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

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to a dopamine-dependent opiate reward system, identical to that seen when an opiate-naïve rat becomes dependent and withdrawn.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

Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal

“…Therefore, understanding the neurobiological substrates mediating the motivational properties of withdrawal from chronic nicotine is an important step in the development of new treatments for nicotine addiction. Previous reports have suggested that a neurobiological switch occurs during the transition from a drug-naive to a drug-dependent motivational state (32). The transition from acute nicotine use to nicotine dependence has been hypothesized to result from neuroadaptative changes that produce the powerful withdrawal syndrome and negative emotional state observed upon cessation of nicotine use (3).…”

The effect of morphine upon DNA methylation in ten regions of the rat brain

“…BDNF expression facilitates opiate-associated neural plasticity 42 and the dopamine-dependent response to opiates. 6 Chronic exposure to opiates is associated with increased BDNF levels in the VTA 23 , and it has been demonstrated that this increase begins rapidly after initial usage. 43 Other studies have reported increased expression of BDNF in the VTA following morphine withdrawal.…”

“…IL-1, IL-6 and TNF- have been shown to reduce morphine analgesia within five minutes of administration 4 , and blockade of IL-1 signalling prolongs morphine-induced analgesia 5 , thereby potentially implicating these three cytokines in morphine tolerance. Microglial activation is further implicated in the development of tolerance through increased expression of brain derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) that facilitates the switch to the dopaminedependent reward system present in addiction 6 . Notably, Bdnf -/-knockout mice do not develop tolerance to morphine 7 .…”

The Neurobiology of Opiate Motivation

“…Electrophysiological, molecular, and behavioral evidence supports the idea that a switch from an inhibitory to an excitatory VTA GABA A receptor does, in fact, occur in animals that have changed from a previously drug-naive motivational state, to an opiate-dependent and withdrawn state Vargas-Perez et al 2009). In previously drug-naive rats, the GABA A receptor agonist muscimol produced inhibition of GABA neurons via their direct actions on GABA A receptors .…”

“…Similarly, it was proposed that the TPP-and dopamine-dependent reinforcement pathways observed by investigators might have their biological bases rooted in the biphasic actions of VTA GABA A receptors Vargas-Perez et al 2009). Such a model would require that opiates exert their actions (at least initially in drug-naive subjects) on the m-opioid receptors found presynaptically in the VTA, which regulate GABA release onto GABA A receptors (Fig.…”