Preclinical Neuropsychopharmacology Research Team
Breese Lab (left to right): Kui-Ling Huang, Bob Angel, Zhen Ming, M.D., George Breese, Ph.D, Hugh Criswell, Ph.D.,
Bonita Blake, Ph.D., DVM, Darin Knapp, Ph.D., Thomas McCown, Ph.D., Marc Weinberg, Ph.D.
The focus of our laboratory is to understand the acute actions of ethanol on brain function and how these actions relate to adaptive changes in brain that accompany prolonged alcohol exposure. Multidisciplinary approaches, which include anatomical, molecular, chemical, behavioral and electrophysiological procedures, make possible this evaluation of ethanol actions on neural mechanisms. The evaluation of acute ethanol assesses the sedative, anti-conflict and electrophysiological properties of ethanol. The consequences of chronic ethanol focus on the adaptive changes induced by this exposure. As always we search for the brain sites that support these acute and chronic actions of ethanol, a strategy followed by examination of chemical and electro-physiological consequences at the relevant brain sites. Recent efforts allowed the laboratory to discover that repeated withdrawals from chronic ethanol sensitize anxiety-like behavior during the final withdrawal, a discovery that opened new research avenues. The nature of cumulative adaptive change by repeated withdrawals is reminiscent of the “kindling” associated with seizures that follow repeated ethanol withdrawals.
A major focus of our research is defining the role of stress in alcoholism—a view that led to proposing the kindling-stress hypothesis of alcoholism. In support of this hypothesis, research found that stress after repeated withdrawals induces an anxiety response not seen in controls, a reflection of adaptive change induced by the repeated chronic ethanol exposures. Importantly, stress during abstinence from ethanol drinking during repeated withdrawals enhances an ethanol deprivation effect (increased voluntary ethanol drinking). A subsequent observation was that repeated stresses prior to a final ethanol exposure sensitize withdrawal-induced anxiety. Based upon literature that CRF, ODN and cytokines are involved in stress, work undertaken has demonstrated that repeated administration of each of these endogenous compounds into brain prior to 5 days of ethanol diet sensitize withdrawal-induced anxiety. Future work will attempt to determine how these findings linking CRF, ODN and cytokines to sensitization relate to other central mechanisms linked to the worsening negative affect that occurs during withdrawal in alcoholics. Another focus of this laboratory is to identify the neuroanatomical basis of the sensitization induced by repeated withdrawals using pharmacological challenges. Ongoing research is exploring the involvement of the dorsal raphe and central amygdala in the sensitization. This strategy has thus far allowed demonstrating an involvement of GABA, serotonergic and CRF mechanisms in the support of sensitization. This knowledge from focusing on brain sites which support these specific neural mechanisms in sensitization will permit subsequent neurochemical assessment of cellular actions at sites identified . The subsequent strategy from this approach will be to determine if epigenetic programming contributes to the neurochemical changes associated with sensitization of withdrawal-induced anxiety.
The identification of the consequences of the persistent adaptation that induces sensitization of withdrawal-induced anxiety at the cellular level will utilize electrophysiological recordings at critical brain sites. One aspect is investigating the presynaptic basis of CRF release of neurotransmitters. Other studies are investigating the mechanism by which flumazenil acts to prevent, and ODN to induce, sensitization of withdrawal-induced anxiety. Finally, the electrophysiological research will examine what changes occur in neural function in critical brain regions after protocols that sensitize withdrawal-induced anxiety.
--Discovered that TRH antagonizes ethanol-induced sedation.
--Identified the inferior collicular cortex as the major contributor to ethanol-induced seizures.
-- Demonstrated that multiple withdrawals from chronic ethanol treatment kindle inferior collicular seizure activity.
--Identified the medial septum as a key area in brain responsible for ethanol-induced sedation and the action of TRH to reduce ethanol sedation.
--Discovered that ethanol has regionally specific actions on selected ligand-gated ion channels in brain.
--Discovered that repeated withdrawals from low dose ethanol kindle emotional behavior (anxiety) during withdrawal that has a persistent effect on brain function.
--Discovered that repeated stresses or CRF prior to chronic ethanol sensitize withdrawal-induced anxiety-like behavior.
--Discovered that baclophen, a GABA-B agonist, prevents sensitization of ethanol withdrawal-induced anxiety.
--Implicated specific neurotransmitter systems in the sensitization of repeated withdrawals and the stress/ethanol withdrawal protocols.
--Discovered that repeated cytokines exposure prior to chronic ethanol supports sensitization of withdrawal-induced anxiety.
--Discovered that repeated dosing with octadecaneuropeptide (ODN) prior to chronic ethanol sensitizes withdrawal-induced anxiety-like behavior.
--Discovered that flumazenil acts as an agonist and ODN as an inverse-agonist on extrasynaptic GABAA receptor function.
--Identified an involvement of extrasynaptic current in the sensitization of withdrawal-induced anxiety.
Current Research Projects
- Defining CNS Transmitters Involved in Withdrawal-Induced Anxiety by Cytokines.
- Investigating CRF and Cytokine Involvement in Stress Sensitization of Withdrawal-Induced Anxiety in Adolescent animals.
- Identifying Sites in Brain Responsible for CRF-Induced Sensitization of Ethanol Withdrawal-Induced Anxiety.
- Identifying Brain Sites and CNS Transmitters that support Stress-Induced Drinking in P-Rats.
- Defining the Molecular Basis for Ethanol and CRF Action on GABA Mechanisms.
- Exploring Gene Therapy to Alleviate Seizures.
- Determining the Molecular Basis of Central Mechanisms Involved in Repeated Withdrawals in Adults and Adolescents.
- Performing Research to Identify if an Epigenetic Mechanism Supports the Persisting Adaptation Responsible for Sensitization of Withdrawal-Induced Anxiety.