GABAergic neurons in the ventral tegmental area (VTA) play a primary role in local inhibition of mesocorticolimbic dopamine (DA) neurons but are not physiologically or anatomically well characterized. We used in vivo extracellular and intracellular recordings in the rat VTA to identify a homogeneous population of neurons that were distinguished from DA neurons by their rapid-firing, nonbursting activity (19.1 +/- 1.4 Hz), short-duration action potentials (310 +/- 10 microseconds), EPSP-dependent spontaneous spikes, and lack of spike accommodation to depolarizing current pulses. These non-DA neurons were activated both antidromically and orthodromically by stimulation of the internal capsule (IC; conduction velocity, 2.4 +/- 0.2 m/sec; refractory period, 0.6 +/- 0.1 msec) and were inhibited by stimulation of the nucleus accumbens septi (NAcc). Their firing rate was moderately reduced, and their IC-driven activity was suppressed by microelectrophoretic application or systemic administration of NMDA receptor antagonists. VTA non-DA neurons were recorded intracellularly and showed relatively depolarized resting membrane potentials (-61.9 +/- 1.8 mV) and small action potentials (68.3 +/- 2.1 mV). They were injected with neurobiotin and shown by light microscopic immunocytochemistry to be multipolar cells and by electron microscopy to contain GABA but not the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH). Neurobiotin-filled dendrites containing GABA received asymmetric excitatory-type synapses from unlabeled terminals and symmetric synapses from terminals that also contained GABA. These findings indicate that VTA non-DA neurons are GABAergic, project to the cortex, and are controlled, in part, by a physiologically relevant NMDA receptor-mediated input from cortical structures and by GABAergic inhibition.

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to a dopamine-dependent opiate reward system, identical to that seen when an opiate-naïve rat becomes dependent and withdrawn.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...

Ventral tegmental area (VTA) GABA neurons are critical substrates modulating the mesocorticolimbic dopamine system implicated in natural and drug reward. The aim of this study was to evaluate the effects of ethanol on glutamatergic and GABAergic modulation of VTA GABA neuron electrical synaptic transmission. We evaluated the effects of systemic ethanol (0.05-2.0 g/kg i.p.), the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801; 0.05-0.2 mg/kg i.v.), the connexin-36 gap junction blocker quinidine (5-20 mg/kg i.v.), the fast-acting barbiturate methohexital (Brevital; 5-10 mg/kg i.v.), and the benzodiazepine chlordiazepoxide (Librium; 5-10 mg/kg i.v.), as well as in situ VTA administration of NMDA and the GABA A receptor agonist muscimol, on VTA GABA neuron spontaneous activity and internal capsule stimulus-induced poststimulus spike discharges (ICPSDs). Systemic ethanol, quinidine, and dizocilpine reduced, whereas local NMDA enhanced, and the systemic and local GABA A receptor modulators did not significantly alter VTA GABA neuron ICPSDs. Ethanol potentiated dizocilpine inhibition of VTA GABA neuron ICPSDs, but not quinidine inhibition. In situ microelectrophoretic application of dopamine markedly enhanced VTA GABA neuron firing rate (131%), spike duration (124%), and spike coupling, which were blocked by systemic quinidine. These findings indicate that VTA GABA neurons are coupled electrically via gap junctions and that the inhibitory effect of ethanol on electrical transmission is primarily via inhibition of NMDA receptor-mediated excitation, not via enhancement of GABA receptor-mediated inhibition. Thus, the rewarding properties of ethanol may result from inhibitory effects on excitatory glutamatergic neurotransmission between electrically coupled networks of midbrain GABA neurons.The two major types of membrane-bound proteins that are directly affected by physiologically relevant levels of ethanol (i.e., concentrations up to 100 mM or 460 mg/dl, at which point ethanol can be lethal in humans) are ligand-gated ion channels and voltage-dependent calcium channels (Harris, 1999). Ligand-gated ion channels, including ␥-GABA, N-methyl-D-aspartate (NMDA), glycine, nicotinic cholinergic, and 5-hydroxytryptamine type 3 receptors play a major role in synaptic transmission and have been shown to be directly modulated by ethanol. In particular, the intoxicating and rewarding properties of ethanol seem to result from either attenuation of NMDA receptor-mediated and/or enhancement of GABA receptor-mediated neurotransmission (for reviews, see Chester and Cunningham, 2002;Davies, 2003).The ventral tegmental area (VTA) is the neuronal origin of the mesocorticolimbic dopamine projection and has been implicated in locomotor activity, cognition, and in the reinforcing/rewarding properties of drugs of abuse (Wise, 1996), including ethanol. With drugs such as cocaine and amphetamine, the link to dopamine systems is readily apparent; however, with other drugs such as opiates and ethanol, the link to dopamin...

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