A vast literature has shown that dopamine (DA) signaling in the nucleus accumbens (NAc) is a critical mediator of addiction-related and goal-directed behaviors. Thus, there is considerable interest in understanding the molecular mechanisms through which DA can alter the NAc firing activity and modulate behavior. Previous studies from the Bonci lab found that cooperative activation of DA D1 and D2 receptors increases firing of NAc neurons. Interestingly, many motivated and addiction-related behaviors are sustained by activity of both D1 and D2 receptors in the NAc. Further, cannabinoid type-1 (CB1) receptors in the NAc can also critically regulate motivated behavior. Thus, the main goal of this proposal is to use in vitro techniques, in particular whole-cell patch-clamp electrophysiology in NAc brain slices prepared from adult male rats to understand the molecular mechanisms through which endogenous cannabinoids (eCBs) and CB1 receptor activity could interact with dopamine receptors to enhance NAc firing activity. The long-term goal is to understand how NAcore CB1 and dopamine receptors interact to drive adaptive as well as pathological motivated behaviors, with the hope of developing novel therapeutic interventions for human neurological conditions. My preliminary data indicate that CB1 receptor antagonists prevent the D1/D2 cooperative enhancement of NAc core firing, suggesting that eCB activation of CB1 receptors could play a critical role in this process. However, the cellular mechanisms through which this occurs, especially the type of eCB which might contribute, remain unknown.
Specific Aim 1 will examine the contribution of CB1 receptors to the D1/D2-mediated enhancement in NAc core firing. The role of CB1 receptors will be determined with several different CB1 receptor antagonists. The contribution of CB1 receptors will also be examined by investigating whether CB1 receptor activators can enhance NAc core firing alone, or whether interaction with a D1 or D2 receptor agonist is required to enhance firing.
Specific Aim 2 will investigate intracellular pathways through which CB1 receptor activation could facilitate NAc core firing. In particular, the identity of the eCB which mediates the CB1/D1/D2 interaction will be examined using inhibitors of PLC, an enzyme critical for several eCB synthesis pathways, and inhibitors of FAAH and MGL, which hydrolyze the eCBs AEA and 2-AG. Also, neurons will be filled with AEA or 2-AG to determine whether these eCBs can increase NAc core firing alone or in combination with D1 or D2 receptor agonists. Together, these experiments will provide important information about the eCB that contributes critically to the D1/D2-mediated enhancement in NAc firing and the possible mechanism(s) through which dopamine and CB1 receptors could interact to enhance NAc firing activity. To facilitate achieving these goals, I will receive ongoing training and mentoring from my sponsor, other lab members, and outside collaborators in the design, implementation, and interpretation of my experiments, in the relevant research literature, and the preparation of my results for submission for publication.
Endogenous cannabinoids (endocannabinoids) modulate many diverse biological targets both in the central nervous system and in the periphery, and therefore play a critical role in many physiological processes such as pain, asthma, glaucoma, nausea, reproduction, immune system and cancer and neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Pharmacological manipulation of this system may allow us to identify new therapeutic intervention for several neurological disorders while eliminating the undesirable side effects associated with cannabis. The results from this proposal may be useful in identifying novel signaling interactions that could represent possible pharmacological targets for treating addiction or other diseases.
| Seif, Taban; Simms, Jeffrey A; Lei, Kelly et al. (2015) D-Serine and D-Cycloserine Reduce Compulsive Alcohol Intake in Rats. Neuropsychopharmacology 40:2357-67 |
| Seif, Taban; Chang, Shao-Ju; Simms, Jeffrey A et al. (2013) Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake. Nat Neurosci 16:1094-100 |
| Seif, T; Makriyannis, A; Kunos, G et al. (2011) The endocannabinoid 2-arachidonoylglycerol mediates D1 and D2 receptor cooperative enhancement of rat nucleus accumbens core neuron firing. Neuroscience 193:21-33 |
