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, 324 (5935), 1732-4

Ventral Tegmental Area BDNF Induces an Opiate-Dependent-Like Reward State in Naive Rats

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Ventral Tegmental Area BDNF Induces an Opiate-Dependent-Like Reward State in Naive Rats

Hector Vargas-Perez et al. Science.

Abstract

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to a dopamine-dependent opiate reward system, identical to that seen when an opiate-naïve rat becomes dependent and withdrawn.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

Figures

Fig. 1
Fig. 1
Motivational effects of a single intra-VTA BDNF infusion in drug-nondependent rats. (A) Blockade of the dopaminergic system with neuroleptics (alpha-flupenthixol, 0.8 mg/kg) blocked the rewarding effects of morphine (10 mg/kg) in nondependent rats after a single intra-VTA BDNF (0.25 μg) infusion, but not after intra-VTA PBS infusion (*P < 0.05). The same treatment failed to block the rewarding effects of morphine in nondependent rats when BDNF was infused rostral, ventral, or lateral to the VTA because of missed cannulae placements (*P < 0.05). Error bars indicate SE of the mean. (B) Intra-VTA BDNF alone did not affect the sizes of the conditioned place preferences produced by acute morphine administration in drug-nondependent rats (*P < 0.05). (C) BDNF restored the rewarding properties of acute morphine administration in drug-nondependent TPP-lesioned rats (*P < 0.05). (D) Cresyl violet–stained coronal section showing one side of a bilateral TPP lesion and (below) a schematic of the anatomical region from which the section displayed was taken. The arrow indicates the TPP lesion area. (E) Cresyl violet–stained coronal section of a typical bilateral intra-VTA cannula placement.
Fig. 2
Fig. 2
Motivational and electrophysiological effects of a single intra-VTA BDNF infusion in drug-nondependent rats. (A) Blockade of the dopaminergic system with alpha-flupenthixol blocked the rewarding effects of an intra-VTA–administered GABAA receptor antagonist bicuculline (50 ng) in nondependent rats after a single intra-VTA BDNF infusion, but not after intra-VTA PBS infusion (*P < 0.05). (B and C) Single-unit extracellular recordings of VTA GABAergic neurons showing the effects of two current applications of muscimol (+50 nA) and baclofen (+50 nA) on the firing rate of representative VTA GABAergic neurons. In saline-treated rats, muscimol always decreased the firing rate of the VTA GABAergic neurons, whereas in BDNF-treated rats, muscimol enhanced the firing rate. Conversely, in both saline-treated and BDNF-treated rats, baclofen moderately decreased the firing rate of these VTA GABA neurons, as in this example.

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