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to a dopamine-dependent opiate reward system, identical to that seen when an opiate-naïve rat becomes dependent and withdrawn.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 γ-aminobutyric acid type A (GABA A ) receptors of VTA GABAergic neurons, from inhibitory to excitatory signaling.The ventral tegmental area (VTA) serves as an anatomical locus controlling the switch from an opiate-nondependent to an opiate-dependent state (1,2). In nondependent rats, opiate reward is mediated by a dopamine-independent neural system, involving the brainstem tegmental pedunculopontine nucleus (TPP) (3). Once chronically exposed to opiates and in a state of withdrawal, opiate reward switches to a dopamine-dependent system (3). It has been observed that the switch between the two motivational systems is due to a switch in γ-aminobutyric acid type A (GABA A ) receptor functioning in VTA GABAergic neurons, from an inhibitory to an excitatory signaling state ( fig. S1) (2).Brain-derived neurotrophic factor (BDNF) is capable of producing this change in GABAergic response, from inhibitory to excitatory, as has been observed in the hippocampus during epileptic seizures (4) and in the spinal cord during neuropathic pain (5). BDNF is present in the VTA (6), and its TrkB receptors are present on both GABA ( fig. S2) and dopamine VTA neurons (7,8 enhance several behavioral effects of drugs, including psychomotor sensitization (6,9) and drug seeking (6,10). We hypothesized that, along with the changes in structural plasticity induced by BDNF in VTA dopaminergic neurons (11), increasing BDNF levels in the VTA would induce a switch to a drug-dependent motivational state in drug-nondependent rats due to the effects of BDNF on GABAergic neurons.First, we examined whether BDNF protein and mRNA levels in the VTA were increased in opiate-dependent rats. Sixteen hours after withdrawal from repeated daily exposure to heroin (0.5 mg/kg, subcutaneously) for 8 days [see supporting online material (SOM)], BDNF protein (F 3,37 = 7.63, P < 0.05) and BDNF mRNA (F 3,19 = 4.04, P < 0.05) levels in the VTA increased by 150% (P < 0.05) and 193%, respectively, of the control drug-naïve rats (P < 0.05). However, there were no increases in BDNF either when rats received a single injection of heroin (P > 0.05) or 15 days after withdrawal from repeated heroin exposure (P > 0.05) ( fig. S3).To explore whether BDNF alone was sufficient to cause a change in the neurobiological substrates mediating opiate reward, we next performed place conditioning procedures on rats after single bi...
Background Withdrawal from chronic ethanol enhances ventral tegmental area (VTA) GABA neuron excitability and reduces mesolimbic dopamine (DA) neurotransmission, which is suppressed by acupuncture at Shenmen (HT7) points (Zhao et al., 2006). The aim of this study was to evaluate the effects of HT7 acupuncture on VTA GABA neuron excitability, ethanol inhibition of VTA GABA neuron firing rate, and ethanol self-administration. A role for opioid receptors (ORs) in ethanol and acupuncture effects is also explored. Methods Using electrophysiological methods in mature rats, we evaluated the effects of HT7 stimulation and opioid antagonists on VTA GABA neuron firing rate. Using behavioral paradigms in rats, we evaluated the effects of HT7 stimulation and opioid antagonists on ethanol self-administration using a modification of the sucrose fading procedure. Results HT7 stimulation produced a biphasic modulation of VTA GABA neuron firing rate characterized by transient enhancement followed by inhibition and subsequent recovery in 5 min. HT7 inhibition of VTA GABA neuron firing rate was blocked by systemic administration of the non-selective μ-opioid receptor (MOR) antagonist naloxone. HT7 stimulation significantly reduced ethanol suppression of VTA GABA neuron firing rate, which was also blocked by naloxone. HT7 acupuncture reduced ethanol self-administration without affecting sucrose consumption. Systemic administration of the δ-opioid receptor (DOR) antagonist naltrindole blocked ethanol suppression of VTA GABA neuron firing rate and significantly reduced ethanol self-administration without affecting sucrose consumption. Conclusions These findings suggest that DOR-mediated opioid modulation of VTA GABA neurons may mediate acupuncture’s role in modulating mesolimbic DA release and suppressing the reinforcing effects of ethanol.
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 selfadministration. 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 selfadministration 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.
Background-Ventral tegmental area (VTA) γ-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.
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