In vivo molecular imaging of the GABA/benzodiazepine receptor complex in the aged rat brain

Hoekzema, Elseline; Rojas, Santiago; Herance, José Raúl; Pareto, Deborah; Abad, Sergio; Jiménez, Xavier F.; Figueiras, Francisca P.; Popota, Foteini; Ruiz, Alba; Flotats, Núria; Fernández, Francisco Santolaria; Rocha, Milagros; Rovira, Mariana; Víctor, Víctor M.; Gispert, Juan Domingo

doi:10.1016/j.neurobiolaging.2010.12.006

Cited by 12 publications

(7 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because the unimpaired aged phenotype retains hippocampal integrity on these measures, such as synaptic connections and encoding properties of hippocampal neurons (Smith et al, 2000; Wilson et al, 2003), GABA A α5 receptor PAMs would not be expected to boost memory performance in unimpaired aged rats. Finally, we have specifically confirmed a reduction in the expression GABA A α5 subunit mRNA in the CA3 region in our model of memory loss in aged Long-Evans rats (Haberman et al, 2011) and others have reported decreased receptor binding for those sites in the hippocampus of aged rodents (Hoekzema et al, 2011). Consequently, it may be especially important to potentiate the inhibitory activity of GABA at remaining GABA A α5 receptors in a condition of excess CA3 activity.…”

Section: Discussionsupporting

confidence: 84%

Selective GABAA α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment

2013

View full text Add to dashboard Cite

A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer's disease. Compounds that act as positive allosteric modulators at GABA A α5 receptors might be useful in targeting this condition because GABA A α5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABA A α5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of γ-aminobutyric acid at GABA A α5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 μg) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data

show abstract

Section: Discussionsupporting

confidence: 84%

Selective GABAA α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment

2013

View full text Add to dashboard Cite

show abstract

“…Our study extends these findings by showing that age-related decreases in tactile surround and interhemispheric inhibition actually benefit performance for older adults when low-amplitude stimulation is applied to a neighboring or contralateral finger. One interpretation of this finding is that age-related reductions in GABA-mediated inhibition reflect an underlying compensatory mechanism aimed at enhancing neural plasticity to adapt to the multifaceted declines of increasing age (Caspary et al, 1999; Grachev et al, 2001; Hoekzema et al, 2012). Such a perspective is based on the idea of homeostatic disinhibition, which compensates for an overall reduced excitatory drive by recruiting additional cognitive reserve during aging (Gleichmann et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Age-Related Reductions in Tactile and Motor Inhibitory Function Start Early but Are Independent

Ruitenberg

Cassady

Reuter‐Lorenz

et al. 2019

Front. Aging Neurosci.

View full text Add to dashboard Cite

Aging is associated with declines in motor and somatosensory function. Some of these motor declines have been linked to age-related reductions in inhibitory function. Here we examined whether tactile surround inhibition also changes with age and whether these changes are associated with those in the motor domain. We tested a group of 56 participants spanning a wide age range (18–76 years old), allowing us to examine when age differences emerge across the lifespan. Participants performed tactile and motor tasks that have previously been linked to inter- and intra-hemispheric inhibition in the somatosensory and motor systems. The results showed that aging is associated with reductions in inhibitory function in both the tactile and motor systems starting around 40 years of age; however, age effects in the two systems were not correlated. The independent effects of age on tactile and motor inhibitory function suggest that distinct mechanisms may underlie age-related reductions in inhibition in the somatosensory and motor systems.

show abstract

“…Furthermore, an increase in the transcripts for the α2 subunit was one of the changes observed AD brains, along with increases or decreases in the transcripts for other subunits (Limon, et al, 2012). Benzodiazepine binding sites have been shown to have a stable decline with aging in the rat brain (Hoekzema, et al, 2012) and there is some evidence that the α2 mRNA also diminishes in the human prefrontal cortex with age, at least during the time from the neonatal period all the way into adulthood (Fillman et al, 2010). It is possible that digressions from the normal rate of α2-expression decline can underlie cognitive impairments in different aging-related diseases.…”

Section: Gabra2 and Schizophreniamentioning

confidence: 99%

α2-containing GABAA receptors: A target for the development of novel treatment strategies for CNS disorders

Engin

Liu

Rudolph

2012

Pharmacology & Therapeutics

123

View full text Add to dashboard Cite

GABAA receptors have important physiological functions, as revealed by pharmacological studies and experiments involving gene-targeted mouse models, and are the target of widely used drugs such as the benzodiazepines. In this review, we are summarizing current knowledge about the function of α2-containing GABAA receptors, a receptor subtype representing approximately 15–20% of all GABAA receptors. This receptor subtype mediates anxiolytic-like, reward-enhancing, and antihyperalgesic actions of diazepam, and has antidepressant-like properties. Secondary insufficiency of α2-containing GABAA receptors has been postulated to play a role in the pathogenesis of schizophrenia, and may be involved in cognitive impairment in other disorders. Moreover, polymorphisms in the GABRA2 gene encoding the GABAA receptor α2 subunit have been found to be linked to chronic alcohol dependence and to polydrug abuse. Thus, α2-containing GABAA receptors are involved in the regulation and/or modulation of emotional behaviors and of chronic pain, and appear to be a valid target for novel therapeutic approaches for the treatment of anxiety, depression, schizophrenia and chronic pain.

show abstract

In vivo molecular imaging of the GABA/benzodiazepine receptor complex in the aged rat brain

Cited by 12 publications

References 36 publications

Selective GABAA α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment

Selective GABAA α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment

Age-Related Reductions in Tactile and Motor Inhibitory Function Start Early but Are Independent

α2-containing GABAA receptors: A target for the development of novel treatment strategies for CNS disorders

Contact Info

Product

Resources

About