Reduced sedation and increased ethanol consumption in knock-in mice expressing an ethanol insensitive alpha 2 subunit of the glycine receptor

Gallegos, Scarlet; Martín, Loreto San; Araya, Anibal; Lovinger, David M.; Homanics, Gregg E.; Aguayo, Luis G.

doi:10.1038/s41386-020-0689-9

Cited by 12 publications

(14 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ethanol intake results agree with a study by Blednov et al (2015) that showed that Glra3 −/− mice increased ethanol intake and preferences in the 24-h intermittent access assay. Overall, the present results agree with previous studies that showed that GlyRs are critical ethanol targets that control alcohol intake, for example, mice with ethanol-insensitive α1 and α2 subunit GlyRs (KI mice) (Munoz et al, 2019;Gallegos et al, 2021) have increased alcohol drinking. Similarly, the loss in α2-containing GlyRs (Glra2 knockout mouse) results in mice having a high ethanol consumption (San Martin et al, 2020).…”

Section: Role Of Glyr α3 Subunits In Nucleus Accumbens Neuronssupporting

confidence: 93%

“…While Western blot analysis showed no significant changes in global α subunit levels in the nAc in Glra3 −/− mice, the results showed a significant decrease in GlyR β subunits in the knockout mice. These results indicate that deletion of Glra3 only slightly reduced the presence of the α subunit pool in the nAc, thus suggesting the presence of a lower level of α3 as compared to α1 and α2 (Forstera et al, 2017;San Martin et al, 2020;Gallegos et al, 2021). However, the data does not allow us to rule out the possibility that compensatory up-regulation of α subunits occurred in the Glra3 −/− mice.…”

Section: Role Of Glyr α3 Subunits In Nucleus Accumbens Neuronsmentioning

confidence: 71%

“…This unchanged duration of LORR in Glra3 −/− mice is consistent with previous published findings (Blednov et al, 2015) and might support a more restricted localization of α3 subunits in the CNS unable to produce a sedative action. On the other hand, previous studies have demonstrated that α1 and α2 subunits are important for the sedative effects of ethanol (Aguayo et al, 2014;San Martin et al, 2020;Gallegos et al, 2021). Thus, these findings suggest that α1 and α2 subunits are more relevant than α3 subunits in terms of alcohol effects on GlyRs in the CNS.…”

Section: Role Of Glyr α3 Subunits In Nucleus Accumbens Neuronsmentioning

confidence: 72%

“…It is broadly accepted that GlyRs expressed in several brain regions are sensitive to pharmacological concentrations of ethanol (Aguayo et al, 1996;Ye et al, 2001;Forstera et al, 2017). In many studies, α1 and α2 are the subunits reported to be more responsible for these effects (Aguayo et al, 2014;Gallegos et al, 2021). Previously, α3 subunits were not considered to be a sensitive target for ethanol modulation because it was reported that they were not sensitive to ethanol when expressed as homomeric GlyRs (Sanchez et al, 2015).…”

Section: Sensitivity Of Glyr α3 Subunits To Ethanol and Picrotoxinmentioning

confidence: 99%

See 3 more Smart Citations

Contribution of GlyR α3 Subunits to the Sensitivity and Effect of Ethanol in the Nucleus Accumbens

Martín

Armijo-Weingart

Araya

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

The glycine receptor (GlyR), a ligand-gated ion channel, is critical for inhibitory neurotransmission in brainstem, spinal cord, and in supraspinal regions. Recent data from several laboratories have shown that GlyRs are expressed in the brain reward circuitry and that α1 and α2 are the principal subunits expressed in the nucleus accumbens (nAc). In the present study, we studied the sensitivity to ethanol of homomeric and heteromeric α3 GlyR subunits in HEK293 cells and dissociated neurons from the nAc. Finally, we explored ethanol-related behaviors in a Glra3 knockout mouse (Glra3–/–). Studies in HEK293 cells showed that while homomeric α3 GlyR subunits were insensitive to ethanol, heteromeric α3β GlyR subunits showed higher sensitivity to ethanol. Additionally, using electrophysiological recordings in dissociated accumbal neurons, we found that the glycine current density increased in Glra3–/– mice and the GlyRs were less affected by ethanol and picrotoxin. We also examined the effect of ethanol on sedation and drinking behavior in Glra3–/– mice and found that the duration in the loss of righting reflex (LORR) was unchanged compared to wild-type (WT) mice. On the other hand, using the drinking in the dark (DID) paradigm, we found that Glra3–/– mice have a larger ethanol consumption compared to WT mice, and that this was already high during the first days of exposure to ethanol. Our results support the conclusion that heteromeric α3β, but not homomeric α3, GlyRs are potentiated by ethanol. Also, the increase in GlyR and GABAAR mediated current densities in accumbal neurons in the KO mice support the presence of compensatory changes to α3 knock out. The increase in ethanol drinking in the Glra3–/– mice might be associated to the reduction in β and compensatory changes in other subunits in the receptor arrangement.

show abstract

Section: Role Of Glyr α3 Subunits In Nucleus Accumbens Neuronssupporting

confidence: 93%

Section: Role Of Glyr α3 Subunits In Nucleus Accumbens Neuronsmentioning

confidence: 71%

Section: Role Of Glyr α3 Subunits In Nucleus Accumbens Neuronsmentioning

confidence: 72%

Section: Sensitivity Of Glyr α3 Subunits To Ethanol and Picrotoxinmentioning

confidence: 99%

See 2 more Smart Citations

Contribution of GlyR α3 Subunits to the Sensitivity and Effect of Ethanol in the Nucleus Accumbens

Martín

Armijo-Weingart

Araya

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…In addition, using KI mice with the same mutation in α2 (K389 and R390), we demonstrated the presence of α2β GlyRs in accumbal neurons (Gallegos et al, 2021). Interestingly, α2 KI mice showed reduced sedation and increased ethanol consumption, suggesting that the α2 subunit is important for the ethanol potentiation of GlyRs in the adult brain (Gallegos et al, 2021). The insensitivity to ethanol of glycinergic synaptic currents in the nAc suggests that these GlyRs are mainly composed of α1β conformations (Munoz et al, 2018).…”

Section: Implication For the Presence Of β Containing Glycine Receptors In The Upper Brainmentioning

confidence: 86%

Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors

Muñoz

Mariqueo

Murath

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Alpha1-containing glycine receptors (GlyRs) are major mediators of synaptic inhibition in the spinal cord and brain stem. Recent studies reported the presence of α2-containing GlyRs in other brain regions, such as nucleus accumbens and cerebral cortex. GlyR activation decreases neuronal excitability associated with sensorial information, motor control, and respiratory functions; all of which are significantly altered during ethanol intoxication. We evaluated the role of β GlyR subunits and of two basic amino acid residues, K389 and R390, located in the large intracellular loop (IL) of the α2 GlyR subunit, which are important for binding and functional modulation by Gβγ, the dimer of the trimeric G protein conformation, using HEK-293 transfected cells combined with patch clamp electrophysiology. We demonstrate a new modulatory role of the β subunit on ethanol sensitivity of α2 subunits. Specifically, we found a differential allosteric modulation in homomeric α2 GlyRs compared with the α2β heteromeric conformation. Indeed, while α2 was insensitive, α2β GlyRs were substantially potentiated by ethanol, GTP-γ-S, propofol, Zn2+ and trichloroethanol. Furthermore, a Gβγ scavenger (ct-GRK2) selectively attenuated the effects of ethanol on recombinant α2β GlyRs. Mutations in an α2 GlyR co-expressed with the β subunit (α2AAβ) specifically blocked ethanol sensitivity, but not propofol potentiation. These results show a selective mechanism for low ethanol concentration effects on homomeric and heteromeric conformations of α2 GlyRs and provide a new mechanism for ethanol pharmacology, which is relevant to upper brain regions where α2 GlyRs are abundantly expressed.

show abstract

Synaptic Effects Induced by Alcohol

Lovinger

Roberto

2023

Current Topics in Behavioral Neurosciences

View full text Add to dashboard Cite

Reduced sedation and increased ethanol consumption in knock-in mice expressing an ethanol insensitive alpha 2 subunit of the glycine receptor

Cited by 12 publications

References 46 publications

Contribution of GlyR α3 Subunits to the Sensitivity and Effect of Ethanol in the Nucleus Accumbens

Contribution of GlyR α3 Subunits to the Sensitivity and Effect of Ethanol in the Nucleus Accumbens

Modulatory Actions of the Glycine Receptor β Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors

Synaptic Effects Induced by Alcohol

Contact Info

Product

Resources

About