Dynamic dichotomy of accumbal population activity underlies cocaine sensitization

Abstract

Locomotor sensitization (LS) is an early behavioral adaptation to addictive drugs, driven by the increase of dopamine in the Nucleus Accumbens (NAc). However, the effect on accumbal population activity remains elusive. Here we used single cell calcium imaging in mice to record the activity of dopamine-1-receptor (D1R) and dopamine-2-receptor (D2R) expressing spiny projection neurons (SPNs) during cocaine LS. Acute exposure to cocaine elevated D1R SPN activity and reduced D2R SPN activity, albeit with high variability between neurons. During LS, the number of D1R and D2R neurons responding in opposite directions increased. Moreover, preventing LS by inhibition of the ERK signaling pathway decreased the number of cocaine responsive D1R SPNs, but had little effect on D2R SPNs. These results indicate that accumbal population dichotomy is dynamic and contains a subgroup of D1R SPNs that eventually drives LS. Insights into the drug-related activity dynamics provides a foundation for understanding the circuit-level addiction pathogenesis.

Drug-induced change in transmitter identity is a shared mechanism generating cognitive deficits

“…Overriding drug-induced gain of GABA in pyramidal neurons prevents the appearance of both locomotor sensitization and memory deficits in the NORT and SAT, thus establishing a causal link between the change in transmitter identity and these behavioral alterations. These findings are consistent with the modulation of these behaviors through the involvement of both the PrL and the NAc, which receives input from PrL neurons that have changed their transmitter identity (16,17,19,23,24,26). The results align with other reports of addictive substances inducing changes in neurotransmitter expression in different brain regions (7-9, 31, 32).…”

“…PCP and METH exert a strikingly similar effect on the neurotransmitter identity of PrL pyramidal neurons, leading us to ask whether the cells affected by each drug project to the same downstream target. We investigated the nucleus accumbens (NAc), since this region receives substantial glutamatergic innervation from the PrL and both the NAc and the PrL are involved in modulating behaviors that are affected by repeated intake of PCP or METH (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). We injected fluoro-gold (FG) into the NAc of VGLUT1-Cre+/-::H2BmCherry+/-mice and screened the PrL for mCherry+/GABA+ neurons expressing the retrograde tracer after exposure to PCP, METH or saline (Fig.…”

Cell-Type-Specific Adaptions in Striatal Medium-Sized Spiny Neurons and Their Roles in Behavioral Responses to Drugs of Abuse

“…They also raise the intriguing idea that psychostimulant exposure may induce enduring alterations that bias MSN microcircuits toward a more dichotomic dynamic. This is in accordance with the observation that repeated cocaine exposure strengthens afferences from the basolateral amygdala onto D1R-MSN, but not D2R-MSN ( MacAskill et al, 2014 ) and progressively enhances and dampens the activity of D1R-MSN and D2-MSN, respectively ( van Zessen et al, 2021 ).…”

A molecularly defined D1 medium spiny neuron subtype negatively regulates cocaine addiction

“…1), and cocaine conditioning induces neuronal activity changes with more Tac2 + neurons inhibited than activated in cocaine-associated context (Fig. 2), which is opposite to the conventional view of D1 MSNs in the direct/indirect pathway model and the in vivo recordings on pan-D1 MSNs (50,51). Second, through bidirectional activity manipulation, we showed that the Tac2 + neurons negatively regulate cocaine reward (Fig.…”

“…shRNA for mouse Tac2 gene (NM_009312.2) was selected on the basis of literature ( 50 ), and the oligonucleotides encoding Tac2 shRNA were as follows: 5′-gatccgCCGCCTCAACCCCATAGCAATTAgaagcttgTAATTGCTATGGGGTTGAGGCttttttt-3′ and 3′-gcGGCGGAGTTGGGGTATCGTTAATcttcgaacATTAACGATACCCCAACTCCGaaaaaaagatc-5′. The oligonucleotides were cloned into the AAV vector backbone AAV-shRNA-Ctrl (Addgene, no.…”