GABA Receptors: Pharmacological Potential and Pitfalls

Jembrek, Maja Jazvinšćak; Vlainić, Josipa

doi:10.2174/1381612821666150914121624

Cited by 102 publications

(65 citation statements)

References 240 publications

(302 reference statements)

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“…The GABA receptors, known to be involved in the development of neuropsychiatric disorders, exert their effects via the ionotropic (GABA A ) type A receptors which are ligand-gated chloridechannel complexes and metabotropic (GABA B ) type B receptors which are G protein coupled receptors [13]. GABA A receptors are a major target of alcohol action and drugs including benzodiazepines, barbiturates and anesthetic steroids [14].…”

Section: Journal Of Addiction Research and Therapymentioning

confidence: 99%

An Association Study of the COMT and GABA Gene Variants with Alcohol Dependence

Singh¹,

Grover²,

Gupta³

et al. 2017

J Addict Res Ther

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Alcohol dependence (AD), associated with high mortality and morbidity is caused due to involvement of both environmental and genetic factors. Behavioral effects of alcohol including cognitive impairment, motor incoordination, tolerance and dependence are likely due to its effect on the multiple brain proteins including neurotransmitters. Dysfunction in these neurotransmitter systems may be at the level of enzymes involved in metabolic degradation, or receptors involved in neurotransmission like dopamine, Gamma-amino butyric acid (GABA), serotonin etc. Genetic polymorphisms in these neurotransmitter systems are implicated in conferring susceptibility to AD. Aim:To identify association of single nucleotide polymorphisms (SNPs) in COMT (rs4680 and rs2075507) and GABAA receptor genes (rs13172914 and rs211014) with AD.Method: A total of 100 AD patients diagnosed on the basis of DSM IV criteria from the outpatient clinic of the National Drug Dependence Treatment Centre (NDDTC) of All India Institute of Medical Sciences (AIIMS), and 100 healthy individuals from the general population were recruited. A detailed history including pattern of drug use and demographic details with pedigree information was noted. Genomic DNA from peripheral blood samples was processed for PCR amplification followed by restriction digestion to screen for the presence of polymorphisms. Genotype and allele frequencies were evaluated and correlated with alcohol use parameters including duration of alcohol use, age at onset of alcohol use, quantity of alcohol consumed (gms/day) and WHO ASSIST score and levels of liver function enzymes (SGPT and SGOT). Statistical analysis was performed using SPSS v21.0.Results: Genetic analysis of the study group revealed COMT rs4680 to be significantly associated with AD (p=0.03), while the other COMT SNP rs2075507 showed an association with increased levels of SGPT in the patients. GABAA receptor gene polymorphisms showed no association with AD. Conclusion:The study suggests a role of COMT gene polymorphism rs4680 in conferring susceptibility to AD.

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Section: Journal Of Addiction Research and Therapymentioning

confidence: 99%

An Association Study of the COMT and GABA Gene Variants with Alcohol Dependence

Singh¹,

Grover²,

Gupta³

et al. 2017

J Addict Res Ther

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“…Furthermore, both BZs and ethanol elicit similar effects at the GABA A receptor through distinct binding sites (Caputo and Bernardi, 2010; Endoh et al, 2008; Jembrek and Vlainic, 2015), suggesting that BZs could augment the reinforcing effects of ethanol and vice versa (see Chester and Cunningham, 2002; Endoh et al, 2008; Koob et al, 2004 for review). However, investigations of this possibility have yielded seemingly equivocal findings, at least in terms of ethanol consumption.…”

Section: Introductionmentioning

confidence: 99%

Reinforcing effectiveness of midazolam, ethanol, and sucrose: behavioral economic comparison of a mixture relative to its component solutions

Townsend

Platt²,

Rowlett³

et al. 2017

Behavioural Pharmacology

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Benzodiazepines (BZs) are relatively safe when administered alone. However, these drugs can produce severe side effects when co-administered with ethanol. Despite these adverse consequences, rates of concurrent BZ and ethanol misuse are increasing, and it is unclear if this behavior is maintained by an enhanced reinforcing effect of the mixture. To address this issue, the current study compared the reinforcing effectiveness of sucrose solutions mixed with midazolam, ethanol, or both. Eight male rats were trained to orally self-administer solutions of either sucrose (S), sucrose + midazolam (SM), sucrose + ethanol (SE), or sucrose + midazolam + ethanol (SME). The response requirement was increased between sessions until the number of reinforcers earned was zero, and the relationship between response requirement and reinforcers earned was analyzed using the behavioral economic approach of exponential model of demand. Baseline intake was similar across drug conditions. Consumption of SM was least affected by increases in cost, indicating it possessed the highest reinforcing effectiveness (i.e., least elastic). The reinforcing effectiveness of S, SE, and SME did not differ significantly. The fact that the reinforcing effectiveness of the SME was less than that of SM does not support the supposition that BZ and ethanol co-administration is maintained by a higher reinforcing effectiveness of the mixture.

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“…In contrast, GABA B receptors are heteromeric G‐protein–coupled receptors, comprised of GABA B1 and GABA B2 subunits, associated with downstream K + and/or Ca 2+ channels . Activation of GABA B receptors induces a slow neuronal inhibition that, due to the pre‐ and postsynaptic expression of GABA B receptors, can result in the inhibition of transmitter release and/or neuronal hyperpolarization …”

mentioning

confidence: 99%

“…4 Activation of GABA B receptors induces a slow neuronal inhibition that, due to the pre-and postsynaptic expression of GABA B receptors, can result in the inhibition of transmitter release and/or neuronal hyperpolarization. 3,5 High concentrations of GABA in the CNS suggest that GABA plays a major role in various brain and spinal cord functions, and modulation of GABA transmission can significantly affect CNS function.Drugs that target GABA A receptors have been used to treat anxiety, insomnia, and epilepsy 5 ; orthosteric GABA B agonists are used to treat muscle rigidity and narcolepsy. 6,7 Activation of GABA B receptors by systemic administration of the GABA B agonist baclofen induces analgesia, a mechanism that is primarily mediated by GABA B receptors expressed on afferent terminals in the dorsal horn of the spinal cord and that also involves cholinergic and endocannabinoid mediators.…”

mentioning

confidence: 99%

Single‐ and Multiple‐Dose Safety, Tolerability, and Pharmacokinetic Profiles of ASP8062: Results From 2 Phase 1 Studies

Walzer

Marek

et al. 2020

Clinical Pharm in Drug Dev

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ASP8062 is an orally active γ‐amino‐butyric acid type B (GABAB) receptor positive allosteric modulator currently in phase 2 development. Safety and pharmacokinetic (PK) profiles of ASP8062 were evaluated in 2 studies in healthy subjects. The first study (a first‐in‐human study) evaluated single ascending doses (SAD) of ASP8062. The second study was composed of 2 parts: part 1 evaluated multiple ascending doses (MAD) of ASP8062 for 14 days, and part 2 was a single‐dose arm to assess the PK of ASP8062 in cerebrospinal fluid (CSF). Fifty‐six men (SAD) and 56 subjects (24 women and 32 men; MAD) were enrolled. Across the SAD dosing range, area under the concentration‐time curve was dose proportional; increases in maximum plasma concentration appeared linear but were slightly less than dose proportional. Time to maximal concentration and half‐life were 1‐4 hours and ∼40‐50 hours, respectively; no food effect was observed. ASP8062 PK properties at steady state were similar to those following a single dose. Steady state was achieved by ∼day 9 with ∼2‐fold accumulation, and ASP8062 was detected in CSF. ASP8062 was well tolerated; no clear evidence of ASP8062's effects on safety, cognition, drug withdrawal, or suicidal ideation/behavior was observed. These data support the development of ASP8062 in indications where the GABAB receptor is a target.

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GABA Receptors: Pharmacological Potential and Pitfalls

Cited by 102 publications

References 240 publications

An Association Study of the COMT and GABA Gene Variants with Alcohol Dependence

An Association Study of the COMT and GABA Gene Variants with Alcohol Dependence

Reinforcing effectiveness of midazolam, ethanol, and sucrose: behavioral economic comparison of a mixture relative to its component solutions

Single‐ and Multiple‐Dose Safety, Tolerability, and Pharmacokinetic Profiles of ASP8062: Results From 2 Phase 1 Studies

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