- Defining the neurobiological basis of the persistence of central nervous system adaptation induced by chronic administration of alcohol and by stress.
- Defining neural circuits involved in the support of specific behavioral responses induced by stress and withdrawal from chronic alcohol exposure.
- Exploration of the neuroimmune involvement in specific regions of brain in the functional changes induced by chronic stress and withdrawal from chronic alcohol.
When an alcoholic ceases drinking, subsequent stress can induce negative affect and craving—responses understood to lead to relapse and to support the kindling/stress hypothesis of alcoholism. Based upon the enduring neuroadaptation induced by alcohol abuse, an extended period of chronic intermittent alcohol (CIA) exposure in rodents was used to model the persistent adaptation that supports stress sensitization of anxiety-like behavior. With this model, the laboratory is utilizing a number of approaches to define the neurobiological basis of the central adaptation supporting stress by defining specific neural systems and neural circuits involved. Pharmacological approaches accompanied by local injection of pharmacological agents are used to identify the neural systems within specific regions of brain that support the ethanol withdrawal and stress induction of negative affect after CIA exposure. In addition to the involvement of CRF in the central amygdala, recent efforts have identified vasopressin (VP) as another transmitter which can substitute for stress to induce an adaptation that can facilitate withdrawal induced anxiety from a single 5 day exposure to alcohol. This effort was complemented by findings showing that a VP receptor antagonist given prior to each of the first two withdrawals of the CIA protocol blocked the anxiety during the final ethanol withdrawal. This latter effort provides further exploration of a neurotransmitter system that can be used to identify brain regions and neural paths that contribute to the adaptation that supports withdrawal and stress induced anxiety after chronic alcohol. While several brain regions have been identified that contribute to CRF involvement of CIA adaptation, the same strategy used to identify these brain sites can be utilized to identify sites other than the central amygdala that contribute to the VP-induced adaptation that sensitizes alcohol withdrawal-induced anxiety. A final strategy that is currently underway to identified brain circuits involved in negative affect following withdrawal from chronic alcohol is the use of the DREADD technology developed in the Pharmacology Department by Dr. Roth. One current finding with this DREADD approach has documented that a neural path from the basolateral amygdala (BLA) is capable of blocking the withdrawal-induced anxiety following the CIA exposure. Obviously, this strategy will be extended to define the sites involved downstream of the BLA. This new strategy available to explore circuits involved in adaptation can be expected to expand our understanding of alcohol abuse and the means by which abuse contributes to the adaptation.
During the period of our investigations of CRF involvement in the stress contribution to CIA withdrawal-induced anxiety, literature had accumulated and shown that stress increases neuroimmune function in brain. Therefore, the hypothesis was proposed that the stress-related maladaptive responses after chronic alcohol involve brain cytokines. To address this novel hypothesis, innovative strategies are proposed to test whether the persisting adaptation by CIA exposure supports stress-induced cytokine induction in selected brain regions, alters regulators of stress-induced brain cytokines, or affects cytokine neural responses from the central amygdala (CeA) and other sites in brain. Currently, we have documented that withdrawal from CIA as well as stress alone increases cytokine mRNAs in the prefrontal cortex. We have also identified that not all brain sites induce common cytokine mRNAs following withdrawal from CIA exposure. Additionally observed was that microinjection of a cytokine into the CeA substituted for stress sensitization of ethanol withdrawal induced negative affect. We have also found that cytokines are found in neurons in the CeA suggestive of a close link between immune and neural function. Most importantly the laboratory has discovered that stress evokes an increase in cytokines mRNAs in the cortex by a neural system distinct from the neural system that supports the mRNA increase following withdrawal from chronic alcohol.