Gabra5-gene haplotype block associated with behavioral properties of the full agonist benzodiazepine chlordiazepoxide.

The gabra5 gene is associated with pharmacological properties (myorelaxant, amnesic, anxiolytic) of benzodiazepines. It is tightly located (0.5 cM) close to the pink-eyed dilution (p) locus which encodes for fur color on mouse chromosome 7. We tested the putative role of the gabra5 gene in pharmacological properties of the full non specific agonist chlordiazepoxide (CDP), using behavioral and molecular approaches in mutated p/p mice and wild type F2 from crosses between two multiple markers inbred strain ABP/Le and C57BL/6By strain. From our results, using rotarod, light-dark box, elevated maze and radial arm maze tests, we demonstrate that p/p mice are more sensitive than WT to the sensory motor, anxiolytic and amnesic effect of CDP. This is associated with the presence of a haplotypic block on the murine chromosome 7 and with an up regulation of gabra5 mRNAs in hippocampi of p/p F2 mice.

Reduced locomotor responses to cocaine in ghrelin-deficient mice.

Ghrelin, an orexigenic hormone produced by the stomach, increases food intake and enhances the locomotor and rewarding effects of cocaine. Consistent with these behavioral effects, ghrelin increases dopamine cell activity in the mesolimbic system resulting in elevated levels of dopamine release and turnover in target regions such as the ventral striatum. In the current study, we examined the psychostimulant effects of acute and daily cocaine in mice with targeted deletion of the ghrelin gene (ghrelin knockout; KO) and that of their wild-type (WT) littermates. We hypothesized that ghrelin-KO mice would be hyporesponsive to the effects of cocaine as reflected in attenuated locomotor activity following both acute and chronic injections, and that this would be correlated with striatal dopamine and dopamine metabolite concentrations. Results show that the locomotor stimulating effect of cocaine (10 mg/kg) was decreased in ghrelin-KO mice as compared with their WT littermates. In addition, repeated daily injection of cocaine resulted in gradual increases in locomotor activity in WT mice, an effect that was attenuated in ghrelin-KO mice. These behavioral effects were correlated with changes in dopamine utilization in the striatum of WT mice that were not seen in ghrelin-KO mice unless these were pretreated with ghrelin. These data suggest that ghrelin is important for normal function of the mesolimbic dopaminergic system, potentially modulating both dopamine release and reuptake.

Localized low-level re-expression of high-affinity mesolimbic nicotinic acetylcholine receptors restores nicotine-induced locomotion but not place conditioning.

High-affinity, beta2-subunit-containing (beta2*) nicotinic acetylcholine receptors (nAChRs) are essential for nicotine reinforcement; however, these nAChRs are found on both gamma-aminobutyric acid (GABA) and dopaminergic (DA) neurons in the ventral tegmental area (VTA) and also on terminals of glutamatergic and cholinergic neurons projecting from the pedunculopontine tegmental area and the laterodorsal tegmental nucleus. Thus, systemic nicotine administration stimulates many different neuronal subtypes in various brain nuclei. To identify neurons in which nAChRs must be expressed to mediate effects of systemic nicotine, we investigated responses in mice with low-level, localized expression of beta2* nAChRs in the midbrain/VTA. Nicotine-induced GABA and DA release were partially rescued in striatal synaptosomes from transgenic mice compared with tissue from beta2 knockout mice. Nicotine-induced locomotor activation, but not place preference, was rescued in mice with low-level VTA expression, suggesting that low-level expression of beta2* nAChRs in DA neurons is not sufficient to support nicotine reward. In contrast to control mice, transgenic mice with low-level beta2* nAChR expression in the VTA showed no increase in overall levels of cyclic AMP response element-binding protein (CREB) but did show an increase in CREB phosphorylation in response to exposure to a nicotine-paired chamber. Thus, CREB activation in the absence of regulation of total CREB levels during place preference testing was not sufficient to support nicotine place preference in beta2 trangenic mice. This suggests that partial activation of high-affinity nAChRs in VTA might block the rewarding effects of nicotine, providing a potential mechanism for the ability of nicotinic partial agonists to aid in smoking cessation.

Functional implications of decreases in neurogenesis following chronic mild stress in mice.

Numerous data from human and animal studies suggest that hippocampal plasticity might be a key element in depression. However, the connection remains loose at best and further data are needed. Human studies are of necessity limited, but animal models can help providing further insight. Unpredictable chronic mild stress (UCMS) is a commonly used model because it mimics depression-like phenotypes satisfactorily. Its rationale is based on the underlying stress-induced difficulties found in many depressed patients. We therefore studied learning and hippocampal neurogenesis in mice from three different inbred strains subjected to UCMS. Learning was assessed in different hippocampus-dependent and independent tasks. The rate of survival of newly generated brain cells was determined in behaviorally-naive animals. Results demonstrated a dramatic reduction of surviving new brain cells in both the hippocampus and the subventricular zone of UCMS-treated animals. This reduction was observed both for neurons and for other cells of the hippocampus. Behavioral data demonstrated an impairment of hippocampus-dependent learning, whereas hippocampus-independent learning was spared. However, the specific results were strongly dependent on strain and sex so that there does not appear to be a direct causative relationship between the deficits in neurogenesis and behavior.

Neuroanatomy of cerebellum and olfactory bulb in a substrain of C57BL/6J inbred mice carrying a spontaneous mutation.

Mice of the inbred C57BL/6JNmg substrain carry a mutation decreasing the size of the zinc-rich hippocampal intra- and infrapyramidal mossy fibre (IIPMF) terminal fields. In the present experiment, it was investigated whether this neurological mutation has also effects on other characteristics of the brain. No morphological differences were found in two other laminated neural structures, the olfactory bulb, where the accessory granular layer is also rich in zinc terminals, and the cerebellum. However, the mutants had a somewhat inferior performance on a motor function task known to test cerebellar involvement. The present findings confirm that previously found effects of this mutation on different types of behaviour are most probably due to the IIPMF. These substrains provide a powerful tool to localise the gene involved and subsequently investigate the plausible pathways leading from gene to behaviour.