scholarly journals Cocaine effects on mouse incentive-learning and human addiction are linked to α2 subunit-containing GABAA receptors

2010 ◽  
Vol 107 (5) ◽  
pp. 2289-2294 ◽  
Author(s):  
Claire I. Dixon ◽  
Hannah V. Morris ◽  
Gerome Breen ◽  
Sylvane Desrivieres ◽  
Sarah Jugurnauth ◽  
...  
Keyword(s):  
Behavioral Sensitization ◽  
Binding Pocket ◽  
Receptor Subtype ◽  
Medium Spiny Neurons ◽  
Gabaergic Neurotransmission ◽  
Spiny Neurons ◽  
Benzodiazepine Binding ◽  
Necessary And Sufficient ◽  
The Brain

Because GABAA receptors containing α2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with α2 gene deletion showed reduced synaptic GABAA receptor-mediated responses. Behaviorally, the deletion abolished cocaine’s ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of α2-GABAA receptors (α2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In α2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of α2−GABAA receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction.

scholarly journals The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

2021 ◽  
Author(s):  
Marlaina R. Stocco ◽  
Ahmed A. El-Sherbeni ◽  
Bin Zhao ◽  
Maria Novalen ◽  
Rachel F. Tyndale
Keyword(s):  
Neurotransmitter Release ◽  
Behavioral Sensitization ◽  
Serotonin Release ◽  
Striatal Dopamine ◽  
Irreversible Inhibitor ◽  
Drug Concentrations ◽  
Metabolite Concentrations ◽  
The Brain

Abstract Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

scholarly journals Striatal Neurodegeneration that Mimics Huntington’s Disease Modifies GABA-induced Currents

2018 ◽  
Vol 8 (12) ◽  
pp. 217
Author(s):  
Jorge Flores-Hernández ◽  
Jeanette Garzón-Vázquez ◽  
Gustavo Hernández-Carballo ◽  
Elizabeth Nieto-Mendoza ◽  
Evelyn Ruíz-Luna ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtype ◽  
Medium Spiny Neurons ◽  
Nitropropionic Acid ◽  
Spiny Neurons ◽  
Excitotoxic Damage ◽  
Induced Currents

Huntington’s Disease (HD) is a degenerative disease which produces cognitive and motor disturbances. Treatment with GABAergic agonists improves the behavior and activity of mitochondrial complexes in rodents treated with 3-nitropropionic acid to mimic HD symptomatology. Apparently, GABA receptors activity may protect striatal medium spiny neurons (MSNs) from excitotoxic damage. This study evaluates whether mitochondrial inhibition with 3-NP that mimics the early stages of HD, modifies the kinetics and pharmacology of GABA receptors in patch clamp recorded dissociated MSNs cells. The results show that MSNs from mice treated with 3-NP exhibited differences in GABA-induced dose-response currents and pharmacological responses that suggests the presence of GABAC receptors in MSNs. Furthermore, there was a reduction in the effect of the GABAC antagonist that demonstrates a lessening of this GABA receptor subtype activity as a result of mitochondria inhibition.

scholarly journals Toxoplasma gondii injected neurons localize to the cortex and striatum and have altered firing

2021 ◽  
Author(s):  
Oscar A. Mendez ◽  
Emiliano Flores Machado ◽  
Jing Lu ◽  
Anita A. Koshy
Keyword(s):  
Toxoplasma Gondii ◽  
Single Neuron ◽  
Latent Infection ◽  
Ex Vivo ◽  
Medium Spiny Neurons ◽  
Patch Clamping ◽  
Spiny Neurons ◽  
The Brain ◽  
Mapping Program

AbstractToxoplasma gondii is an intracellular parasite that causes a long-term latent infection of neurons. Using a custom MATLAB-based mapping program in combination with a mouse model that allows us to permanently mark neurons injected with parasite proteins, we found that Toxoplasma-injected neurons (TINs) are heterogeneously distributed in the brain, primarily localizing to the cortex followed by the striatum. Using immunofluorescence co-localization assays, we determined that cortical TINs are commonly (>50%) excitatory neurons (FoxP2+) and that striatal TINs are often (>65%) medium spiny neurons (MSNs) (FoxP2+). As MSNs have highly characterized electrophysiology, we used ex vivo slices from infected mice to perform single neuron patch-clamping on striatal TINs and neighboring uninfected MSNs (bystander MSNs). These studies demonstrated that TINs have highly abnormal electrophysiology, while the electrophysiology of bystander MSNs was akin to that of MSNs from uninfected mice. Collectively, these data offer new neuroanatomic and electrophysiologic insights into CNS toxoplasmosis.

scholarly journals Putative role of pharmacogenetics to elucidate the mechanism of tardive dyskinesia in schizophrenia

2019 ◽  
Vol 20 (17) ◽  
pp. 1199-1223 ◽  
Author(s):  
Anton JM Loonen ◽  
Bob Wilffert ◽  
Svetlana A Ivanova
Keyword(s):  
Oxidative Stress ◽  
Tardive Dyskinesia ◽  
Genetic Variants ◽  
Long Term Potentiation ◽  
Specific Gene ◽  
Medium Spiny Neurons ◽  
Spiny Neurons ◽  
Long Term Treatment

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

Recent progress on the role of GABAergic neurotransmission in the pathogenesis of Alzheimer’s disease

2016 ◽  
Vol 27 (4) ◽  
pp. 449-455 ◽  
Author(s):  
Ghulam Abbas ◽  
Wajahat Mahmood ◽  
Nurul Kabir
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gaba Receptor ◽  
Amyloid Β ◽  
Receptor Subtypes ◽  
Causative Role ◽  
Gabaergic Neurotransmission ◽  
Promising Target ◽  
The Brain

AbstractDespite their possible causative role, targeting amyloidosis, tau phosphorylation, acetylcholine esterase, glutamate, oxidative stress and mitochondrial metabolism have not yet led to the development of drugs to cure Alzheimer’s disease (AD). Recent preclinical and clinical reports exhibit a surge in interest in the role of GABAergic neurotransmission in the pathogenesis of AD. The interaction among GABAergic signaling, amyloid-β and acetylcholine is shown to affect the homeostasis between excitation (glutamate) and inhibition (GABA) in the brain. As a consequence, over-excitation leads to neurodegeneration (excitotoxicity) and impairment in the higher level functions. Previously, the glutamate arm of this balance received the most attention. Recent literature suggests that over-excitation is primarily mediated by dysfunctional GABA signaling and can possibly be restored by rectifying anomalous metabolism observed in the GABAergic neurons during AD. Additionally, neurogenesis and synaptogenesis have also been linked with GABAergic signaling. This association may provide a basis for the needed repair mechanism. Furthermore, several preclinical interventional studies revealed that targeting various GABA receptor subtypes holds potential in overcoming the memory deficits associated with AD. In conclusion, the recent scientific literature suggests that GABAergic signaling presents itself as a promising target for anti-AD drug development.

The Role of the Brain Histaminergic Neuron System in Methamphetamine-Induced Behavioral Sensitization in Rats

1996 ◽  
Vol 801 (1 Cellular and) ◽  
pp. 353-360 ◽  
Author(s):  
CHIHIRO ITO ◽  
MITSUMOTO SATO ◽  
KENJI ONODERA ◽  
TAKEHIKO WATANABE
Keyword(s):  
Behavioral Sensitization ◽  
Neuron System ◽  
The Brain ◽  
Histaminergic Neuron

scholarly journals Injection with Toxoplasma gondii protein affects neuron health and survival

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Oscar A Mendez ◽  
Emiliano Flores Machado ◽  
Jing Lu ◽  
Anita Koshy
Keyword(s):  
Toxoplasma Gondii ◽  
Single Neuron ◽  
Latent Infection ◽  
Medium Spiny Neurons ◽  
Patch Clamping ◽  
Spiny Neurons ◽  
The Brain ◽  
Mapping Program

Toxoplasma gondii is an intracellular parasite that causes a long-term latent infection of neurons. Using a custom MATLAB-based mapping program in combination with a mouse model that allows us to permanently mark neurons injected with parasite proteins, we found that Toxoplasma-injected neurons (TINs) are heterogeneously distributed in the brain, primarily localizing to the cortex followed by the striatum. In addition, we determined that cortical TINs are commonly (>50%) excitatory neurons (FoxP2+) and that striatal TINs are often (>65%) medium spiny neurons (MSNs) (FoxP2+). By performing single neuron patch-clamping on striatal TINs and neighboring uninfected MSNs, we discovered that TINs have highly aberrant electrophysiology. As approximately 90% of TINs will die by 8 weeks post-infection, this abnormal physiology suggests that injection with Toxoplasma protein— either directly or indirectly— affects neuronal health and survival. Collectively, these data offer the first insights into which neurons interact with Toxoplasma and how these interactions alter neuron physiology in vivo.

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