Effect of Modulation of the Astrocytic Glutamate Transporters’ Expression on Cocaine-Induced Reinstatement in Male P Rats Exposed to Ethanol

2020 ◽  
Author(s):  
Alaa M Hammad ◽  
Fawaz Alasmari ◽  
Youssef Sari
Keyword(s):  
Locomotor Activity ◽  
Glutamate Transporter ◽  
Glutamate Transporters ◽  
Ethanol Exposure ◽  
Ethanol Intake ◽  
Cocaine Exposure ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Lactam Antibiotic ◽  
Glutamate Transporter 1

Abstract Aim Reinforcing properties of ethanol and cocaine are mediated in part through the glutamatergic system. Extracellular glutamate concentration is strictly maintained through several glutamate transporters, such as glutamate transporter 1 (GLT-1), cystine/glutamate transporter (xCT) and glutamate aspartate transporter (GLAST). Previous findings revealed that cocaine and ethanol exposure downregulated GLT-1 and xCT, and that β-lactam antibiotics restored their expression. Methods In this study, we investigated the effect of ampicillin/sulbactam (AMP/SUL) (200 mg/kg, i.p.), a β-lactam antibiotic, on cocaine-induced reinstatement and locomotor activity in male alcohol preferring (P) rats using free choice ethanol (15 and 30%, v/v) and water. We also investigated the effect of co-exposure to ethanol and cocaine (20 mg/kg, i.p.) on GLT-1, xCT and GLAST expression in the nucleus accumbens (NAc) core, NAc shell and dorsomedial prefrontal cortex (dmPFC). Results Cocaine exposure decreased ethanol intake and preference. Cocaine and ethanol co-exposure acquired place preference and increased locomotor activity compared to ethanol-exposed rats. GLT-1 and xCT expression were downregulated after cocaine and ethanol co-exposure in the NAc core and shell, but not in dmPFC. AMP/SUL attenuated reinstatement to cocaine as well attenuated the decrease in locomotor activity and ethanol intake and preference. These effects were associated with upregulation of GLT-1 and xCT expression in the NAc core/shell and dmPFC. GLAST expression was not affected after ethanol and cocaine co-exposure or AMP/SUL treatment. Conclusion Our findings demonstrate that astrocytic glutamate transporters within the mesocorticolimbic area are critical targets in modulating cocaine-seeking behavior while being consuming ethanol.

scholarly journals Effects of Cocaine Exposure on Astrocytic Glutamate Transporters and Relapse-Like Ethanol-Drinking Behavior in Male Alcohol-Preferring Rats

2020 ◽  
Vol 55 (3) ◽  
pp. 254-263 ◽  
Author(s):  
Alaa M Hammad ◽  
Youssef Sari
Keyword(s):  
Drugs Of Abuse ◽  
Drinking Behavior ◽  
Glutamate Transporter ◽  
Glutamate Transporters ◽  
Brain Regions ◽  
Ethanol Intake ◽  
Free Access ◽  
Cocaine Exposure ◽  
Extracellular Glutamate ◽  
Lactam Antibiotic

Abstract Aim Glutamate has been considered as neurotransmitter that is critical in triggering relapse to drugs of abuse, including ethanol and cocaine. Extracellular glutamate concentrations are tightly regulated by several mechanisms, including reuptake through glutamate transporters. Glutamate transporter type 1 (GLT-1) is responsible for clearing the majority of extracellular glutamate. The astrocytic cystine/glutamate antiporter (xCT) regulates also glutamate homeostasis. In this study, we investigated the effects of cocaine exposure and ampicillin/sulbactam (AMP/SUL), a β-lactam antibiotic known to upregulate GLT-1 and xCT, on relapse-like ethanol intake and the expression of astrocytic glutamate transporters in mesocorticolimbic brain regions. Methods Male alcohol-preferring (P) rats had free access to ethanol for 5 weeks. On Week 6, rats were exposed to either cocaine (20 mg/kg, i.p.) or saline for 12 consecutive days. Ethanol bottles were then removed for 7 days; during the last 5 days, either AMP/SUL (100 or 200 mg/kg, i.p.) or saline was administered to the P rats. Ethanol bottles were reintroduced, and ethanol intake was measured for 4 days. Results Cocaine exposure induced an alcohol deprivation effect (ADE), which was associated in part by a decrease in the expression of GLT-1 and xCT in the nucleus accumbens (NAc) core. AMP/SUL (100 mg/kg, i.p.) attenuated the ADE, while AMP/SUL (200 mg/kg, i.p.) reduced ethanol intake during 4 days of ethanol re-exposure and upregulated GLT-1 and xCT expression in the NAc core, NAc shell and dorsomedial prefrontal cortex (dmPFC). Conclusion This study suggests that these astrocytic glutamate transporters might be considered as potential targets for the treatment of polysubstance abuse.

scholarly journals Functional Roles of High-Affinity Glutamate Transporters in Cochlear Afferent Synaptic Transmission in the Mouse

2010 ◽  
Vol 103 (5) ◽  
pp. 2581-2586 ◽  
Author(s):  
Zhiqiang Chen ◽  
Sharon G. Kujawa ◽  
William F. Sewell
Keyword(s):  
Hearing Loss ◽  
Otoacoustic Emissions ◽  
Excitatory Amino Acid ◽  
Spiral Ganglion ◽  
Glutamate Transporter ◽  
Glutamate Transporters ◽  
Acoustic Stimulation ◽  
Noise Induced Hearing Loss ◽  
Glutamate Transporter 1 ◽  
Ganglion Neurons

In the cochlea, afferent transmission between inner hair cells and auditory neurons is mediated by glutamate receptors. Glutamate transporters located near the synapse and in spiral ganglion neurons are thought to maintain low synaptic levels of glutamate. We analyzed three glutamate transporter blockers for their ability to alter the effects of glutamate, exogenously applied to the synapse via perfusion of the scala tympani of the mouse, and compared that action to their ability to alter the effects of intense acoustic stimulation. Threo-beta-benzyloxyaspartate (TBOA) is a broad-spectrum glutamate transporter antagonist, affecting all three transporters [glutamate/aspartate transporter (GLAST), glutamate transporter-1 (GLT1), and excitatory amino acid carrier 1 (EAAC1)]. l-serine- O-sulfate (SOS) blocks both GLAST and EAAC1 without effect on GLT1. Dihydrokainate (DHK) is selective for GLT1. Infusion of glutamate (10 μM for 220 min), TBOA (200 μM for 220 min), or SOS (100 μM for 180 min) alone did not alter auditory neural thresholds. When infused together with glutamate, TBOA and SOS produced significant neural threshold shifts, leaving otoacoustic emissions intact. In addition, both TBOA and SOS exacerbated noise-induced hearing loss by producing larger neural threshold shifts and delaying recovery. DHK did not alter glutamate- or noise-induced hearing loss. The evidence points to a major role for GLAST, both in protecting the synapse from exposure to excess extracellular glutamate and in attenuating hearing loss due to acoustic overstimulation.

scholarly journals The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics

2021 ◽  
Vol 15 ◽  
Author(s):  
Crystal M. Wilkie ◽  
Jessica C. Barron ◽  
Kyle J. Brymer ◽  
Jocelyn R. Barnes ◽  
Firoozeh Nafar ◽  
...  
Keyword(s):  
Glutamate Uptake ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Brain Regions ◽  
Brain Diseases ◽  
Dependent Manner ◽  
Beta Lactam ◽  
Lactam Antibiotic ◽  
Glutamate Transporter 1 ◽  
Activity Dependent

Pharmacological upregulation of glutamate transporter-1 (GLT-1), commonly achieved using the beta-lactam antibiotic ceftriaxone, represents a promising therapeutic strategy to accelerate glutamate uptake and prevent excitotoxic damage in neurological conditions. While excitotoxicity is indeed implicated in numerous brain diseases, it is typically restricted to select vulnerable brain regions, particularly in early disease stages. In healthy brain tissue, the speed of glutamate uptake is not constant and rather varies in both an activity- and region-dependent manner. Despite the widespread use of ceftriaxone in disease models, very little is known about how such treatments impact functional measures of glutamate uptake in healthy tissue, and whether GLT-1 upregulation can mask the naturally occurring activity-dependent and regional heterogeneities in uptake. Here, we used two different compounds, ceftriaxone and LDN/OSU-0212320 (LDN), to upregulate GLT-1 in healthy wild-type mice. We then used real-time imaging of the glutamate biosensor iGluSnFR to investigate functional consequences of GLT-1 upregulation on activity- and regional-dependent variations in glutamate uptake capacity. We found that while both ceftriaxone and LDN increased GLT-1 expression in multiple brain regions, they did not prevent activity-dependent slowing of glutamate clearance nor did they speed basal clearance rates, even in areas characterized by slow uptake (e.g., striatum). Unexpectedly, ceftriaxone but not LDN decreased glutamate release in the cortex, suggesting that ceftriaxone may alter release properties independent of its effects on GLT-1 expression. In sum, our data demonstrate the complexities of glutamate uptake by showing that GLT-1 expression does not necessarily translate to accelerated uptake. Furthermore, these data suggest that the mechanisms underlying activity- and regional-dependent differences in glutamate dynamics are independent of GLT-1 expression levels.

scholarly journals Reduced cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice

2020 ◽  
Author(s):  
Judit Cabana-Domínguez ◽  
Elena Martín-García ◽  
Ana Gallego-Roman ◽  
Rafael Maldonado ◽  
Noèlia Fernàndez-Castillo ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Short Term Memory ◽  
Long Term Potentiation ◽  
Cocaine Addiction ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Normal Behavior ◽  
Cocaine Seeking ◽  
Seeking Behavior

ABSTRACTBackground and PurposeCocaine addiction causes serious health problems and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in the PLCB1 gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution of PLCB1 gene to cocaine addictive properties in mice.Experimental approachWe used heterozygous Plcb1 knockout mice (Plcb1+/-) and characterized their behavioral phenotype. Subsequently, mice were trained for operant conditioning and self-administered cocaine for 10 days. Plcb1+/- mice were assessed for cocaine motivation, followed by 26 days of extinction and finally evaluated for cue-induced reinstatement of cocaine seeking. Gene expression alterations after reinstatement were assessed in medial prefrontal cortex (mPFC) and hippocampus (HPC) by RNAseq.Key ResultsPlcb1+/- mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Importantly, after cocaine self-administration and extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex of Plcb1+/- mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation.Conclusions and ImplicationsTo conclude, we found that heterozygous deletion of the Plcb1 gene decreases cue-induced reinstatement of cocaine seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction.

scholarly journals Potential Benefits of N-Acetylcysteine in Preventing Pregabalin-Induced Seeking-Like Behavior

Healthcare ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 376
Author(s):  
Atiah H. Almalki ◽  
Hashem O. Alsaab ◽  
Walaa F. Alsanie ◽  
Ahmed Gaber ◽  
Turki Alkhalifa ◽  
...  
Keyword(s):  
Substance Use ◽  
Drug Abuse ◽  
Conditioned Place Preference ◽  
Glutamate Transporter ◽  
Glutamate Transporters ◽  
Place Preference ◽  
Medical Problems ◽  
Potential Benefits ◽  
Glutamate Transporter 1 ◽  
Conditioned Place Preference Paradigm

Substance-use disorder is globally prevalent and responsible for numerous social and medical problems. Pregabalin (Lyrica), typically used to treat diabetic neuropathy, has recently emerged as a drug of abuse. Drug abuse is associated with several neuronal changes, including the downregulation of glutamate transporters such as glutamate transporter 1 and cystine/glutamate antiporter. We investigated the effects of N-acetylcysteine, a glutamate transporter 1 and xCT upregulator, on pregabalin addiction using a conditioned place preference paradigm. Pregabalin (60 mg/kg) was found to induce conditioned place preference when compared to a vehicle. A 100 mg/kg dose of N-acetylcysteine was found to block pregabalin-seeking behaviors. These results support previous findings showing that glutamate transporters play an important role in pregabalin-induced seeking behaviors. N-acetylcysteine may represent a beneficial agent in preventing the abuse potential of pregabalin.

scholarly journals Neuropeptide S Reinstates Cocaine-Seeking Behavior and Increases Locomotor Activity through Corticotropin-Releasing Factor Receptor 1 in Mice

2009 ◽  
Vol 29 (13) ◽  
pp. 4155-4161 ◽  
Author(s):  
C. Paneda ◽  
S. Huitron-Resendiz ◽  
L. M. Frago ◽  
J. A. Chowen ◽  
R. Picetti ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Corticotropin Releasing Factor ◽  
Neuropeptide S ◽  
Cocaine Seeking ◽  
Seeking Behavior

scholarly journals Reduced cue-induced reinstatement of cocaine-seeking behavior in Plcb1 +/− mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Judit Cabana-Domínguez ◽  
Elena Martín-García ◽  
Ana Gallego-Roman ◽  
Rafael Maldonado ◽  
Noèlia Fernàndez-Castillo ◽  
...  
Keyword(s):  
Short Term Memory ◽  
Long Term Potentiation ◽  
Cocaine Addiction ◽  
Phenotypic Characterization ◽  
Cocaine Exposure ◽  
Normal Behavior ◽  
Term Potentiation ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Postmortem Brains

AbstractCocaine addiction causes serious health problems, and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in the PLCB1 gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution of the PLCB1 gene to cocaine addictive properties using Plcb1+/− mice. First, we performed a general phenotypic characterization and found that Plcb1+/− mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Subsequently, mice were trained for operant conditioning, self-administered cocaine for 10 days, and were tested for cocaine motivation. After extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/− mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex of Plcb1+/− mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation. To conclude, we found that heterozygous deletion of the Plcb1 gene decreases cue-induced reinstatement of cocaine-seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction.

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