ~ 26

Author(s):

Kuei Y. Tseng ◽

Adriana Caballero ◽

Alexander Dec ◽

Daryn K. Cass ◽

Natalie Simak ◽

...

Keyword(s):

Basal Ganglia ◽

Guanylyl Cyclase ◽

Soluble Guanylyl Cyclase ◽

Experimental Parkinsonism ◽

Cgmp Signaling

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Local inhibition shapes afferent excitatory drive of output neurons in the songbird basal ganglia network

BMC Neuroscience ◽

10.1186/1471-2202-9-s1-o6 ◽

2008 ◽

Vol 9 (S1) ◽

Author(s):

Arthur Leblois ◽

David J Perkel

Keyword(s):

Basal Ganglia ◽

Local Inhibition ◽

Output Neurons ◽

Excitatory Drive

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Dopamine depletion induced up-regulation of HCN3 enhances rebound excitability of basal ganglia output neurons

Neurobiology of Disease ◽

10.1016/j.nbd.2009.01.007 ◽

2009 ◽

Vol 34 (1) ◽

pp. 178-188 ◽

Cited By ~ 6

Author(s):

Bernhard H. Meurers ◽

Gustavo Dziewczapolski ◽

Anton Bittner ◽

Tao Shi ◽

Fredrik Kamme ◽

...

Keyword(s):

Basal Ganglia ◽

Dopamine Depletion ◽

Output Neurons

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CB1 Cannabinoid Receptor Inhibits Synaptic Release of Glutamate in Rat Dorsolateral Striatum

Journal of Neurophysiology ◽

10.1152/jn.2001.85.1.468 ◽

2001 ◽

Vol 85 (1) ◽

pp. 468-471 ◽

Cited By ~ 277

Author(s):

Gregory Gerdeman ◽

David M. Lovinger

Keyword(s):

Basal Ganglia ◽

Synaptic Transmission ◽

Neurotransmitter Release ◽

Cannabinoid Receptors ◽

Glutamate Release ◽

Brain Slices ◽

Cb1 Receptor ◽

Motor Deficits ◽

Dependent Manner ◽

Dorsolateral Striatum

CB1 cannabinoid receptors in the neostriatum mediate profound motor deficits induced when cannabinoid drugs are administered to rodents. Because the CB1 receptor has been shown to inhibit neurotransmitter release in various brain areas, we investigated the effects of CB1 activation on glutamatergic synaptic transmission in the dorsolateral striatum of the rat where the CB1 receptor is highly expressed. We performed whole cell voltage-clamp experiments in striatal brain slices and applied the CB1 agonists HU-210 or WIN 55,212–2 during measurement of synaptic transmission. Excitatory postsynaptic currents (EPSCs), evoked by electrical stimulation of afferent fibers, were significantly reduced in a dose-dependent manner by CB1 agonist application. EPSC inhibition was accompanied by an increase in two separate indices of presynaptic release, the paired-pulse response ratio and the coefficient of variation, suggesting a decrease in neurotransmitter release. These effects were prevented by application of the CB1 antagonist SR141716A. When Sr2+ was substituted for Ca2+ in the extracellular solution, application of HU-210 (1 μM) significantly reduced the frequency, but not amplitude, of evoked, asynchronous quantal release events. Spontaneous release events were similarly decreased in frequency with no change in amplitude. These findings further support the interpretation that CB1 activation leads to a decrease of glutamate release from afferent terminals in the striatum. These results reveal a novel potential role for cannabinoids in regulating striatal function and thus basal ganglia output and may suggest CB1-targeted drugs as potential therapeutic agents in the treatment of Parkinson's disease and other basal ganglia disorders.

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