Biology subjects

Kuhn, H. M.

Publications and source records attributed to Kuhn, H. M..

4 recordsLinked to original sources

bioRxiv2026

Negative affective states are not detected in rats following an intravenous self-administration regimen leading to incubation of oxycodone craving

In rats, cue-induced opioid craving intensifies (incubates) during abstinence from opioid self-administration and then remains high for a prolonged period. The prolonged plateau models persistent vulnerability to cue-induced craving and relapse in humans recovering from opioid use disorder. However, a very significant contributor to relapse vulnerability in these individuals is the presence of negative affective states that can persist for months to years, far beyond physical dependence. The goal of this study was to determine if the incubation of craving model recapitulates this aspect of relapse vulnerability. We began by comparing rats trained to self-administer oxycodone using a regimen leading to persistent elevation of cue-induced craving (6 h/d x 10 d) and rats trained to self-administer saline. We assessed somatic withdrawal signs in early abstinence and conducted behavioral tests modeling negative affect (open field, social preference, sucrose preference, and elevated plus maze) in late abstinence. Some somatic withdrawal signs were greater in oxycodone rats on abstinence day (AD)1, but cumulative scores did not differ between groups on AD1-3. On AD41-46, no group differences were found in behavioral tests modeling negative affect. To compare early and late abstinenceperiods, a second cohort of rats self-administered saline and oxycodoneand then received two cue-induced seeking tests (AD1 and AD40; oxycodone rats exhibited incubation of craving) and two series of negative affect tests (AD2-7 and AD41-48). While some time-dependent changes in affect were observed within each group, they were suggestive of reduced anxiety-like behavior in oxycodone rats. Finally, because rats are single-housed during our incubation studies, we compared drug-naive rats after 8-9 weeks of single vs pair housing and found no difference in behavioral tests modeling negative affect. We conclude that the persistence of elevated cue-induced craving observed after a standard opioid incubation regimen is not accompanied by negative affective states, probably due to lower drug intake during the intravenous regimen compared to non-contingent escalating dose regimens typically used to study withdrawal signs. This does not negate the utility of the incubation model for studying cue-induced opioid craving and its neurobiological basis.

neuroscience↗

bioRxiv2025

Incubation of oxycodone craving is associated with CP-AMPAR upregulation in D1 and D2 receptor-expressing medium spiny neurons in nucleus accumbens core and shell

A major problem in treating opioid use disorder is persistence of craving after protracted abstinence. This has been modeled in rodents using the incubation of craving model, in which cue-induced drug seeking increases over the first weeks of abstinence from drug self-administration and then remains high for an extended period. Incubation has been reported for several opioids, including oxycodone, but little is known about underlying synaptic plasticity. In contrast, it is well established that incubation of cocaine and methamphetamine craving depends on strengthening of glutamate synapses in the nucleus accumbens (NAc) through incorporation of calcium-permeable AMPARs (CP-AMPARs). CP-AMPARs have higher conductance than the calcium-impermeable AMPARs that mediate NAc excitatory transmission in drug-naive animals, as well as other distinct properties. Here we examined AMPAR transmission in medium spiny neurons (MSN) of NAc core and shell subregions in rats during forced abstinence from extended-access oxycodone self-administration. In early abstinence (prior to incubation), CP-AMPAR levels were low. After 17-33 days of abstinence (when incubation is stably plateaued), CP-AMPAR levels were significantly elevated in both subregions. These results explain the prior demonstration that infusion of a selective CP-AMPAR antagonist into NAc core or shell subregions prevents expression of oxycodone incubation. Then, using transgenic rats, we found CP-AMPAR upregulation on both D1 and D2 receptor-expressing MSN, which contrasts with selective upregulation on D1 MSN after cocaine and methamphetamine incubation. Overall, our results demonstrate a common role for CP-AMPAR upregulation in psychostimulant and oxycodone incubation, albeit with differences in MSN subtype-specificity.

neuroscience↗

bioRxiv2025

Dopamine and calcium dynamics in the nucleus accumbens core during food seeking

Extinction-reinstatement paradigms have been used to study reward seeking for both food and drug rewards. The nucleus accumbens is of particular interest in reinstatement due to its ability to energize motivated behavior. Indeed, previous work has demonstrated that suppression of neuronal activity or dopaminergic signaling in the nucleus accumbens reduces reinstatement to food seeking. In this study, we sought to further establish a connection between glutamatergic input, measured by proxy via a genetically encoded calcium indicator, and dopamine (DA) tone, measured simultaneously with a red-shifted DA biosensor. We performed this sensor multiplexing in the nucleus accumbens core in the classic extinction-reinstatement paradigm with food reward. We detected DA transients that changed in magnitude and/or temporally shifted over the course of self-administration training. In our calcium traces we observed a decrease from baseline time-locked to the lever press for food reward, which became more prominent with training. Both patterns were reduced in the first session of extinction with no deflections from baseline detected in either the DA or calcium traces in the last extinction session. When we recorded during reinstatement tests, bootstrapping analysis detected a calcium response when reinstatement was primed by cue or pellet+cue presentation, while a DA response was detected for pellet+cue reinstatement. These data further establish a role for nucleus accumbens core activity and DA in reinstatement of food seeking and represent the first attempt to simultaneously record the two during an extinction-reinstatement task.

neuroscience↗

bioRxiv2024

Cocaine, via ΔFosB, remodels gene expression and excitability in ventral hippocampus

Ventral hippocampus (vHPC) CA1 pyramidal neurons send glutamatergic projections to nucleus accumbens (NAc), and this vHPC-NAc circuit mediates cocaine seeking and reward, but it is unclear whether vHPC-NAc neuron properties are modulated by cocaine exposure to drive subsequent behavior. The immediate early gene transcription factor {Delta}FosB is induced throughout the brain by cocaine and is critical for cocaine seeking, but its function in vHPC-NAc neurons is not understood. We now show that circuit-specific knockout of {Delta}FosB in vHPC-NAc neurons impaired cocaine reward expression and forced abstinence-induced seeking. We also found that vHPC-NAc excitability was decreased by experimenter-administered repeated cocaine and cocaine self-administration, and this cocaine-induced excitability decrease was mediated by {Delta}FosB expression. To uncover the mechanism of this change in circuit function, we used circuit-specific translating ribosome affinity purification (TRAP) to assess cocaine-induced, {Delta}FosB-dependent changes in gene expression in vHPC-NAc. We found that cocaine causes a {Delta}FosB-dependent increase in the expression of calreticulin, an ER-resident calcium-buffering protein. Calreticulin expression mediated vHPC-NAc excitability and was necessary for cocaine reward. These findings uncover a novel, non-canonical mechanism by which cocaine increases calreticulin in vHPC leading to decreased vHPC-NAc excitability and drives cocaine seeking and reward.

neuroscience↗