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Our previous studies consistently showed that MDMA-induced locomotor hyperactivity is dramatically increased by coadministration of ethanol (EtOH) in rats, indicating possible potentiation of MDMA abuse liability. Thus, we aimed to identify the brain region(s) and neuropharmacological substrates involved in the pharmacodynamics of this potentiation. We first showed that potentiation of locomotor activity by the combination of ip administration of EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) is delay sensitive and maximal when both drugs are injected simultaneously. Then, we used the 2-deoxyglucose quantitative autoradiography technique to assess the impact of EtOH, MDMA, or their combination on local cerebral metabolic rates for glucose (CMRglcs). We showed a specific metabolic activation in the ventral striatum (VS) under MDMA + EtOH versus MDMA or EtOH alone. We next tested if reversible (tetrodotoxin, TTX) or permanent (6-hydrodoxyopamine, 6-OHDA) lesion of the VS could affect locomotor response to MDMA and MDMA + EtOH. Finally, we blocked dopamine D1 or glutamate NMDA receptors in the VS and measured the effects of MDMA and MDMA + EtOH on locomotor activity. We showed that bilateral reversible inactivation (TTX) or permanent lesion (6-OHDA) of the VS prevented the potentiation by EtOH of MDMA-induced locomotor hyperactivity. Likewise, blockade of D1 or NMDA receptors in the VS also reduced the potentiation of MDMA locomotor activity by EtOH. These data indicate that dopamine D1 and glutamate NMDA receptor-driven mechanisms in the VS play a key role in the pharmacodynamics of EtOH-induced potentiation of the locomotor effects of MDMA. [ABSTRACT FROM AUTHOR]

Studies of the neuropharmacological substrates of spatial memory formation have focused on the contribution of septohippocampal pathways. Although these pathways include, among others, cholinergic and GABAergic fibers innervating the hippocampus, research has essentially been oriented towards the role of their cholinergic component. Recently, a few studies investigated the role of GABAergic septohippocampal projections. These only focused on almost immediate or recent memory and yielded discrepant results. GABAergic lesions impaired learning or had no effects. Given the role of the hippocampus in memory consolidation and the potential modulatory influence of the septum on hippocampal function, it is relevant to study the role of the septohippocampal interface in memory stabilization. We performed investigations with relatively selective lesions of GABAergic (using oxerin-saporin) or/and cholinergic (using 192 IgG-saporin) medial septum/vertical limb of the diagonal band of Broca (MS/vDBB) neurons in rats, and assessed acquisition of a spatial memory and its subsequent recall in the water maze. Following a 6-day training phase during which all groups improved performance to comparable levels, retention was tested 1, 5, or 25 days later. At the 1-day delay, all groups performed above chance and did not differ significantly among each other. At the 5-day delay, only rats with GABAergic or combined lesions exhibited a retention deficit. At the 25-day delay, all three lesion groups performed at chance level; in these groups, performance was significantly lower than that found in sham-operated rats. Immunochemical and histochemical verifications of the lesion extent/selectivity showed extensive GABAergic damage after intraseptal orexin-saporin infusions or cholinergic damage after 192 IgG-saporin infusions, with relatively limited damage to the other neurotransmitter system. Our data show that GABAergic and cholinergic septohippocampal neurons both contribute to memory stabilization, and could do so in a sequential way: GABAergic processes could be engaged at an earlier stage than cholinergic ones during system consolidation of a spatial memory. © 2010 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

GABAB receptors mediate slow synaptic inhibition in the nervous system. In transfected cells, functional GABAB receptors are usually only observed after coexpression of GABAB(1) and GABAB(2) subunits, which established the concept of heteromerization for G-protein-coupled receptors. In the heteromeric receptor, GABAB(1) is responsible for binding of GABA, whereas GABAB(2) is necessary for surface trafficking and G-protein coupling. Consistent with these in vitro observations, the GABAB(1) subunit is also essential for all GABAB signaling in vivo. Mice lacking the GABAB(1) subunit do not exhibit detectable electrophysiological, biochemical, or behavioral responses to GABAB agonists. However, GABAB(1) exhibits a broader cellular expression pattern than GABAB(2), suggesting that GABAB(1) could be functional in the absence of GABAB(2). We now generated GABAB(2)-deficient mice to analyze whether GABAB(1) has the potential to signal without GABAB(2) in neurons. We show that GABAB(2)-/- mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity, and severe memory impairment, analogous to GABAB(1)-/- mice. This clearly demonstrates that the lack of heteromeric GABAB(1,2) receptors underlies these phenotypes. To our surprise and in contrast to GABAB(1)-/- mice, we still detect atypical electrophysiological GABAB responses in hippocampal slices of GABAB(2)-/- mice. Furthermore, in the absence of GABAB(2), the GABAB(1) protein relocates from distal neuronal sites to the soma and proximal dendrites. Our data suggest that association of GABAB(2) with GABAB(1) is essential for receptor localization in distal processes but is not absolutely necessary for signaling. It is therefore possible that functional GABAB receptors exist in neurons that naturally lack GABAB(2) subunits.