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to a dopamine-dependent opiate reward system, identical to that seen when an opiate-naïve rat becomes dependent and withdrawn.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

SUMMARY Dopaminergic neurons in the ventral tegmental area (VTA) are well known for their role in mediating the positive reinforcing effects of drugs of abuse. Here, we identify in rodents and humans a population of VTA dopamine neurons co-expressing corticotropin releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates CRF mRNA in dopaminergic neurons of the posterior VTA, activates local CRF1 receptors, and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of CRF mRNA and specific pharmacological blockade of CRF1 receptors in the VTA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal, and limited the escalation of nicotine intake. These results link the brain reward and stress systems within the same brain region in signaling the negative motivational effects of nicotine withdrawal.

The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist a-flupenthixol (a-flu) and in DA D 2 receptor knockout mice. Conversely, a-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine. Taken together, these results suggest that dopaminergic signaling is necessary for the opponent motivational response to nicotine in dependent, but not non-dependent, rodents. Further, signaling at the DA D 2 receptor is critical in mediating withdrawal aversions in nicotine-dependent animals. We suggest that the alleviation of nicotine withdrawal primarily may be driving nicotine motivation in dependent animals. Neuropsychopharmacology (2010) 35, 943-954;

Drug administration to avoid unpleasant drug withdrawal symptoms has been hypothesized to be a crucial factor that leads to compulsive drug-taking behavior. However, the neural relationship between the aversive motivational state produced by drug withdrawal and the development of the drug-dependent state still remains elusive. It has been observed that chronic exposure to drugs of abuse increases brain-derived neurotrophic factor (BDNF) levels in ventral tegmental area (VTA) neurons. In particular, BDNF expression is dramatically increased during drug withdrawal, which would suggest a direct connection between the aversive state of withdrawal and BDNF-induced neuronal plasticity. Using lentivirus-mediated gene transfer to locally knock down the expression of the BDNF receptor tropomyosinreceptor-kinase type B in rats and mice, we observed that chronic opiate administration activates BDNF-related neuronal plasticity in the VTA that is necessary for both the establishment of an opiate-dependent state and aversive withdrawal motivation. Our findings highlight the importance of a bivalent, plastic mechanism that drives the negative reinforcement underlying addiction.

Nicotine addiction is a worldwide epidemic that claims millions of lives each year. Genetic deletion of α5 nicotinic acetylcholine receptor (nAChR) subunits has been associated with increased nicotine intake, however, it remains unclear whether acute nicotine is less aversive or more rewarding, and whether mice lacking the α5 nAChR subunit can experience withdrawal from chronic nicotine. We used place conditioning and conditioned taste avoidance paradigms to examine the effect of α5 subunit-containing nAChR deletion (α5 -/-) on conditioned approach and avoidance behaviour in nondependent and nicotine-dependent and -withdrawn mice, and compared these motivational effects with those elicited after dopamine receptor antagonism. We show that nondependent α5 -/- mice find low, non-motivational doses of nicotine rewarding, and do not show an aversive conditioned response or taste avoidance to higher aversive doses of nicotine. Furthermore, nicotine-dependent α5 -/- mice do not show a conditioned aversive motivational response to withdrawal from chronic nicotine, although they continue to exhibit a somatic withdrawal syndrome. These effects phenocopy those observed after dopamine receptor antagonism, but are not additive, suggesting that α5 nAChR subunits act in the same pathway as dopamine and are critical for the experience of nicotine's aversive, but not rewarding motivational effects in both a nondependent and nicotine-dependent and -withdrawn motivational state. Genetic deletion of α5 nAChR subunits leads to a behavioural phenotype that exactly matches that observed after antagonizing dopamine receptors, thus we suggest that modulation of nicotinic receptors containing α5 subunits may modify dopaminergic signalling, suggesting novel therapeutic treatments for smoking cessation.