Mesolimbic dopamine neurons: Effects of 6-hydroxydopamine-induced destruction and receptor blockade on drug-induced rotation of rats

1977 ◽  
Vol 55 (1) ◽  
pp. 35-41 ◽  
Author(s):  
P. H. Kelly ◽  
K. E. Moore
Keyword(s):  
Dopamine Neurons ◽  
Receptor Blockade ◽  
Mesolimbic Dopamine ◽  
Drug Induced ◽  
6 Hydroxydopamine

scholarly journals Acute dopamine receptor blockade in substantia nigra pars reticulata: a possible model for drug-induced Parkinsonism

2018 ◽  
Vol 120 (6) ◽  
pp. 2922-2938 ◽  
Author(s):  
Verónica Alejandra Cáceres-Chávez ◽  
Ricardo Hernández-Martínez ◽  
Jesús Pérez-Ortega ◽  
Marco Arieli Herrera-Valdez ◽  
Jose J. Aceves ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Substantia Nigra Pars Reticulata ◽  
Receptor Blockade ◽  
Drug Induced ◽  
Tonic Firing ◽  
Neuron Firing ◽  
Similar Preparation ◽  
6 Hydroxydopamine ◽  
Irregular Firing

Dopamine (DA) depletion modifies the firing pattern of neurons in the substantia nigra pars reticulata (SNr), shifting their mostly tonic firing toward irregularity and bursting, traits of pathological firing underlying rigidity and postural instability in Parkinson’s disease (PD) patients and animal models of Parkinsonism (PS). Drug-induced Parkinsonism (DIP) represents 20–40% of clinical cases of PS, becoming a problem for differential diagnosis, and is still not well studied with physiological tools. It may co-occur with tardive dyskinesia. Here we use in vitro slice preparations including the SNr to observe drug-induced pathological firing by using drugs that most likely produce it, DA-receptor antagonists (SCH23390 plus sulpiride), to compare with firing patterns found in DA-depleted tissue. The hypothesis is that SNr firing would be similar under both conditions, a prerequisite to the proposal of a similar preparation to test other DIP-producing drugs. Firing was analyzed with three complementary metrics, showing similarities between DA depletion and acute DA-receptor blockade. Moreover, blockade of either nonselective cationic channels or Cav3 T-type calcium channels hyperpolarized the membrane and abolished bursting and irregular firing, silencing SNr neurons in both conditions. Therefore, currents generating firing in control conditions are in part responsible for pathological firing. Haloperidol, a DIP-producing drug, reproduced DA-receptor antagonist firing modifications. Since acute DA-receptor blockade induces SNr neuron firing similar to that found in the 6-hydroxydopamine model of PS, output basal ganglia neurons may play a role in generating DIP. Therefore, this study opens the way to test other DIP-producing drugs. NEW & NOTEWORTHY Dopamine (DA) depletion enhances substantia nigra pars reticulata (SNr) neuron bursting and irregular firing, hallmarks of Parkinsonism. Several drugs, including antipsychotics, antidepressants, and calcium channel antagonists, among others, produce drug-induced Parkinsonism. Here we show the first comparison between SNr neuron firing after DA depletion vs. firing found after acute blockade of DA receptors. It was found that firing in both conditions is similar, implying that pathological SNr neuron firing is also a physiological correlate of drug-induced Parkinsonism.

Functional interaction of dopamine and glutamate in the nucleus accumbens in the regulation of locomotion

1993 ◽  
Vol 71 (5-6) ◽  
pp. 407-413 ◽  
Author(s):  
Michael Wu ◽  
Stefan M. Brudzynski ◽  
Gordon J. Mogenson
Keyword(s):  
Locomotor Activity ◽  
Nucleus Accumbens ◽  
Nmda Receptor ◽  
Aspartic Acid ◽  
Receptor Agonist ◽  
Dopamine Neurons ◽  
Mesolimbic Dopamine ◽  
Axon Terminals ◽  
6 Hydroxydopamine ◽  
Dose Dependent

The interaction of dopamine and glutamate in the nucleus accumbens in the regulation of locomotion was investigated. Microinjection of N-methyl-D-aspartic acid (NMDA, a glutamatergic NMDA receptor agonist) or α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA, a quisqualic receptor agonist which is a glutamatergic non-NMDA receptor agonist) into the nucleus accumbens caused a substantial increase in locomotor activity. This increase in locomotor activity was significantly reduced by prior administration of the dopamine D2 agonist quinpirole, but not the D1 agonist, SKF 38393, into the same brain sites. The reduction in locomotion produced by quinpirole was dose dependent. Eight days after the ventral tegmental area was lesioned with 6-hydroxydopamine to destroy the dopamine projection and the axon terminals of the mesolimbic dopamine neurons in nucleus accumbens, the hyperkinetic effects produced by injections of NMDA and AMPA into the nucleus accumbens were substantially reduced. These results suggested that the glutamate agonist induced locomotion is mediated by dopamine. Thus, it appears that NMDA- or AMPA-induced locomotion is due to the activation of glutamate receptors on the mesolimbic dopamine terminals in the nucleus accumbens which release dopamine and subsequently increase locomotion.Key words: nucleus accumbens, dopamine, glutamate, quinpirole, locomotion, N-methyl-D-aspartic acid, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid.

scholarly journals Supramammillary neurons projecting to the septum regulate dopamine and motivation for environmental interaction in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Andrew J. Kesner ◽  
Rick Shin ◽  
Coleman B. Calva ◽  
Reuben F. Don ◽  
Sue Junn ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Dopamine Neurons ◽  
Theta Oscillations ◽  
Mesolimbic Dopamine ◽  
Sucrose Consumption ◽  
Behavioral Interaction ◽  
Hypothalamic Structure ◽  
Hippocampal Theta ◽  
Substances Of Abuse ◽  
Stimulation Of

AbstractThe supramammillary region (SuM) is a posterior hypothalamic structure, known to regulate hippocampal theta oscillations and arousal. However, recent studies reported that the stimulation of SuM neurons with neuroactive chemicals, including substances of abuse, is reinforcing. We conducted experiments to elucidate how SuM neurons mediate such effects. Using optogenetics, we found that the excitation of SuM glutamatergic (GLU) neurons was reinforcing in mice; this effect was relayed by their projections to septal GLU neurons. SuM neurons were active during exploration and approach behavior and diminished activity during sucrose consumption. Consistently, inhibition of SuM neurons disrupted approach responses, but not sucrose consumption. Such functions are similar to those of mesolimbic dopamine neurons. Indeed, the stimulation of SuM-to-septum GLU neurons and septum-to-ventral tegmental area (VTA) GLU neurons activated mesolimbic dopamine neurons. We propose that the supramammillo-septo-VTA pathway regulates arousal that reinforces and energizes behavioral interaction with the environment.

scholarly journals Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats

2021 ◽  
pp. 1-24
Author(s):  
Juho-Matti Renko ◽  
Arun Kumar Mahato ◽  
Tanel Visnapuu ◽  
Konsta Valkonen ◽  
Mati Karelson ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Dopamine Neurons ◽  
Dopamine Depletion ◽  
Wild Type ◽  
Disease Modifying Therapy ◽  
Immortalized Cells ◽  
Midbrain Dopamine ◽  
6 Hydroxydopamine

Background: Parkinson’s disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF’s receptor, the transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo. Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons from MPP +-induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and could have protected dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying therapy for PD.

scholarly journals Adeno-Associated Viral Delivery of GDNF Promotes Recovery of Dopaminergic Phenotype following a Unilateral 6-Hydroxydopamine Lesion

2002 ◽  
Vol 11 (3) ◽  
pp. 215-227 ◽  
Author(s):  
John Mcgrath ◽  
Elishia Lintz ◽  
Barry J. Hoffer ◽  
Greg A. Gerhardt ◽  
E. Matthew Quintero ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Viral Vectors ◽  
Medial Forebrain Bundle ◽  
Therapeutic Potential ◽  
Clinical Situation ◽  
Dopamine Neurons ◽  
Nigrostriatal System ◽  
Nigrostriatal Pathway ◽  
Neurotoxic Lesion ◽  
6 Hydroxydopamine

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for dopamine neurons that has been proposed for use in the treatment of Parkinson's disease (PD). Previous studies using viral vectors to deliver GDNF in rodent models of PD have entailed administering the virus either prior to or immediately after neurotoxin-induced lesions, when the nigrostriatal pathway is largely intact, a paradigm that does not accurately reflect the clinical situation encountered with Parkinson's patients. In this study, recombinant adeno-associated virus carrying the gene encoding GDNF (rAAV-GDNF) was administered to animals bearing a maximal lesion in the nigrostriatal system, more closely resembling fully developed PD. Rats were treated with 6-hydroxydopamine into the medial forebrain bundle and assessed by apomorphine-induced rotational behavior for 5 weeks prior to virus administration. Within 4 weeks of a single intrastriatal injection of rAAV-GDNF, unilaterally lesioned animals exhibited significant behavioral recovery, which correlated with increased expression of dopaminergic markers in the substantia nigra, the medial forebrain bundle, and the striatum. Our findings demonstrate that rAAV-GDNF is capable of rescuing adult dopaminergic neurons from near complete phenotypic loss following a neurotoxic lesion, effectively restoring a functional dopaminergic pathway and diminishing motoric deficits. These data provide further support for the therapeutic potential of rAAV-GDNF-based gene therapy in the treatment of PD.

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