This study reports pharmacological and physiological effects of cis-and trans-(3-aminocyclopentanyl)butylphosphinic acid . These compounds are conformationally restricted analogs of the orally active GABA B/C receptor antagonist (3-aminopropyl)-n-butylphosphinic acid (CGP36742 or SGS742). cis- [IC 50 (1) ϭ 5.06 M and IC 50 (2) ϭ 11.08 M; n ϭ 4] and trans-3-ACPMPA [IC 50 (1) ϭ 72.58 M and IC 50 (2) ϭ 189.7 M; n ϭ 4] seem competitive at GABA C receptors expressed in Xenopus laevis oocytes, having no effect as agonists (1 mM) but exerting weak antagonist (1 mM) effects on human GABA A and GABA B receptors. cis-3-ACPBPA was more potent and selective than the trans-compound, being more than 100 times more potent at GABA C than GABA A or GABA B receptors. cis-3-ACPBPA was further evaluated on dissociated rat retinal bipolar cells and dose-dependently inhibited the native GABA C receptor (IC 50 ϭ 47 Ϯ 4.5 M; n ϭ 6). When applied to the eye as intravitreal injections, cis-and trans-3-ACPBPA prevented experimental myopia development and inhibited the associated vitreous chamber elongation, in a dose-dependent manner in the chick model. Doses only 10 times greater than required to inhibit recombinant GABA C receptors caused the antimyopia effects. Using intraperitoneal administration, cis-(30 mg/ kg) and trans-3-ACPBPA (100 mg/kg) enhanced learning and memory in male Wistar rats; compared with vehicle there was a significant reduction in time for rats to find the platform in the Morris water maze task (p Ͻ 0.05; n ϭ 10). As the physiological effects of cis-and trans-3-ACPBPA are similar to those reported for CGP36742, the memory and refractive effects of CGP36742 may be due in part to its GABA C activity.GABA is an abundant neurotransmitter that mediates inhibition throughout the retina and central nervous system. Three main classes of GABA receptors exist and are termed GABA A , GABA B , and GABA C receptors (Bormann, 2000;Chebib and Johnston, 2000). The GABA A and GABA C are ionotropic receptors, belonging to the Cys-loop family of ligand-gated ion channels, which includes nicotinic acetylcholine, strychnine-sensitive glycine, serotonin type 3, and some invertebrate anionic glutamate receptors (Bormann, 2000;Chebib and Johnston, 2000). Both GABA A and GABA C receptors are chloride channels that mediate fast synaptic inhibition when activated by GABA. In contrast, GABA B receptors are members of the metabotropic receptor family; these receptors couple via G proteins (G i/o ) to interact with neuronal inwardly rectifying potassium and voltage-gated calcium channels, mediating slow synaptic inhibition by increasing ABBREVIATIONS: TPMPA, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid; 3-APMPA, (3-aminopropyl)-methylphosphinic acid; cis-and trans-3-ACPMPA, cis-and trans-(3-aminocyclopentanyl)methylphosphinic acid; cis-and trans-3-ACPBPA, cis-and trans-(3-aminocyclopentanyl)butylphosphinic acid; CGP36742 or SGS742, (3-aminopropyl)-n-butylphosphinic acid; GIRK, G protein-coupled inwardly rectifying potassium ...

GABA A receptors are sensitive to subtle changes in the environment in both early-life and adulthood. These neurochemical responses to stress in adulthood are sex-dependent. Acute stress induces rapid changes in GABA A receptors in experimental animals, with the direction of the changes varying according to the sex of the animals and the stress-paradigm studied. These rapid alterations are of particular interest as they provide an example of fast neurotransmitter system plasticity that may be mediated by stress-induced increases in neurosteroids, perhaps via effects on phosphorylation and/or receptor trafficking. Interestingly, some studies have also provided evidence for long-lasting changes in GABA A receptors as a result of exposure to stressors in early-life. The short-and long-term stress sensitivity of the GABAergic system implicates GABA A receptors in the non-genetic etiology of psychiatric illnesses such as depression and schizophrenia in which stress may be an important factor. Keywords: depression, development, GABA A receptor, schizophrenia, sex differences, stress. 1999), particularly in the ratio 2 : 2 : 1, although stoichiometry may vary (i.e. 2 : 1 : 2, 3 : 2 : 0) . Different receptor subtypes vary in their pharmacological sensitivities, channel kinetics as well as their ontogenic, regional, and cellular distributions. Of recent interest is the different composition of GABA A receptors located at synaptic compared with extrasynaptic sites (Belelli et al. 2009). For example, receptors containing c 2 subunits are predominantly clustered in synaptic locations, while receptors containing d subunits are generally diffusely located at extrasynaptic sites (Essrich et al. 1998;Jacob et al. 2008). Receptors at extrasynaptic sites provide tonic inhibition as demonstrated by the slow decay kinetics and high affinity for GABA of d-subunit containing GABA A receptors, allowing for sensitivity to GABA that spills over from the synapse (Saxena and Macdonald 1994;Banks et al. 2000). This tonic inhibition appears to serve an important role in brain function given that d-subunit knockout mice display spontaneous seizures indicative of a drastic loss of inhibitory tone (Mihalek et al. 1999). GABA A receptor pharmacologyThe orthosteric site The orthosteric site of GABA A receptors is the site where GABA binds to induce chloride channel opening and membrane currents. The orthosteric site is selectively blocked by the antagonist bicuculline but no selective GABA A receptor agonist exists that does not act on GABA B or GABA C receptors (Johnston 2005). For example, muscimol acts as a bicuculline-sensitive agonist at GABA A receptor orthosteric sites but also acts as a more potent bicuculline-insensitive agonist at GABA C receptors (Johnston 2005). High-and low-affinity binding sitesThe orthosteric binding site has been extensively studied using radiolabeled agonists such as [ . Analysis of Scatchard's plots from such studies has lead to a general consensus that there exist both high-affinity (nM) and low-affin...

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