Each year, the disease and trauma associated with alcohol abuse disorders result in tremendous financial and human cost worldwide. In individuals, chronic consumption of high volumes of ethanol produces neuroadaptive changes that alter the function of a variety of brain regions. Classically, much research has focused on the role played by alterations to reward signaling pathways (e.g. the mesolimbic dopamine pathway) in the manifestation and maintenance of addictive disorders. However, more recently research has begun to focus on the neurobiological substrates of cognitive deficits commonly displayed by substance abusing individuals, and evidence is accumulating that frontal cortical regions like the prefrontal cortex (PFC) are damaged or dysfunctional in patients meeting criteria for alcohol abuse and dependence disorders. Networks of cortical neurons serve to process information from sensory modalities and other brain regions, and when network function is sufficiently altered or diminished, behavioral abnormalities like the inability to control certain behaviors emerge. In fact, a hallmark of addiction pathology is the inability of the dependent individual to control their own drug-seeking behavior. One source of altered network function could be changes to neuromodulatory systems that regulate cortical activity. Endocannabinoids (eCB) are a class of neuromodulators that regulate PFC function, and the eCB system is itself perturbed by chronic ethanol exposure. eCBs are retrograde neurotransmitters that are released In response to cell depolarization, and their major receptor in the central nervous system is the CBI receptor. In the cortex, CBI is localized to presynaptic terminals at both glutamatergic and GABAergic synapses, and activation of CBI at either type of synapse results in decreased release of the respective neurotransmitter. Additionally, the expression and function of CB1 is diminished after chronic ethanol treatment. The long-term goal of the proposed study is to characterize how ethanol-induced changes in CBI expression and function alter cortical network activity. This study will employ a PFC explant culture model using tissue from CBI knockout mice and techniques including electrophysiology and biochemical assays.
The specific aims are: (1) Characterize the contribution of the eCB system toward the regulation of up-states in organotypic cultures of PFC, and (2) test the hypothesis that alterations in eCB signaling after chronic EtOH exposure contribute to enhanced up-states in organotypic cultures of PFC. Findings from this work may help to reduce relapse in abstinent individuals by elucidating therapeutic targets for the treatment of alcohol abuse and dependence.
|Pava, Matthew J; Woodward, John J (2014) Chronic ethanol alters network activity and endocannabinoid signaling in the prefrontal cortex. Front Integr Neurosci 8:58|
|Pava, Matthew J; den Hartog, Carolina R; Blanco-Centurion, Carlos et al. (2014) Endocannabinoid modulation of cortical up-states and NREM sleep. PLoS One 9:e88672|
|Pava, Matthew J; Woodward, John J (2012) A review of the interactions between alcohol and the endocannabinoid system: implications for alcohol dependence and future directions for research. Alcohol 46:185-204|
|Pava, Matthew J; Blake, Emily M; Green, Stephen T et al. (2012) Tolerance to cannabinoid-induced behaviors in mice treated chronically with ethanol. Psychopharmacology (Berl) 219:137-47|
|Woodward, John J; Pava, Matthew (2012) Ethanol inhibition of up-states in prefrontal cortical neurons expressing the genetically encoded calcium indicator GCaMP3. Alcohol Clin Exp Res 36:780-7|