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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    817—Amphetamine and Related Drugs: Neural Mechanisms of Addiction

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    817.09: Ketamine prevents the decrease in dopamine neuron activity following acute amphetamine withdrawal

    Location: Halls B-H

    *P. BELUJON, A. A. GRACE;
    Neurosci., Univ. Pittsburgh, Pittsburgh, PA

    Abstract Body: Breaking the cycle of drug use leading to reuse and abuse is a challenging process. Indeed, the negative affect following drug withdrawal often drives an individual to subsequent use to relieve this state, leading directly to abuse and addiction. Thus, drug addiction is not a static phenomenon but more a cycle composed of different stages: anticipation of drug intake, self administration/reinforcement, withdrawal with negative affect, and subsequent re-administration of drug. For drugs such as cocaine and amphetamine, the increase of dopamine (DA) release from the ventral tegmental area (VTA) appears to be critical for their acute reinforcing actions, since it facilitates reward-driven behaviors. However, this positive affect is followed by a negative emotional state each time a drug is taken, including the first time. This suggests that the rewarding positive hedonic experience engages secondary anhedonic processes that are compensatory and opposite to these positive emotions; this has been described as the opponent process theory of motivation.
    Anhedonia, or the inability to experience pleasure from rewarding events, has been repeatedly associated with dysfunction in the DA system. Many studies have focused on anhedonia in drug addiction after repeated drug administration; however, the negative emotional state appears even after a drug is taken for the first time. Therefore, this negative state drives additional drug intake and we propose this is due to a decrease in DA activity.
    Using in vivo extracellular single-unit recordings from identified DA neurons from the VTA in chloral hydrate-anaesthetized rats, we found that there is a decrease specifically in tonic DA neuron activity 18 hours following an acute 1.5 mg/kg i.p. dose of amphetamine, and that this underlies the negative affective state of acute drug withdrawal. Moreover, we found that ketamine administration one hour prior to recording circumvents the decrease in DA neuron tonic firing that we propose underlies this negative withdrawal state.
    Therefore, this data suggest that ketamine could be an effective preventative measure to break the cycle of drug use leading to abuse.

    Lay Language Summary: Our work suggests that the novel antidepressant ketamine could be an effective preventative measure to break the cycle of drug use leading to abuse.
    Drug addiction is a chronic relapsing disorder that represents a prominent social and economical burden to our societies. One of the most challenging processes in treating addiction is to break the cycle of use and reuse of a drug. Each time an individual takes a stimulant, they initially experience the event as rewarding. However, this is followed by a slow deterioration leading to the opposite state: a negative affect (or anhedonia) during withdrawal that will drive an individual to take more drugs in order to offset this negative experience. The dopamine system plays a major role in reward, and decreased function of this system is associated with anhedonia, or loss of pleasurable experiences. Our results suggest that administering an antidepressant during the negative affect period might decrease the propensity to take more drugs in the withdrawn state by restoring the dopaminergic system to normal.
    To test this hypothesis, we measured the state of the dopaminergic system in anesthetized rats 18 hours after a single injection of amphetamine or of a physiological solution. We then counted the number of active dopaminergic neurons by passing an electrode repeatedly in a specific pattern throughout the ventral tegmental area; a region implicated in reward. A dopamine neuron in the ventral tegmentum must be active in order to be responsive to stimuli; therefore, the fewer active dopamine neurons, the less responsive the dopamine system to rewarding events. We also tested the effect of ketamine, a novel antidepressant compound, when injected one hour before measuring dopamine neuron activity.
    Acute amphetamine injection induced a decrease specifically in the number of active dopamine neurons 18 hours following an acute dose of amphetamine, causing the dopamine system to be in a hypo-responsive state. This condition is similar to what we also observed in models of depression. Moreover, we found that ketamine administration one hour prior to recording prevents the decrease in number of active dopamine neurons that we propose underlies the negative withdrawal state.
    These results suggest that there is a substantial decrease in the number of responsive dopamine neurons after acute administration of amphetamine, which would induce a diminution of the dopamine-dependent positive affect, driving a negative affective state during acute withdrawal. This would lead an individual to take more amphetamine to block this negative state. Administration of the antidepressant ketamine blocked the diminution of DA activity. Therefore, blocking the negative state with ketamine might block relapse in individuals that are at high risk for drug abuse by removing a primary drive to retake drugs.
    Some individuals are able to use recreational drugs without ever experiencing negative consequences or addiction. Others will experience negative affect after one use, which will lead to reuse of a drug and eventually abuse. Therefore, understanding the mechanisms involved in the transition from recreational use to excessive drug intake is key to prevent an individual in retaking a drug. Our results suggest a potential effective way to prevent some individuals to take additional drug to overcome withdrawal negative affect. Indeed the use of ketamine could decrease abuse potential by breaking the cycle of drug-induced pleasure followed by withdrawal negative affective state.