Divergent Prelimbic Cortical Pathways Interact with BDNF to Regulate Cocaine-seeking

Area of Science:

• Neuroscience
• Addiction Research
• Molecular Psychiatry

Background:

• Cocaine addiction is characterized by high relapse rates, with unclear underlying neuronal pathways.
• Brain-Derived Neurotrophic Factor (BDNF) has shown potential in reducing cocaine-seeking behavior.
• N-methyl-D-aspartate receptor (NMDAR) antagonists block the effects of BDNF on relapse.

Purpose of the Study:

• To investigate whether synaptic activity in prelimbic (PrL) cortex excitatory projection neurons is sufficient for BDNF's relapse-reducing effect.
• To elucidate the specific neuronal pathways through which BDNF modulates cocaine relapse.
• To determine the differential roles of PrL projections to the nucleus accumbens core (NAc) and paraventricular thalamic nucleus (PVT) in cocaine relapse.

Main Methods:

• Utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology in male rats to inhibit PrL cortex neuronal activity.
• Administered BDNF microinfusion into the PrL cortex immediately after cocaine self-administration.
• Employed cre-dependent retroviral vectors to selectively inhibit PrL projections to the NAc core or PVT.

Main Results:

• Inhibition of the entire PrL cortex blocked BDNF's relapse-reducing effect and also reduced seeking in control rats.
• Selective inhibition of the PrL-NAc pathway prevented the BDNF-induced decrease in cocaine-seeking.
• Selective inhibition of the PrL-PVT pathway reduced cocaine-seeking in the absence of BDNF, an effect abolished by BDNF infusion.

Conclusions:

• Synaptic activity in the PrL-NAc pathway mediates the therapeutic effect of BDNF on cocaine relapse.
• Inhibition of the PrL-PVT pathway produces a therapeutic effect similar to BDNF, but independently.
• Two divergent PrL cortical outputs differentially regulate cocaine relapse, offering distinct therapeutic targets.