The aim of the two studies presented here was to evaluate the effects of cocaine and mefloquine (MFQ) on γ-aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Cocaine: In vivo, lower doses of intravenous cocaine (0.25-0.5 mg/kg), or methamphetamine (METH), enhanced VTA GABA neuron firing rate via D2/D5 receptor activation. Higher cocaine doses (1.0-2.0 mg/kg) inhibited their firing rate. Cocaine and lidocaine inhibited the firing rate and spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25-2 mg/kg (IC50 1.2 mg/kg), but neither DA nor METH reduced ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC50 13 µM) current-evoked spikes and sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC50 13 µM), increased IPSC paired-pulse facilitation, and decreased sIPSC frequency, without affecting mIPSC frequency or amplitude. These findings suggest cocaine reduces activity-dependent GABA release on DA neurons in the VTA, and that cocaine's use-dependent blockade of VTA GABA neuron voltage-sensitive sodium channels (VSSCs) may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement. Mefloquine: Mefloquine (MFQ) is an anti-malarial agent, Connexin-36 (Cx36) gap junction blocker, 5-HT3 antagonist, and calcium ionophore. Mounting evidence of a Cx36-mediated VTA GABA neuron syncytium suggests MFQ-related dysphoria may attribute to its gap junction blocking effects on VTA synaptic homeostasis. We observed that MFQ (25 µM) increased DA neuron spontaneous IPSC frequency 6 fold, and mIPSC 3 fold. Carbenoxolone (CBX, 100 µM) only increased sIPSC frequency 2 fold, and did not affect DA mIPSC frequency. Ondansetron did not mimic MFQ. Additionally, MFQ did not affect VTA DA evoked IPSC paired pulse ratio (PPR). However, Mefloquine did induce a 3.5 fold increase in bath-applied GABA current. Remarkably, MFQ did not affect VTA GABA neuron inhibition. At VTA DA neuron excitatory synapses MFQ increased sEPSC frequency in-part due to an increase in the AMPA/NMDA ratio. These finding suggest MFQ alters VTA synapses differentially depending on neuron and synapse type, and that these alterations appear to involve MFQ's gap junction blocking and calcium ionophore actions.

Les interneurones de la couche moléculaire du cervelet (ICM: cellules en panier et cellules étoilées) sont connectés par des synapses électriques fréquentes et puissantes chez les jeunes rats et souris autour de la fin de la deuxième semaine postnatale. Les courants capacitifs des ICM montrent une composante lente qui reflète la charge des interneurones couplés électriquement. Leur analyse permet de quantifier le nombre de cellules directement couplées à une cellule et le nombre équivalent de cellules couplées (Alcami et Marty, soumis), et d'établir une difference de couplage entre les cellules en panier et les cellules étoilées pendant le développement postnatal. Elle a mené à proposer une topologie de réseau des cellules en panier. La force du couplage peut être modulée par les courants intrinsèques, dont Ih dans le domaine hyperpolarisant. Les synapses électriques modifient la propagation et les patrons d'activité dans le réseau des ICM en réponse à une excitation du réseau.L'étude de la connectivité des ICM par des synapses chimiques GABAergiques nous a mené à réexaminer les sources d'erreur des mesures d'activité électrique en configuration cellule attachée (Alcami et coll., 2012). Les mesures en cellule attachée peuvent modifier l'activité électrique des ICM en introduisant un couplage conductif entre la pipette d'enregistrement et l'intérieur cellulaire, résultant d'une combinaison de mécanismes de couplage passifs et actifs. / Molecular layer interneurons of the cerebellum (MLIs: basket cells and stellate cells) are connected by frequent and strong electrical synapses in young rats and mice around the end of the second postnatal week. Capacitive currents of MLIs show a slow component that reflects the charge of electrically-coupled MLIs. The analysis of capacitive currents makes it possible to quantify the number of directly connected cells and the equivalent number of coupled cells (Alcami and Marty, submitted). They were used to show a difference in coupling between basket and stellate cells and propose a model of the basket cell coupled network. Electrical coupling strength can be modulated by intrinsic currents, like the h current in the hyperpolarizing range. Electrical synapses modify the propagation and the patterns of activity in the MLI network, when the network is excited.The study of connectivity of MLIs by chemical GABAergic synapses led us to reevaluate the sources of error of cell-attached recordings (Alcami et al., 2012). Cell-attached measurements can modify cellular electrical activity of MLIs, by introducing a conductif coupling between the recording pipette and the cell interior, resulting from a combination of passive and active coupling.