Biology subjects

Dobbs, L. K.

Publications and source records attributed to Dobbs, L. K..

5 recordsLinked to original sources

bioRxiv2026

Enkephalin Gates D2-MSN Disinhibition of the Ventral Pallidum During Cocaine Abstinence

Background: Cocaine seeking after abstinence is associated with increased ventral pallidum (VP) activity. This increase appears to involve an opioid peptide that suppresses GABA release from D2 receptor-expressing medium spiny neurons (D2-MSNs) to the VP, but its identity is unclear. We previously found that cocaine abstinence increases enkephalin mRNA expression in D2-MSNs and that exogenous enkephalin inhibits GABA release from these neurons. We therefore hypothesized that cocaine-enhanced enkephalin release from D2-MSNs suppresses GABA release into the VP, which disinhibits VP neurons and promotes cocaine seeking. Methods: To examine how enkephalin alters striatal circuit plasticity and cocaine seeking following abstinence, we performed ex vivo electrophysiology and cocaine self-administration in mice lacking enkephalin selectively from D2-MSNs (D2-PenkKO). Recordings were obtained from the primary D2-MSNs targets : VP neurons and D1 receptor-expressing MSNs (D1-MSNs). Results: Following cocaine abstinence, GABA release from D2-MSNs to VP neurons was reduced in controls, but not D2-PenkKOs. In contrast, cocaine abstinence did not alter GABA release to D1-MSNs. Optogenetically evoked GABA release from D2-MSNs inhibited VP neuron firing in saline-abstinent controls and D2-PenkKOs, but not cocaine-abstinent controls. Female, but not male, D2-PenkKOs self-administered less cocaine in early acquisition and exhibited blunted cue-induced cocaine seeking after abstinence. Conclusion: Abstinence from cocaine self-administration increases D2-MSN enkephalin expression, leading to auto-inhibition of GABA release onto VP neurons, but not D1-MSNs, thereby selectively disinhibiting VP neuron activity. These findings identify enkephalin as a key mediator of cocaine abstinence-induced striatopallidal circuit plasticity and suggest that this plasticity contributes to cocaine seeking following abstinence.

neuroscience↗

bioRxiv2025

C57 and DBA mouse strains express distinct cocaine avoidance phenotypes in an operant runway independent of differences in striatal dynorphin-enkephalin balance

RationaleHuman self-report data and rodent models indicate cocaine can induce negative affect, which may impact future cocaine use severity. Despite this, understanding of the neurobiology driving cocaine avoidance is limited. Within the striatum, the opioid peptides enkephalin and dynorphin are associated with cocaine reward and aversion, respectively. Additionally, striatal dynorphin signaling resulting from stress or cocaine withdrawal acts as a negative reinforcer to increase cocaine seeking. ObjectivesWe validated the use of the cocaine self-administration runway in mice to measure the development of cocaine avoidance and tested whether mice with higher relative striatal dynorphin-to-enkephalin expression are resistant to developing cocaine avoidance. MethodsCocaine avoidance in the self-administration runway was measured in two inbred mouse strains, C57BL/6J and DBA/2J, known to have opposite striatal dynorphin/enkephalin milieus, and in mice lacking enkephalin selectively from striatal medium spiny neurons (D2-PenkKO). ResultsBoth inbred strains developed cocaine avoidance, though they expressed it differently. Across training, DBA/2J mice increased their latency to self-administer cocaine, and C57BL/6J increased the number of retreats away from the cocaine-paired goal box. D2-PenkKOs developed similar cocaine avoidance compared to littermate controls. ConclusionsMice develop avoidance to self-administer cocaine in the runway across a range of strains. Pre-existing strain differences in the striatal dynorphin/enkephalin milieu, however, do not appear to alter the development of cocaine avoidance, and striatal enkephalin is not necessary for the development of cocaine avoidance. This suggests higher relative striatal dynorphin does not facilitate cocaine seeking by mitigating cocaine avoidance.

neuroscience↗

bioRxiv2025

Shifted balance between ventral striatal prodynorphin and proenkephalin biases development of cocaine place avoidance

Evidence from human self-report and rodent models indicate cocaine can induce a negative affective state marked by panic and anxiety, which may reduce future cocaine use or promote co-use with opiates. Dynorphin-mediated signaling within the striatum is associated with negative affect following cocaine withdrawal and stress-induced cocaine seeking. Here, we used a trace conditioning procedure to first establish the optimum parameters to capture this transient cocaine negative affective state in wild type mice, then we investigated striatal opioid peptides as a substrate mediating cocaine conditioned place avoidance (CPA). Previous reports indicate that trace conditioning, where drug administration occurs after removal from the conditioning chamber, results in CPA to ethanol, nicotine, and amphetamine. We tested different cocaine doses, conditioning session lengths, and apparatus types, to determine which combination yields the best cocaine CPA. Cocaine CPA was moderately larger at the highest cocaine dose (25 mg/kg), but this did not generalize across apparatus types and the effect was transient, thus data were collapsed across all parameters. Cocaine conditioning scores were variable, but also became more polarized across conditioning, with approximately equal proportions developing preference and avoidance. We then correlated cocaine CPA with striatal gene expression levels of the opioid peptides enkephalin (Penk) and dynorphin (Pdyn) using qPCR. Cocaine CPA was correlated with low Pdyn levels and a low Pdyn:Penk ratio in the ventral, but not dorsal, striatum. Consistent with this, mice with higher striatal Pdyn relative to Penk were more resistant to developing cocaine CPA compared to littermate controls. This approach revealed a subset of subjects sensitive to the aversive state immediately following cocaine administration. Our findings suggest striatal dynorphin has opposing roles in mediating the aversion associated with acute cocaine intoxication versus cocaine withdrawal.

neuroscience↗

bioRxiv2023

Striatal enkephalin supports maintenance of conditioned cocaine reward during extinction

Drug predictive cues and contexts exert powerful control over behavior and can incite drug seeking and taking. This association and the behavioral output are encoded within striatal circuits, and regulation of these circuits by G-protein coupled receptors affects cocaine-related behaviors. Here, we investigated how opioid peptides and G-protein coupled opioid receptors expressed in striatal medium spiny neurons (MSNs) regulate conditioned cocaine seeking. Augmenting levels of the opioid peptide enkephalin in the striatum facilitates acquisition of cocaine conditioned place preference (CPP). In contrast, opioid receptor antagonists attenuate cocaine CPP and facilitate extinction of alcohol CPP. However, whether striatal enkephalin is necessary for acquisition of cocaine CPP and maintenance during extinction remains unknown. We generated mice with a targeted deletion of enkephalin from dopamine D2-receptor expressing MSNs (D2-PenkKO) and tested them for cocaine CPP. Low striatal enkephalin levels did not attenuate acquisition or expression of CPP; however, D2-PenkKOs showed faster extinction of cocaine CPP. Single administration of the non-selective opioid receptor antagonist naloxone prior to preference testing blocked expression of CPP selectively in females, but equally between genotypes. Repeated administration of naloxone during extinction did not facilitate extinction of cocaine CPP for either genotype, but rather prevented extinction in D2-PenkKO mice. We conclude that while striatal enkephalin is not necessary for acquisition of cocaine reward, it maintains the learned association between cocaine and its predictive cues during extinction learning. Further, sex and pre-existing low striatal enkephalin levels may be important considerations for use of naloxone in treating cocaine use disorder.

neuroscience↗

bioRxiv2018

Cholinergic interneurons as a novel target of CRF in the striatum that is spared by repeated stress

Acute stressors can stimulate appetitive and exploratory behaviors, not just produce negative affect that impair performance. Corticotropin releasing factor (CRF), which is released in the brain in response to stress, acts on different targets and circuits to mediate both the negative and positive effects of stress. In the nucleus accumbens, CRF facilitates appetitive behavior through mechanisms not fully understood. Here we report that cholinergic interneurons (CINs) are a novel target for CRF actions in the striatum. CRF enhances the spontaneous firing via activation of CRF-type 1 receptors expressed on CINs. This causes the activation muscarinic acetylcholine receptors type 5, which mediate CRF potentiation of dopamine transmission in the striatum. Repeated stress selectively dampens some CRF functions but spare effect on CINs and changes CRF-R1 expression in a cell-specific manner. These data highlight the existence of diverse CRF targets within the striatum, which vary in their resilience to stress.

neuroscience↗