Although significant advances in the treatment of opiate addiction have been made, relapse to opiate use after
abstinence continues to impede successful treatment, highlighting the need for efforts to dissect the
mechanism of opiate-dependent changes in brain function. Long-lasting associations between opiates and the
context in which they are taken result in cues that lead to drug craving and ultimately relapse. The
hippocampus represents a key structure in the integration of emotional processing, learning and memory, and
reward-related behaviors. While the ventral subdivision of the hippocampus (vHPC) is involved in processing
emotional values of salient stimuli and goal-directed behaviors, the dorsal hippocampus (dHPC) plays a critical
role in episodic, spatial, and associative memory. In addition, it has been shown that the dHPC is necessary for
context- and cue-associated reward behaviors, including the expression of reward seeking. Further, we found
that chemogenetic inhibition of glutamatergic dHPC neurons reduces cue-induced morphine-seeking in an
instrumental model of relapse. Together, these findings indicate that the dHPC is important for the
development and maintenance of opioid-cue associations necessary for drug-seeking behavior. Integration of
rewarding and aversive stimuli relies on the mesolimbic reward circuit, where the nucleus accumbens (NAc)
plays a crucial role. The NAc facilitates reward seeking by integrating dopaminergic reinforcement signals with
glutamate-encoded environmental and cue stimuli. Although glutamatergic inputs to the NAc from the ventral
hippocampus have been reported, our preliminary data show that dense projections to the NAc also originate
in the dHPC. Interestingly, we found that photo-stimulation of excitatory dHPC neurons is rewarding and
reinforcing using a real-time place preference test and instrumental self-stimulation, respectively. Interestingly,
this dHPC stimulation was accompanied by enhanced activity of accumbal neurons and evoked local field
potentials within the NAc. No studies have examined whether the dHPC¿NAc is involved in opioid-seeking
behavior. Characterization of the cellular mechanisms initiated by the alterations in glutamatergic transmission
from the dHPC to the NAc observed during opioid self-administration is necessary to identify novel molecular
targets that might prevent drug relapse triggered by the exposure to drug-associated cues. Therefore, the
overall goal of this proposal is to investigate the role of excitatory transmission from the dHPC to the NAc in
opioid-seeking behavior and identify novel molecular targets that may mitigate the influence of drug-cue
associations on relapse. Accordingly, the aims here will 1) determine whether dHPC to NAc projecting neurons
are necessary and sufficient for fentanyl-seeking; 2) examine the effects of fentanyl-seeking behavior on
function and plasticity of NAc neurons downstream of dHPC projections; 3) determine the role of dHPC¿NAc
dynorphin- or enkephalin-containing synapses in fentanyl-seeking behavior. Findings generated from this
project will have significant translational potential for understanding the mechanisms of drug relapse.