Relapse to cocaine can be initiated after long periods of abstinence in response to cues (visual, auditory, tactile) associated with drug-taking. Repeated use of cocaine induces long-term changes (neuroadaptations) in the key brain regions potentially by usurping the learning mechanisms normally used to reinforce natural rewards. The rewarding properties and interoceptive feelings linked to cocaine become associated with environmental cues. This association is clinically important since intense drug craving causing the addicts to remain highly susceptible to relapse can predominantly occur in response to such environmental cues. However, we still have a poor understanding of the molecular mechanisms underlying drug-dependent learned associations. In the present proposal, we will test the hypothesis that expression of a conditioned behavioral response to a previously cocaine-paired environment requires phospholipase D (PLD) signaling in the amygdala, a key brain area for the formation and expression of associative memories downstream to serotonin (5-hydroxytryptamine, 5-HT) 2C receptors (5-HT2CRs). We propose to investigate the requirement of PLD and 5-HT2CR function for the expression of cocaine induced conditioned hyperactivity behavior using pharmacological intervention and to determine the effect of modulating PLD activity specifically in the amygdala and study its effect on 5-HT2CR mediated suppression of conditioned hyperactivity. Such amygdala specific experimental investigation of cocaine-cue associated neuroadaptations in long-term memory mechanism act two-fold by advancing the basic understanding of the signaling mechanism associated with drug-environment conditioned associations and performing preliminary investigations of therapeutic potential in preclinical models directed towards reducing the risk of relapse.
Cocaine addiction is a chronic, relapsing behavioral disorder and exposure to environmental cues associated with cocaine consumption triggers relapse in addicts. The present proposal will examine potential protein partner interaction that could be the basis of behavioral responses to cocaine-associated environmental cues and further investigates effects of specific drugs that target these proteins towards better understanding how to eliminate the addictive effects, thus providing initial studies that may lead to developing and testing new treatment approaches.
|Krishnan, Balaji; Scott, Michael T; Pollandt, Sebastian et al. (2016) Fear potentiated startle increases phospholipase D (PLD) expression/activity and PLD-linked metabotropic glutamate receptor mediated post-tetanic potentiation in rat amygdala. Neurobiol Learn Mem 128:65-79|
|Krishnan, Balaji (2016) Amygdala-Hippocampal Phospholipase D (PLD) Signaling As Novel Mechanism of Cocaine-Environment Maladaptive Conditioned Responses. Int J Neuropsychopharmacol :|