GPePV neurons identified as key players in controlling cocaine addiction behaviors

By Vijay Kumar MalesuReviewed by Benedette Cuffari, M.Sc.Aug 25 2024

Study: Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity. Image Credit: Alex Mit / Shutterstock.com

In a recent study published in Neuron, researchers examine how globus pallidus externus parvalbumin-positive (GPe^PV) cells regulate cocaine-induced behaviors through interactions with ventral tegmental area dopamine (VTA^DA) cells.

A closer look at the interaction between VTA^DA and GPe neurons

Ventral tegmental area dopamine (VTA^DA) cells are essential to motivation, reward, and substance abuse behaviors. Although targeting the entire dopamine system is ineffective for treating addiction due to potential off-target effects, modulating specific dopamine subcircuits may offer therapeutic benefits with fewer side effects.

Previous studies have reported that VTA^DA cells project to the amygdala in cocaine withdrawal-related anxiety. However, the lack of unique genetic markers to study subtypes of VTA^DA cells has prevented extensive analysis into their functions.

GPe has traditionally been associated with habit formation and motor behaviors. Recently, the researchers of the current study identified that GPe neurons are critically involved in the development of cocaine-induced behavioral changes. These experiments demonstrated that the number and activity of GPe neurons that innervate VTA^DA cells significantly increases following cocaine exposure.

Nevertheless, further research is needed to fully understand the specific mechanisms by which GPe cells influence cocaine-induced behaviors, which will facilitate the development of novel therapeutic strategies to target these pathways in substance abuse treatment.

About the study

Cocaine was administered to mice at a dose of 15 mg/kg, while clozapine-N-oxide (CNO) was given at five mg/kg. Carnosic acid was administered intraperitoneally at 830 μg/kg, 2.5 mg/kg, and 7.5 mg/kg, and intracranially at 10 μM.

In transsynaptic tracing/cTRIO experiments, cocaine or saline was administered prior to rabies virus (RABV) injection, followed by the injection of various viral constructs into different brain regions including the nucleus accumbens (NAc), amygdala, dorsolateral striatum (DLS), and VTA. 

Animals were sacrificed five days following RABV injection. For mapping inputs to GPe^PV cells in saline- and cocaine-treated mice, specific viral injections were performed, followed by similar RABV injections and subsequent sacrifice for further investigation.

Electrophysiology assessments involved whole-cell patch clamp recordings in acute brain slices, with spontaneous and evoked recordings captured continuously. Fiber photometry experiments measured activity in various neuron populations using specific viral constructs and optical fibers implanted in targeted brain regions.

Behavioral assays included cocaine-conditioned place preference (CPP) and locomotion tests, with chemogenetic and carnosic acid interventions examined for their effects on cocaine-related behaviors.

Study findings 

The current study explored the role of GPe^PV cells in controlling cocaine-induced behavioral changes by examining their interaction with VTA^DA neurons projecting to the lateral shell of the nucleus accumbens (NAcLat). To identify the specific VTA^DA populations mediate the effects of GPe neurons on cocaine-related behaviors, researchers chemogenetically inhibited both ventral midbrain-projecting GPe^PV cells and various VTA^DA subpopulations.

Inhibition of GPe^PV→ventral midbrain cells using human muscarinic M4 designer receptor exclusively activated by designer drugs inhibitory (hM4Di) delivered through adeno-associated virus (AAV) and CNO-releasing microspheres blocked the development of CPP and sensitization, thus confirming previous findings. Interestingly, this inhibition did not affect anxiety-related behaviors during withdrawal, as demonstrated during the elevated plus maze and open field tests.

The researchers also determined whether distinct VTA^DA cell populations were influenced by GPe^PV cells. Since GPe^PV cell activation leads to DA cell activation, inhibiting either population was hypothesized to yield similar effects.

To this end, retrograde viral vectors were used to target VTA^DA neurons projecting to various brain regions, including the NAcLat. Only inhibition of VTA^DA cells during cocaine administration prevented reward and sensitization. This effect was consistent with the results from RABV mapping and optogenetic studies, which demonstrated that optical stimulation of GPe^PV inputs reduced the latency to the first action potential in VTA^DA→NAcLat cells, indicating a disinhibitory connection.

The current study also explored how cocaine influences GPe^PV cell activity, in which the researchers hypothesized that DA release from VTA^DA→NAcLat cells in the dorsomedial striatum (DMS) may trigger changes in GPe^PV cells. Cocaine treatment reduced inhibitory inputs from the DMS to GPe^PV cells, thereby elevating their activity.

Activation of dorsomedial striatum dopamine receptor D2 (DMS^D2) cells, which project to GPe^PV cells, prevented cocaine CPP and sensitization, which mirrors the effects of GPe^PV inhibition. Voltage-clamp recordings indicated that cocaine decreased spontaneous inhibitory postsynaptic currents (sIPSCs) in GPe^PV cells without affecting excitatory currents, thereby suggesting that cocaine reduces inhibitory drive onto GPe^PV cells.

Single-nucleus ribonucleic acid sequencing (snRNA-seq) revealed significant downregulation of the Kcnq3 and Kcnq5 genes, which encode voltage-gated potassium channels crucial for regulating cellular excitability. Subsequent treatment with carnosic acid, a KCNQ3/5 channel opener, reduced GPe^PV cell excitability and effectively blocked cocaine CPP, sensitization, and volitional cocaine intake in a self-administration model. Thus, targeting KCNQ3/5 channels with carnosic acid could be a promising therapeutic strategy for reducing cocaine reward and preventing addiction-related behaviors by modulating GPe^PV cell activity.

Conclusions

GPe neurons are key regulators of cocaine reward and sensitization that modulate dopamine activity in the VTA. By activating KCNQ3/5 channels, reducing GPe^PV cell excitability effectively diminishes cocaine-seeking behaviors.

VTA^DA→NAcLat cells, through connections to the DMS, enhance GPe^PV activity, thereby creating a feedback loop that influences dopamine levels in the nucleus accumbens. Carnosic acid, a KCNQ3/5 opener, shows promise as an anti-addictive agent, offering a novel therapeutic approach for cocaine addiction.