The cycle of drug-misuse, addiction, and relapse is universal. People typically misuse drugs in the same environment with the same people, which leads to strong learned associations between the reward feeling of the drugs and the context environment in which it is taken. These strong associations between the reward and the environment is one of the leading causes of relapse to drug craving and drug seeking behavior in humans and rodents. In our lab, we study the cellular, biochemical, and molecular mechanisms in the hippocampus that underlie these aberrant learned associations with the environment and drugs of abuse, specially opiates.
Morphine administration paired to a specific contextual environment triggers persistent structural and functional changes in dendritic spines that have been proposed to mediate the aberrant learning associated with addiction. Using ex vivo imaging approaches, our lab has shown that morphine conditioned place preference (mor CPP) decreases the number of dendritic spines of hippocampal CA1 neurons, mediated by NR2B containing NMDA receptors, yet the timing and dynamics of these events and their potential relationship to the association between morphine reward and context are unknown. We currently have three ongoing projects in the lab to address these questions:
1) To date, studying hippocampal plasticity and dendritic spines has primarily relied on ex vivo analyses conducted in brain slices. While informative, these studies, as terminal experiments, cannot follow the dynamics of structural plasticity with high temporal resolution, nor pinpoint the loci of plasticity within the network, nor compare structural changes with alterations in behavior. To observe neural networks in real time as mor CPP and reinstatement take place, we have designed a virtual reality condition place preference (VR-CPP) paradigm that can be paired with 2-photon imaging, making this combination of behavior and network surveillance possible.
2) Using the context-dependent locomotor sensitization paradigm, a model of how repeated use of a drug such as morphine produces enhanced craving, we found impaired LTP in the CA1 region of the hippocampus and attenuation of NMDAR currents by the calcium-gated potassium channel SK2. Calcium entry via NMDARs induces potassium efflux through SK2 channels and subsequent hyperpolarization and NMDAR inactivation. These results suggest the SK2-NMDAR negative feedback loop plays a role in opiate-induced impairment of hippocampal plasticity, resulting in long-lasting drug-paired contextual associations. We are currently using the classical CPP paradigm and cue-driven reinstatement of self-administration to uncover the role of SK2 channel (calcium-activated potassium channel) adaptations in the CA1 region of the dorsal hippocampus in drug-related memory formation and their involvement in contextual relapse.
3) A recent genome-wide association study (GWAS) by Nelson et al. found that the presence of single nucleotide polymorphisms (SNPs) in cornichon family homolog 3 (CNIH3) is the strongest correlating genetic factor for protection against opioid addiction despite drug misuse (Mol Psychiatry, 2016). CNIH3 is an AMPA receptor (AMPAR) auxiliary protein which modulates AMPAR trafficking and maintenance to the post-synaptic membrane, highly expressed in the hippocampus. We are currently investigating the role of CNIH3 investigate the effects of CNIH3 on AMPAR-dependent mechanisms such as AMPAR subunit trafficking to the membrane, synaptic structural morphology, or AMPAR-associated behaviors. CNIH3 on AMPAR-dependent mechanisms in the hippocampus through biochemical, morphological, and behavioral methods.