Baclofen administration alters fear extinction and GABAergic protein levels

Abstract

The investigation of GABAergic systems in learning and extinction has principally focused on ionotropic GABAA receptors. Less well characterized is the metabotropic GABAB receptor, which when activated, induces a more sustained inhibitory effect and has been implicated in regulating oscillatory activity. Few studies have been carried out utilizing GABAB ligands in learning, and investigations of GABAB in extinction have primarily focused on interactions with drugs of abuse. The current study examined changes in GABAB receptor function using the GABAB agonist baclofen (2mg/mL) or the GABAB antagonist phaclofen (0.3mg/mL) on trace cued and contextual fear conditioning and extinction. The compounds were either administered during training and throughout extinction in Experiment 1, or starting 24 hours after training and throughout extinction in Experiment 2. All drugs were administered 1mL/kg via intraperitoneal injection. These studies demonstrated that the administration of baclofen during training and extinction trials impaired animals’ ability to extinguish the fear association to the CS, whereas the animals that were administered baclofen starting 24 hours after training (Experiment 2) did display some extinction. Further, contextual fear extinction was impaired by baclofen in both experiments. Tissue analyses suggest the cued fear extinction deficit may be related to changes in the GABAB2 receptor subunit in the amygdala. The data in the present investigation demonstrate that GABAB receptors play an important role in trace cued and contextual fear extinction, and may function differently than GABAA receptors in learning, memory, and extinction.

Postnatal alterations in GABAB receptor tone produce sensorimotor gating deficits and protein level differences in adulthood

“…The drugs were administered subcutaneously (SC) at a volume of 1 ml/kg. Drug concentrations were determined based on previous studies investigating learning and memory deficits in adult rodents (Heaney et al, 2012).…”

“…Additional signaling via GABA B Rs is induced by reductions in adenylate cyclase activity (Hill and Bowery, 1981;Kerr and Ong, 1992;Couve et al, 2000). In rodent adulthood, activation of GABA B Rs has been linked with oscillatory function and numerous behavioral domains (Scanziani, 2000;Heaney et al, 2012). In rodent development, GABA B Rs provide the majority of inhibitory tone in early postnatal life.…”

Postnatal maturation of GABAergic modulation of sensory inputs onto lateral amygdala principal neurons

“…) and the application of the GABA B receptor agonist baclofen results in reduced extinction learning (Heaney et al . ). While this suggests that presynaptic GABA B receptors play an important role in shaping LA sensory input activity in adult animals, the developmental regulation of this has not been studied.…”

KCTD12 modulation of GABA(B) receptor function

“…Increased fear learning was also observed in rats treated with baclofen (Heaney et al. ), suggesting that KCTD12 deletion has a similar effect to increased GABA B R function. Pharmacological enhancement of GABA B R function in seizures (Mares ) and ethanol intake (Colombo et al.…”

“…The KCTD12 homozygous knockout mice displays increased fear learning to conditioned stimulus (Cathomas et al 2015). Increased fear learning was also observed in rats treated with baclofen (Heaney et al 2012), suggesting that KCTD12 deletion has a similar effect to increased GABA B R function. Pharmacological enhancement of GABA B R function in seizures (Mares 2012) and ethanol intake (Colombo et al 2000(Colombo et al , 2006Addolorato et al 2002Addolorato et al , 2007Besheer et al 2004;Liang et al 2006).…”