Ventral tegmental area BDNF induces an opiate-dependent-like reward state in naive rats.

The neural mechanisms underlying the transition from a drug-nondependent to a drug-dependent state remain elusive. Chronic exposure to drugs has been shown to increase brain-derived neurotrophic factor (BDNF) levels in ventral tegmental area (VTA) neurons. BDNF infusions into the VTA potentiate several behavioral effects of drugs, including psychomotor sensitization and cue-induced drug seeking. We found that a single infusion of BDNF into the VTA promotes a shift from a dopamine-independent to a dopamine-dependent opiate reward system, identical to that seen when an opiate-naïve rat becomes dependent and withdrawn. This shift involves a switch in the gamma-aminobutyric acid type A (GABAA) receptors of VTA GABAergic neurons, from inhibitory to excitatory signaling.

Acute and chronic ethanol modulate dopamine D2-subtype receptor responses in ventral tegmental area GABA neurons.

BACKGROUND: Ventral tegmental area (VTA) gamma-aminobutyric acid (GABA) neurons appear to be critical substrates underlying the acute and chronic effects of ethanol on dopamine (DA) neurotransmission in the mesocorticolimbic system implicated in drug reward. VTA GABA neuron firing rate is reduced by acute ethanol and enhanced by DA via D2 receptor activation. The objective of this study was to evaluate the role of D2 receptors in acute ethanol inhibition of VTA GABA neuron activity, as well as the adaptation of D2 receptors by chronic ethanol consumption. METHODS: Using electrophysiological methods, we evaluated the effects of intraperitoneal ethanol on DA activation of VTA GABA neurons, the effects of DA antagonists on ethanol inhibition of their firing rate, as well as adaptations in firing rate following chronic ethanol consumption. Using single cell quantitative RT-polymerase chain reaction (PCR), we evaluated the expression of VTA GABA neuron D2 receptors in rats consuming ethanol versus pair-fed controls. RESULTS: In acute ethanol studies, microelectrophoretic activation of VTA GABA neurons by DA was inhibited by acute intraperitoneal ethanol, and intravenous administration of the D2 antagonist eticlopride blocked ethanol suppression of VTA GABA neuron firing rate. In chronic ethanol studies, while there were no signs of withdrawal at 24 hours, or significant adaptation in firing rate or response to acute ethanol, there was a significant down-regulation in the expression of D2 receptors in ethanol-consuming rats versus pair-fed controls. CONCLUSIONS: Inhibition of DA activation of VTA GABA neuron firing rate by ethanol, as well as eticlopride block of ethanol inhibition of VTA GABA neuron firing rate, suggests an interaction between ethanol and DA neurotransmission via D2 receptors, perhaps via enhanced DA release in the VTA subsequent to ethanol inhibition of GABA neurons. Down-regulation of VTA GABA neuron D2 receptors by chronic ethanol might result from persistent DA release onto GABA neurons.

BH3 mimetic ABT-737 and a proteasome inhibitor synergistically kill melanomas through Noxa-dependent apoptosis.

The Bcl-2 family is important in modulating sensitivity to anticancer drugs in many cancers, including melanomas. The BH3 mimetic ABT-737 is a potent small molecule inhibitor of the anti-apoptotic proteins Bcl-2/Bcl-X(L)/Bcl-w. In this report, we examined whether ABT-737 is effective in killing melanoma cells in combination with the proteasome inhibitor MG-132, and further evaluated the mechanisms of action. Viability, morphological, and Annexin V apoptosis assays showed that ABT-737 alone exhibited little cytotoxicity, yet it displayed strong synergistic lethality when combined with MG-132. In addition, the detection of Bax/Bak activation indicated that the combination treatment synergistically induced mitochondria-mediated apoptosis. Furthermore, mechanistic analysis revealed that this combination treatment induced expression of the pro-apoptotic protein Noxa- and caspase-dependent degradation of the anti-apoptotic protein, Mcl-1. Finally, siRNA-mediated inhibition of Mcl-1 expression significantly increased sensitivity to ABT-737 in these cells, and knocking down Noxa expression protected the cells from cytotoxicity induced by the combination treatment. These findings demonstrate that ABT-737 combined with MG-132 synergistically induced Noxa-dependent mitochondrial-mediated apoptosis. In summary, this study indicates promising therapeutic potential of targeting anti-apoptotic Bcl-2 family members in treating melanoma, and it validates rational molecular approaches that target anti-apoptotic defenses when developing cancer treatments.

Contingent and non-contingent effects of low-dose ethanol on GABA neuron activity in the ventral tegmental area.

Ventral tegmental area (VTA) GABA neurons appear to be critical regulators of mesocorticolimbic dopamine (DA) neurotransmission, which has been implicated in alcohol reward. The aim of this study was to evaluate the effects of low-dose "non-contingent" intravenous (IV) ethanol (0.01-0.1 g/kg) on VTA GABA neuron firing rate and synaptic responses, as well as VTA GABA neuron firing rate during low-dose "contingent" IV ethanol self-administration. Intravenous administration of 0.01-0.03 g/kg ethanol significantly increased VTA GABA neuron firing rate and afferent-evoked synaptic responses. In the runway self-administration paradigm, presentation of an olfactory cue (S+; almond extract) or no-cue (S-; no odor) in the Start box was paired with IV administration of low-dose ethanol (0.01 g/kg) or saline in the Target box. Runway excursion times decreased significantly in association during S+, and increased significantly during S- conditions. The firing rate of VTA GABA neurons markedly increased when rats received 0.01 g/kg IV ethanol in the Target box. VTA GABA neuron firing increased in the Start box of the runway in association with S+, but not S-. These findings demonstrate that VTA GABA neurons are activated by low-dose IV ethanol and that their firing rate increases in anticipation of ethanol reward.