A Conditioned Place Preference for Heroin Is Signaled by Increased Dopamine and Direct Pathway Activity and Decreased Indirect Pathway Activity in the Nucleus Accumbens

Abstract

Repeated pairing of a drug with a neutral stimulus, such as a cue or context, leads to the attribution of the drug's reinforcing properties to that stimulus, and exposure to that stimulus in the absence of the drug can elicit drug-seeking. A principal role for the NAc in the response to drug-associated stimuli has been well documented. Direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) have been shown to bidirectionally regulate cue-induced heroin-seeking in rats expressing addiction-like phenotypes, and a shift in NAc activity toward the direct pathway has been shown in mice following cocaine conditioned place preference (CPP). However, how NAc signaling guides heroin CPP, and whether heroin alters the balance of signaling between dMSNs and iMSNs, remains unknown. Moreover, the role of NAc dopamine signaling in heroin reinforcement is unclear. Here, we integrate fiber photometry for in vivo monitoring of dopamine and dMSN/iMSN calcium activity with a heroin CPP procedure in rats to begin to address these questions. We identify a sensitization-like response to heroin in the NAc, with prominent iMSN activity during initial heroin exposure and prominent dMSN activity following repeated heroin exposure. We demonstrate a ramp in dopamine activity, dMSN activation, and iMSN inactivation preceding entry into a heroin-paired context, and a decrease in dopamine activity, dMSN inactivation, and iMSN activation preceding exit from a heroin-paired context. Finally, we show that buprenorphine is sufficient to prevent the development of heroin CPP and reduce Fos activation in the NAc after conditioning. Together, these data support the hypothesis that an imbalance in NAc activity contributes to the development of drug-cue associations that can drive addiction processes.

A computational model of learning flexible navigation in a maze by layout-conforming replay of place cells

“…After replay, the PC-MSN synaptic strength encodes the geodesic proximity between the firing field center of each place cell and the goal location. As a result, the activity of the MSN population will ramp up when an animal approaches the goal location, which conforms to a line of experimental observations (van der Meer and Redish, 2011 ; Howe et al, 2013 ; Atallah et al, 2014 ; London et al, 2018 ; Sjulson et al, 2018 ; O'Neal et al, 2022 ). During goal-directed navigation, the attractor network periodically generates a series of replay trajectories from the rat's location to lookahead along each explorable path (Johnson and Redish, 2007 ; Pfeiffer and Foster, 2013 ), and the trajectory leading to a maximal MSN activity is followed by the rat with a maximal probability.…”

“…{p(t), t (i) 0 < t < t (i) 1 } defines the i-th sub-trajectory with the initial direction given by n (i) = p(t (i) 0 ) − x. A line of studies (van der Meer and Redish, 2011;Howe et al, 2013;Atallah et al, 2014;London et al, 2018;Sjulson et al, 2018;O'Neal et al, 2022) has shown that the activity of MSN ramps up when a rat is approaching the goal location. Previous studies (Pfeiffer and Foster, 2013;Xu et al, 2019;Widloski and Foster, 2022) have also observed that rats show tendencies to follow replay trajectories that are approaching the goal location.…”

Characterization and mu opioid receptor sensitivity of neuropeptide Y interneurons in the nucleus accumbens

“…The target-specific regulation of GABA release onto MSNs means that local MOR activation would disinhibit D1-MSNs to a greater degree than D2-MSNs. The resulting disparity in MSN output (favoring D1-MSNs) could promote naturally rewarding behaviors like food consumption (Bakshi and Kelley, 1993; Castro et al, 2021) or social interaction (Gunaydin et al, 2014; Trezza et al, 2011), as well as the rewarding properties of exogenous opioids (Koo et al, 2014; O’Neal et al, 2022). It is also fascinating to note that LTSIs in the dorsal striatum exert an inhibitory influence on dopamine release (Holly et al, 2021).…”

Pyfiber: an open source python library that facilitates the merge of operant behavior and fiber photometry- focus on intravenous self-administration

“…Combining fiber photometry and operant behavior can also help uncover neural signatures in response to reward-related discriminative and conditioned stimuli. In the scope of drug-related behaviors, some studies have used conditioned place preference (CPP) to explore neural correlates of an exposure to a drug-associated context (Calipari et al, 2016; O’Neal et al, 2022). However, in CPP, animals do not freely self-administer the drug, which limits potential translatability.…”