Role of a Lateral Orbital Frontal Cortex-Basolateral Amygdala Circuit in Cue-Induced Cocaine-Seeking Behavior

Abstract

Cocaine addiction is a disease characterized by chronic relapse despite long periods of abstinence. The lateral orbitofrontal cortex (lOFC) and basolateral amygdala (BLA) promote cocaine-seeking behavior in response to drug-associated conditioned stimuli (CS) and share dense reciprocal connections. Hence, we hypothesized that monosynaptic projections between these brain regions mediate CS-induced cocaine-seeking behavior. Male Sprague-Dawley rats received bilateral infusions of a Cre-dependent adeno-associated viral (AAV) vector expressing enhanced halorhodopsin 3.0 fused with a reporter protein (NpHR-mCherry) or a control AAV (mCherry) plus optic fiber implants into the lOFC (Experiment 1) or BLA (Experiment 2). The same rats also received bilateral infusions of a retrogradely transported AAV vector expressing Cre recombinase (Retro-Cre-GFP) into the BLA (Experiment 1) or lOFC (Experiment 2). Thus, NpHR-mCherry or mCherry expression was targeted to lOFC neurons that project to the BLA or to BLA neurons that project to the lOFC in different groups. Rats were trained to lever press for cocaine infusions paired with 5-s CS presentations. Responding was then extinguished. At test, response-contingent CS presentation was discretely coupled with optogenetic inhibition (5-s laser activation) or no optogenetic inhibition while lever responding was assessed without cocaine/food reinforcement. Optogenetic inhibition of lOFC to BLA, but not BLA to lOFC, projections in the NpHR-mCherry groups disrupted CS-induced reinstatement of cocaine-seeking behavior relative to (i) no optogenetic inhibition or (ii) manipulations in mCherry control or (iii) NpHR-mCherry food control groups. These findings suggest that the lOFC sends requisite input to the BLA, via monosynaptic connections, to promote CS-induced cocaine-seeking behavior.

Chemogenetic Inactivation of Orbitofrontal Cortex Decreases Cue‐induced Reinstatement of Ethanol and Sucrose Seeking in Male and Female Wistar Rats

“…Our target region for inactivation was lateral, as opposed to medial, OFC as previous studies comparing functional roles of rodent OFC subregions have shown an important role for lateral OFC in value representation and reward seeking (Arguello et al, 2017;Burton et al, 2014;Fuchs et al, 2004;Lasseter et al, 2009;Lasseter et al, 2011;Lopatina et al, 2016;Lopatina et al, 2015;Lopatina et al, 2017) including reinstatement of EtOH seeking (Arinze and Moorman, 2020). Unlike Arinze and Moorman (2020), we did not dissociate separable contributions of OFC subregions, so we have referred throughout the text to OFC broadly.…”

Role of Projections between Piriform Cortex and Orbitofrontal Cortex in Relapse to Fentanyl Seeking after Palatable Food Choice-Induced Voluntary Abstinence

“…Additionally, muscimol plus baclofen (GABAa and GABAb receptor agonists) inactivation of OFC or selective inactivation of Fos-expressing neurons, using the Daun02 inactivation procedure (Cruz et al, 2013), decreases relapse to heroin seeking after forced abstinence (Fanous et al, 2012). Inhibition of OFC neuronal activity or inhibition of OFC projections to basolateral amygdala (BLA) decreases cueinduced and context-induced reinstatement of cocaine seeking after extinction (Fuchs et al, 2004;Lasseter et al, 2009Lasseter et al, , 2011Lasseter et al, , 2014Arguello et al, 2017). Finally, in vivo electrophysiology studies showed that cocaine or heroin self-administration impairs OFC-mediated decision-making processes (Jentsch et al, 2002;Torregrossa et al, 2008;Lucantonio et al, 2012Lucantonio et al, , 2015, and OFC activity is associated with choosing cocaine or heroin versus food in the discrete-trial choice procedure .…”

Extending the Time Domain of Neuronal Silencing with Cryptophyte Anion Channelrhodopsins

“…Until recently the only optogenetic tools available for inhibition of neuronal spiking had been rhodopsin ion pumps such as halorhodopsin and archaeorhodopsin that transport Cl – in or H + out of the cell, respectively ( Zhang et al, 2007 ; Chow et al, 2010 ; Chuong et al, 2014 ). However, the pumps translocate at most only one charge per captured photon and therefore their optogenetic use typically requires high light intensities (10–20 mW mm −2 ; Maurice et al, 2015 ; Parker et al, 2016 ; Arguello et al, 2017 ).…”