Behavioural Brain Research 150 (2004) 117–125 Research report Chronic prenatal ethanol exposure alters hippocampal GABA A receptors and impairs spatial learning in the guinea pig U. Iqbal a , H.C. Dringenberg a,b,c , J.F. Brien a,c , J.N. Reynolds a,c,∗ a Department of Pharmacology and Toxicology, Queen’s University, Kingston, Ont., Canada K7L 3N6 b Department of Psychology, Queen’s University, Kingston, Ont., Canada K7L 3N6 c The Center for Neurosciences Studies, Queen’s University, Kingston, Ont., Canada K7L 3N6 Received 14 May 2003; received in revised form 14 May 2003; accepted 3 July 2003 Abstract Chronic prenatal ethanol exposure (CPEE) can injure the developing brain, and may lead to the fetal alcohol syndrome (FAS). Previous studies have demonstrated that CPEE upregulates -aminobutyric acid type A (GABA A ) receptor expression in the cerebral cortex, and decreases functional synaptic plasticity in the hippocampus, in the adult guinea pig. This study tested the hypothesis that CPEE increases GABA A receptor expression in the hippocampus of guinea pig offspring that exhibit cognitive deficits in a hippocampal-dependent spatial learning task. Timed, pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight per day), isocaloric-sucrose/pair-feeding, or water throughout gestation. GABA A receptor subunit protein expression in the hippocampus was measured at two development ages: near-term fetus and young adult. In young adult guinea pig offspring, CPEE increased spontaneous locomotor activity in the open-field and impaired task acquisition in the Morris water maze. CPEE did not change GABA A receptor subunit protein expression in the near-term fetal hippocampus, but increased expression of the 2/3-subunit of the GABA A receptor in the hippocampus of young adult offspring. CPEE did not change either [ 3 H]flunitrazepam binding or GABA potentiation of [ 3 H]flunitrazepam binding, but decreased the efficacy of allopregnanolone potentiation of [ 3 H]flunitrazepam binding, to hippocampal GABA A receptors in adult offspring. Correlational analysis revealed a relationship between increased spontaneous locomotor activity and growth restriction in the hippocampus induced by CPEE. Similarly, an inverse relationship was found between performance in the water maze and the efficacy of allopregnanolone potentiation of [ 3 H]flunitrazepam binding in the hippocampus. These data suggest that alterations in hippocampal GABA A receptor expression and pharmacological properties contribute to hippocampal-related behavioral and cognitive deficits associated with CPEE. © 2003 Elsevier B.V. All rights reserved. Keywords: Fetal alcohol syndrome; Spatial learning; GABA A receptor; Hippocampus; Guinea pig; Prenatal ethanol exposure; Neurosteroid 1. Introduction Maternal consumption of ethanol during pregnancy can injure the developing fetus, leading to the expression of dys- morphology and dysfunction in the offspring. Among the body systems that are adversely affected by prenatal ethanol exposure, the central nervous system (CNS) is considered to be the most sensitive to ethanol-induced perturbation. The term alcohol-related neurodevelopmental disorder (ARND) is used to describe the CNS dysfunction that may result from ethanol exposure during pregnancy. The hippocampus is a selectively vulnerable structure to prenatal ethanol exposure [1]. It is generally accepted that ∗ Corresponding author. Tel.: +1-613-533-6946; fax: +1-613-533-6412. E-mail address: jnr@post.queensu.ca (J.N. Reynolds). prenatal ethanol exposure can alter hippocampal synaptic plasticity and can adversely affect hippocampal-dependent learning, as well as cause other mental defects. Previous studies in our laboratory using the guinea pig as the ex- perimental animal model have demonstrated that chronic prenatal ethanol exposure (CPEE) results in loss of hip- pocampal CA1 pyramidal cells in young postnatal off- spring [2], impairs performance in a spatial learning task and decreases synaptic plasticity in the hippocampus of adult offspring [3], and decreases both potassium ion and veratridine-stimulated glutamate release in young postna- tal offspring [4]. In addition, CPEE produces increases in GABA A receptor number and in GABA A receptor subunit protein expression in the cerebral cortex of adult guinea pigs [5]. The results of these studies lead us to suggest that changes in the efficiency or plasticity of inhibitory GABAergic circuits in the hippocampus could contribute 0166-4328/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0166-4328(03)00246-8