High frequency DBS-like optogenetic stimulation of nucleus accumbens dopamine D2 receptor-containing neurons attenuates cocaine reinstatement in male rats

Swinford-Jackson, Sarah E.; Huffman, Phillip J.; Knouse, Melissa C.; Thomas, Arthur S.; Rich, Matthew T.; Mankame, Sharvari; Worobey, Samantha J.; Sarmiento, Mateo; Coleman, Ayanna; Pierce, R. Christopher

doi:10.1038/s41386-022-01495-y

Cited by 13 publications

(11 citation statements)

References 71 publications

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“…Low frequency opto-DBS of accumbens D1DR-and D2DR-containing accumbens neurons similarly attenuated cocaine-primed reinstatement of cocaine seeking in male rats despite these subtypespecific differences in the induction of long-term synaptic plasticity. Low frequency opto-DBS of either subpopulation of neurons failed to influence cocaine seeking in female rats similar to our recent work using high-frequency opto-DBS (28), which indicates that there may be important sex differences in the efficacy of accumbens DBS. The present results indicate that low frequency DBS may suppress cocaine seeking in males via actions on both D1DR-MSNs and D2DR-MSNs, although the cellular mechanisms by which stimulation influences behavior appear to be distinct.…”

Section: Discussionsupporting

confidence: 87%

“…An indwelling silastic catheter (SAI Infusion Technologies, Libertyville, Il) was inserted into the jugular vein and sutured in place as previously described (33, 34). Following catheter insertion, rats received intra-nucleus accumbens shell implantation of electrodes (12, 13) or viral vector infusion with fiber optic implantation (28), as previously described.…”

Section: Methodsmentioning

confidence: 99%

“…Ex vivo electrophysiology: Rats expressing Cre-dependent eYFP or ChR2 in the nucleus accumbens were collected for whole-cell patch-clamp recordings (28,(35)(36)(37) using methods designed to improve neuronal health in adult rodents (38,39). MSNs were identified by their morphology and low resting membrane potential (-70 to -85 mV), and D1DR-or D2DRcontaining neurons were further identified by eYFP expression.…”

Section: Animalsmentioning

confidence: 99%

“…Recent studies have begun to explore the cell subtype-specificity of DBS to modulate behavior using optogenetic approaches. Mimicking high-frequency electrical DBS with optogenetic stimulation within nucleus accumbens neuronal subtypes indicated that 130 Hz opto-DBS of D2DR-containing, but not D1DR-containing neurons attenuated cocaine seeking in male rats (28). Low frequency opto-DBS (12 Hz) of neurons projecting from the prefrontal cortex onto accumbens D1DR-MSNs blocked cocaine-evoked locomotor sensitization and altered long-term synaptic plasticity; importantly, these effects were only elicited by 12 Hz electrical DBS when administered in combination with a D1DR antagonist (29).…”

Section: Introductionmentioning

confidence: 99%

“…Nucleus accumbens DBS attenuated cocaine seeking over a range of frequencies in male rats, including frequencies as low as 12 Hz. To parse out potential mechanisms underlying this effect, we focused on changes in long term synaptic plasticity in accumbens MSNs from naive and cocaine-trained, male and female, D1DR-Cre and D2DR-Cre rats (28,(30)(31)(32). Slice electrophysiology experiments showed that low frequency stimulation elicited long term potentiation (LTP) in both accumbens MSN subtypes from naive male and female rats.…”

Section: Introductionmentioning

confidence: 99%

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Low frequency optogenetic deep brain stimulation of nucleus accumbens dopamine D1 or D2 receptor-containing neurons attenuates cocaine seeking selectively in male rats in part by reversing synaptic plasticity deficits

Swinford-Jackson

Rich

Huffman

et al. 2023

Preprint

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Clinically, deep brain stimulation (DBS) utilizes relatively high frequencies (>100 Hz). In preclinical models, 160 Hz stimulation of the nucleus accumbens in rodents prevents relapse of drug seeking. However, the ability of varied frequencies of accumbens DBS to attenuate drug seeking, and the neuronal subtype specificity of this effect, is unclear. The present study examined the effect of DBS in the nucleus accumbens on neuronal plasticity and cocaine-primed reinstatement of cocaine seeking behavior in rats. Electrical DBS of the accumbens shell attenuated cocaine primed reinstatement across a range of frequencies in male rats, including as low as 12 Hz. The majority of nucleus accumbens neurons are medium spiny neurons (MSNs), which can be differentiated in terms of projections and effects on cocaine-related behaviors by expression of dopamine D1 receptors (D1DRs) or D2DRs. In slice electrophysiology experiments, 12 Hz electrical stimulation evoked long term potentiation (LTP) in eYFP labeled D1DR-MSNs and D2DR-MSNs from cocaine naive male and female rats. However, in rats that self-administered cocaine and underwent extinction training, a paradigm identical to our reinstatement experiments, electrical DBS only elicited LTP in D2DR-MSNs from male rats; this effect was replicated by optical stimulation in rats expressing Cre-dependent ChR2 in D2DR-MSNs. Low-frequency optogenetic-DBS in D1DR-containing or D2DR-containing neurons attenuated cocaine-primed reinstatement of cocaine seeking in male but not female rats. These results suggest that administering DBS in the nucleus accumbens shell at lower frequencies effectively, but sex-specifically, suppresses cocaine craving, perhaps in part by reversing synaptic plasticity deficits selectively in D2DR-MSNs.

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Section: Discussionsupporting

confidence: 87%