Ryan Ting-A-Kee

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

BDNF and Drug Dependence Brain-derived neurotrophic factor (BDNF) is a growth factor involved in neuronal plasticity that is expressed after chronic administration of drugs of abuse and may play a crucial role in chronic opiate effects. Vargas-Perez et al. (p. 1732, published online 28 May) found that BDNF was directly involved in the switching mechanism in the ventral tegmental area, from an opiate-naïve, dopamine-independent drug reward substrate to an opiate-dependent, dopamine-dependent motivational substrate. In the ventral tegmental area, BDNF changed the action of GABA-A receptors from inhibitory to excitatory. This change led to behavioral changes that defined a neurobiological boundary between the acute phase of drug-taking and addiction. A growth factor involved in neuronal plasticity alters neurons in a specific area of the brain after chronic exposure to opioid drugs. 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to a dopamine-dependent opiate reward system, identical to that seen when an opiate-naïve rat becomes dependent and withdrawn.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 (GABAA) receptors of VTA GABAergic neurons, from inhibitory to excitatory signaling.

Dopaminergic Signaling Mediates the Motivational Response Underlying the Opponent Process to Chronic but Not Acute Nicotine

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 α-flupenthixol (α-flu) and in DA D2 receptor knockout mice. Conversely, α-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 D2 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.

BDNF Signaling in the VTA Links the Drug-Dependent State to Drug Withdrawal Aversions

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 tropomyosin-receptor-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.

The Neurobiology of Opiate Motivation

Opiates are a highly addictive class of drugs that have been reported to possess both dopamine-dependent and dopamine-independent rewarding properties. The search for how, if at all, these distinct mechanisms of motivation are related is of great interest in drug addiction research. Recent electrophysiological, molecular, and behavioral work has greatly improved our understanding of this process. In particular, the signaling properties of GABA(A) receptors located on GABA neurons in the ventral tegmental area (VTA) appear to be crucial to understanding the interplay between dopamine-dependent and dopamine-independent mechanisms of opiate motivation.

GABAA receptors mediate the opposing roles of dopamine and the tegmental pedunculopontine nucleus in the motivational effects of ethanol

Recent work has demonstrated that changes in ventral tegmental area (VTA) GABAA receptor ion conductance properties are responsible for switching morphine’s positive reinforcing properties from a dopamine‐independent to a dopamine‐dependent pathway when an animal transitions from a non‐deprived (minimal drug exposure) to a dependent (chronic drug exposure) and withdrawn state. Here we show that a double dissociation of ethanol’s positive reinforcing properties is exactly opposite to that seen with morphine. In C57BL/6 mice, ethanol‐conditioned place preferences were blocked in dopamine D2 receptor knockout non‐deprived mice, but not by a lesion of the tegmental pedunculopontine nucleus (TPP). On the other hand, TPP lesions, but not a D2 receptor mutation, blocked ethanol‐conditioned place preferences in ethanol‐dependent and withdrawn mice. The opposite effects of ethanol and opiates can be explained by their proposed actions through a common VTA GABAA receptor switching mechanism.

Different neural systems mediate morphine reward and its spontaneous withdrawal aversion

The opponent‐process theory posits that the aversive state of acute opiate withdrawal is a consequence of, and depends on, the previous rewarding state evoked by acute morphine reward. Although the brainstem tegmental pedunculopontine nucleus (TPP) is crucial for the rewarding component of morphine, the source of the later aversive component is not known. It is possible that (i) the second aversive process takes place within the TPP itself or (ii) morphine reward in the TPP activates an unconditioned opponent motivational process in another region of the brain. The effects of reversible inactivation of the TPP on the motivational properties of acute morphine and its spontaneous withdrawal effects in non‐drug‐dependent rats were examined using a place‐conditioning paradigm. Reversible inactivation of the TPP with lidocaine or bupivacaine immediately before the morphine injection blocked the rewarding properties of morphine in non‐dependent rats. Blocking the rewarding effects of morphine also blocked the opponent aversive effects of acute morphine withdrawal. In contrast, reversible inactivation of the TPP during the acute morphine withdrawal did not block this opponent aversive process. Our results confirm that the TPP is a critical neural substrate underlying the acute rewarding effects of morphine in non‐dependent rats. Furthermore, the opponent aversive process of acute morphine withdrawal is induced by the acute rewarding effects of morphine. However, the TPP does not directly mediate the spontaneous withdrawal aversion (the opponent process), suggesting that a different system, triggered by the changes in the TPP after the primary drug response, produces the aversion itself.

A test of the opponent-process theory of motivation using lesions that selectively block morphine reward

The opponent‐process theory of motivation postulates that motivational stimuli activate a rewarding process that is followed by an opposed aversive process in a homeostatic control mechanism. Thus, an acute injection of morphine in nondependent animals should evoke an acute rewarding response, followed by a later aversive response. Indeed, the tegmental pedunculopontine nucleus (TPP) mediates the rewarding effects of opiates in previously morphine‐naive animals, but not other unconditioned effects of opiates, or learning ability. The aversive opponent process for acute morphine reward was revealed using a place‐conditioning paradigm. The conditioned place aversion induced by 16‐h spontaneous morphine withdrawal from an acute morphine injection in nondependent rats was abolished by TPP lesions performed prior to drug experience. However, TPP‐lesioned rats did show conditioned aversions for an environment paired with the acute administration of the opioid antagonist naloxone, which blocks endogenous opioids. The results show that blocking the rewarding effects of morphine with TPP lesions also blocked the opponent aversive effects of acute morphine withdrawal in nondependent animals. Thus, this spontaneous withdrawal aversion (the opponent process) is induced by the acute rewarding effects of morphine and not by other unconditioned effects of morphine, the pharmacological effects of morphine or endogenous opioids being displaced from opiate receptors.

Infusion of brain-derived neurotrophic factor into the ventral tegmental area switches the substrates mediating ethanol motivation.

Recent work has shown that infusion of brain‐derived neurotrophic factor (BDNF) into the ventral tegmental area (VTA) promotes a switch in the mechanisms mediating morphine motivation, from a dopamine‐independent to a dopamine‐dependent pathway. Here we showed that a single infusion of intra‐VTA BDNF also promoted a switch in the mechanisms mediating ethanol motivation, from a dopamine‐dependent to a dopamine‐independent pathway (exactly opposite to that seen with morphine). We suggest that intra‐VTA BDNF, via its actions on TrkB receptors, precipitates a switch similar to that which occurs naturally when mice transit from a drug‐naive, non‐deprived state to a drug‐deprived state. The opposite switching of the mechanisms underlying morphine and ethanol motivation by BDNF in previously non‐deprived animals is consistent with their proposed actions on VTA GABAA receptors.

Adenosine A1 and A2A receptors are not upstream of caffeine’s dopamine D2 receptor-dependent aversive effects and dopamine-independent rewarding effects

Caffeine is widely consumed throughout the world, but little is known about the mechanisms underlying its rewarding and aversive properties. We show that pharmacological antagonism of dopamine not only blocks conditioned place aversion to caffeine, but also reveals dopamine blockade‐induced conditioned place preferences. These aversive effects are mediated by the dopamine D2 receptor, as knockout mice showed conditioned place preferences in response to doses of caffeine that C57Bl/6 mice found aversive. Furthermore, these aversive responses appear to be centrally mediated, as a quaternary analog of caffeine failed to produce conditioned place aversion. Although the adenosine A2A receptor is important for caffeine’s physiological effects, this receptor seems only to modulate the appetitive and aversive effects of caffeine. A2A receptor knockout mice showed stronger dopamine‐dependent aversive responses to caffeine than did C57Bl/6 mice, which partially obscured the dopamine‐independent and A2A receptor‐independent preferences. Additionally, the A1 receptor, alone or in combination with the A2A receptor, does not seem to be important for caffeine’s rewarding or aversive effects. Finally, excitotoxic lesions of the tegmental pedunculopontine nucleus revealed that this brain region is not involved in dopamine blockade‐induced caffeine reward. These data provide surprising new information on the mechanism of action of caffeine, indicating that adenosine receptors do not mediate caffeine’s appetitive and aversive effects. We show that caffeine has an atypical reward mechanism, independent of the dopaminergic system and the tegmental pedunculopontine nucleus, and provide additional evidence in support of a role for the dopaminergic system in aversive learning.

Tegmental pedunculopontine glutamate and GABA-B synapses mediate morphine reward.

The tegmental pedunculopontine nucleus (TPP) of the midbrain is critical in mediating the acute rewarding effects of opiates. However, the circuitry and neurochemistry underlying this effect has not been determined. Here we identify TPP receptors and cell types involved in systemic morphine reward and suggest an anatomical and neurochemical model for reward in the TPP. Simple hypothetical anatomical models for serial cell arrangements and receptors in the TPP were proposed and predictions of behavioral outcome (reward or no reward) then were made, based on the administration of agonists and antagonists directly into the TPP of rats. We report that TPP-administered NMDA produced rewarding effects, although GABA agonists and antagonists had no motivational effects on their own. However, the NMDA receptor antagonist AP-7 and the GABA-B receptor antagonist saclofen, while having no motivational effects on their own, blocked systemic morphine reward as measured by conditioned place preference. These results provide positive evidence for GABA-B and glutamate synapses in the TPP, which mediates systemic morphine reward and suggest that a serial pathway for morphine reward in the TPP is unlikely.