Cocaine increases dopaminergic connectivity in the nucleus accumbens

Abstract

The development of addictive behavior is associated with functional and structural plasticity in the mesocorticolimbic pathway. Increased connectivity upon cocaine administration has been inferred from increases in dendritic spine density, but without observations of presynaptic elements. Recently, we established a method that enables analyses of both dendritic spines and glutamatergic boutons and presented evidence that cocaine induces changes in striatal connectivity. As the pharmacological and behavioral effects of cocaine directly implicate dopaminergic neurons and their afferents, a remaining question is whether dopaminergic striatal innervations also undergo structural plasticity. To address this issue, we generated transgenic mice in which the fluorophore tdTomato is expressed under the promoter of the dopamine transporter gene. In these mice, specific labeling of dopaminergic boutons was observed in the striatum. Of note, the accordance of our results for control mice with previous electron microscopy studies confirms that our method can be used to decipher the spatial organization of boutons in relation to dendritic elements. Following repeated cocaine administration that led to behavioral locomotor sensitization, an increased density of dopaminergic boutons was observed 1 day later in the nucleus accumbens shell specifically, and not in other striatal regions. Combined labeling of dopaminergic boutons and striatal dendrites showed that cocaine significantly increased the percentage of dendritic spines associated with a dopaminergic bouton. Our results show that chronic cocaine administration induces structural plasticity of dopaminergic boutons that could participate in dopamine-dependent neuronal adaptations in the striatum.

GPRIN3 Controls Neuronal Excitability, Morphology, and Striatal-Dependent Behaviors in the Indirect Pathway of the Striatum

“…Since MSNs arborization is positively regulated by dopamine (Meredith et al, 1995), the higher neuronal arborization observed in GPRIN3 KO mice suggests more dopamine inputs compared with control mice. These suggest a morphological state resembling chronic exposure to cocaine (MacAskill et al, 2014;Spencer et al, 2017;Dos Santos et al, 2018), corroborating our hypothesis that the lack of GPRIN3 induces a "presensitization process. "…”

Serotonergic Signaling Controls Input-Specific Synaptic Plasticity at Striatal Circuits

“…We then investigated the postsynaptic subcellular localization of 5-HT4R in dSPNs. The viral construct AAVrh9-PPTA-Cre (AAV-PPTA-Cre), which contains an expression cassette consisting of Cre recombinase driven by the dSPN-specific promoter of the PPTA gene (substance P), and the AAVrh9-pCAG-flex-tdTomato-WRPE (AAV-FLEX-tdTOMATO) construct expressing ''flexed'' tdTomato (Dos Santos et al, 2017;Hikida et al, 2010;Yagishita et al, 2014) were co-injected into the DLS. In dSPNs, we measured the number of co-localizing 5-HT4Rs in 3D-reconstructed dendrites and segmented headspines.…”

“…The DLS was targeted (+0.5 AP; ± 2.6 LM; À2.9 DV) and a volume of 2 ml/site of the mix was injected at a rate of 0.1 ml/min. Mice were perfused 2-3 weeks after the injection (Dos Santos et al, 2017;Hikida et al, 2010). In VGLUT2-Cre mice, double injections of the AAVrh9-PPTA-CRE/AAV9.CAG.Flex.tdTomato.WPRE.bGH mix in the DLS and of AAV9.CAG.Flex.eGFP.WPRE.bGH in the thalamus were also performed.…”

Persistent effects of obesity: a neuroplasticity hypothesis

“…Some of the earliest work studying the effects of cocaine on midbrain synapses showed that a single in vivo exposure of cocaine was sufficient to alter AMPA channels at excitatory synapses in the VTA . Furthermore, cocaine increases dopaminergic terminal density and striatal spinogenesis, and cocaine withdrawal increases surface‐level AMPARs in the ventral striatum . Related changes in dopamine transmission have also been reported following obesity and HFD exposure.…”