scholarly journals Selective D2 and D3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

2018 ◽  
Author(s):  
Daniel F. Manvich ◽  
Alyssa K. Petko ◽  
Rachel C. Branco ◽  
Stephanie L. Foster ◽  
Kirsten A. Porter-Stransky ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Drugs Of Abuse ◽  
Ex Vivo ◽  
Medium Spiny Neurons ◽  
D3 Receptor ◽  
Receptor Antagonists ◽  
Fast Scan Cyclic Voltammetry ◽  
Spiny Neurons ◽  
Cocaine Responses ◽  
Da Release

AbstractBackgroundThe D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for the treatment of several diseases including schizophrenia, Parkinson’s disease, and substance use disorders. However, studies investigating the modulatory impact of D3R antagonism on dopamine neurotransmission or the effects drugs of abuse have produced mixed results, in part because D3R-targeted compounds often also interact with D2 receptors (D2R). The purpose of this study was to compare the consequences of selective D2R or D3R antagonism on the behavioral effects of cocaine in mice, and to identify the neurobiological mechanisms underlying their modulatory effects.MethodsWe characterized the effects of selective D2R or D3R antagonism in mice on 1) basal and cocaine-induced locomotor activity, 2) presynaptic dopamine release and clearance in the nucleus accumbens using ex vivo fast scan cyclic voltammetry, and 3) dopamine-mediated signaling in D1-expressing and D2-expressing medium spiny neurons using ex vivo electrophysiology.ResultsPretreatment with the selective D2R antagonist L-741,626 attenuated, while pretreatment with the selective D3R antagonist PG01037 enhanced, the locomotor-activating effects of acute and repeated cocaine administration. While both antagonists potentiated cocaine-induced increases in presynaptic DA release, D3R blockade uniquely facilitated DA-mediated excitation of D1-expressing medium spiny neurons in the nucleus accumbens.ConclusionsSelective D3R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D2R antagonism or nonselective D2-like receptor antagonists, likely by facilitating D1-mediated excitation in the nucleus accumbens. These findings provide important insights into the neuropharmacological actions of D3R antagonists on mesolimbic dopamine neurotransmission.

scholarly journals Binge Alcohol Drinking Alters Synaptic Processing of Executive and Emotional Information in Core Nucleus Accumbens Medium Spiny Neurons

2021 ◽  
Vol 15 ◽  
Author(s):  
Jenya Kolpakova ◽  
Vincent van der Vinne ◽  
Pablo Giménez-Gómez ◽  
Timmy Le ◽  
In-Jee You ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Alcohol Drinking ◽  
Drugs Of Abuse ◽  
Alcohol Exposure ◽  
Medium Spiny Neurons ◽  
Dependent Manner ◽  
Emotional Information ◽  
Core Nucleus ◽  
Spiny Neurons

The nucleus accumbens (NAc) is a forebrain region mediating the positive-reinforcing properties of drugs of abuse, including alcohol. It receives glutamatergic projections from multiple forebrain and limbic regions such as the prefrontal cortex (PFCx) and basolateral amygdala (BLA), respectively. However, it is unknown how NAc medium spiny neurons (MSNs) integrate PFCx and BLA inputs, and how this integration is affected by alcohol exposure. Because progress has been hampered by the inability to independently stimulate different pathways, we implemented a dual wavelength optogenetic approach to selectively and independently stimulate PFCx and BLA NAc inputs within the same brain slice. This approach functionally demonstrates that PFCx and BLA inputs synapse onto the same MSNs where they reciprocally inhibit each other pre-synaptically in a strict time-dependent manner. In alcohol-naïve mice, this temporal gating of BLA-inputs by PFCx afferents is stronger than the reverse, revealing that MSNs prioritize high-order executive processes information from the PFCx. Importantly, binge alcohol drinking alters this reciprocal inhibition by unilaterally strengthening BLA inhibition of PFCx inputs. In line with this observation, we demonstrate that in vivo optogenetic stimulation of the BLA, but not PFCx, blocks binge alcohol drinking escalation in mice. Overall, our results identify NAc MSNs as a key integrator of executive and emotional information and show that this integration is dysregulated during binge alcohol drinking.

scholarly journals Selective D2 and D3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

2019 ◽  
Vol 44 (8) ◽  
pp. 1445-1455 ◽  
Author(s):  
Daniel F. Manvich ◽  
Alyssa K. Petko ◽  
Rachel C. Branco ◽  
Stephanie L. Foster ◽  
Kirsten A. Porter-Stransky ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
D3 Receptor ◽  
Receptor Antagonists ◽  
Cocaine Responses

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 Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia

2017 ◽  
Vol 114 (19) ◽  
pp. 5029-5034 ◽  
Author(s):  
Grietje Krabbe ◽  
S. Sakura Minami ◽  
Jon I. Etchegaray ◽  
Praveen Taneja ◽  
Biljana Djukic ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Frontotemporal Dementia ◽  
Knockout Mice ◽  
Nuclear Factor Κb ◽  
Medium Spiny Neurons ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Spiny Neurons ◽  
Increased Risk ◽  
Excessive Grooming

Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive–compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.

scholarly journals Sex-Specific Role for Egr3 in Nucleus Accumbens D2-Medium Spiny Neurons Following Long-Term Abstinence From Cocaine Self-administration

2020 ◽  
Vol 87 (11) ◽  
pp. 992-1000 ◽  
Author(s):  
Michel Engeln ◽  
Swarup Mitra ◽  
Ramesh Chandra ◽  
Utsav Gyawali ◽  
Megan E. Fox ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Specific Role ◽  
Medium Spiny Neurons ◽  
Self Administration ◽  
Spiny Neurons

scholarly journals Trafficking of calcium-permeable and calcium-impermeable AMPA receptors in nucleus accumbens medium spiny neurons co-cultured with prefrontal cortex neurons

2017 ◽  
Vol 116 ◽  
pp. 224-232 ◽  
Author(s):  
Craig T. Werner ◽  
Conor H. Murray ◽  
Jeremy M. Reimers ◽  
Niravkumar M. Chauhan ◽  
Kenneth K.Y. Woo ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Nucleus Accumbens ◽  
Ampa Receptors ◽  
Medium Spiny Neurons ◽  
Spiny Neurons

scholarly journals Presence of Inhibitory Glycinergic Transmission in Medium Spiny Neurons in the Nucleus Accumbens

2018 ◽  
Vol 11 ◽  
Author(s):  
Braulio Muñoz ◽  
Gonzalo E. Yevenes ◽  
Benjamin Förstera ◽  
David M. Lovinger ◽  
Luis G. Aguayo
Keyword(s):  
Nucleus Accumbens ◽  
Medium Spiny Neurons ◽  
Spiny Neurons

Pitx3 Deficiency in Mice Affects Cholinergic Modulation of GABAergic Synapses in the Nucleus Accumbens

2006 ◽  
Vol 96 (4) ◽  
pp. 2034-2041 ◽  
Author(s):  
Mischa de Rover ◽  
Johannes C. Lodder ◽  
Marten P. Smidt ◽  
Arjen B. Brussaard
Keyword(s):  
Nucleus Accumbens ◽  
Medium Spiny Neurons ◽  
Wild Type ◽  
Cholinergic Modulation ◽  
Firing Patterns ◽  
Neural Adaptations ◽  
Cholinergic Interneurons ◽  
Spiny Neurons ◽  
Gating Mechanism ◽  
Deficient Mice

We investigated to what extent Pitx3 deficiency, causing hyperdopaminergic transmission in the nucleus accumbens microcircuitry, may lead to developmental changes. First, spontaneous firing activity of cholinergic interneurons in the nucleus accumbens was recorded in vitro. Firing patterns in the Pitx3-deficient mice were more variable and intrinsically different from those observed in wild-type mice. Next, to test whether the irregular firing patterns observed in mutant mice affected the endogenous nicotinic modulation of the GABAergic input of medium spiny neurons, we recorded spontaneous GABAergic inputs to these cells before and after the application of the nicotinic receptor blocker mecamylamine. Effects of mecamylamine were found in slices of either genotype, but in a rather inconsistent manner. Possibly this was attributable to heterogeneity in firing of nearby cholinergic interneurons. Thus paired recordings of cholinergic interneurons and medium spiny neurons were performed to more precisely control the experimental conditions of the cholinergic modulation of GABAergic synaptic transmission. We found that controlling action potential firing in cholinergic neurons leads to a conditional increase in GABAergic input frequency in wild-type mice but not in Pitx3-deficient mice. We conclude that Pitx3-deficient mice have neural adaptations at the level of the nucleus accumbens microcircuitry that in turn may have behavioral consequences. It is discussed to what extent dopamine release in the nucleus accumbens may be a long-term gating mechanism leading to alterations in cholinergic transmission in the nucleus accumbens, in line with previously reported neural adaptations found as consequences of repeated drug treatment in rodents.

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