Up-regulation of CB1 cannabinoid receptors located at glutamatergic terminals in the medial prefrontal cortex of the obese Zucker rat

Leyre Echeazarra; Sergio Barrondo; Gontzal García Del Caño; Itziar Bonilla-Del Río; Jon Egaña-Huguet; Nagore Puente; Xabier Aretxabala; Mario Montaña; Maider López de Jesús; Imanol González-Burguera; Miquel Saumell-Esnaola; María Aránzazu Goicolea; Pedro Grandes; Joan Sallés

doi:10.3389/fnana.2022.1004702

Up-regulation of CB₁ cannabinoid receptors located at glutamatergic terminals in the medial prefrontal cortex of the obese Zucker rat

Front Neuroanat. 2022 Oct 18:16:1004702. doi: 10.3389/fnana.2022.1004702. eCollection 2022.

Authors

Leyre Echeazarra^{1

2}, Sergio Barrondo^{3

4

5}, Gontzal García Del Caño^{5

6}, Itziar Bonilla-Del Río^{7

8}, Jon Egaña-Huguet^{7

8}, Nagore Puente^{7

8}, Xabier Aretxabala⁶, Mario Montaña³, Maider López de Jesús^{3

5}, Imanol González-Burguera^{5

6}, Miquel Saumell-Esnaola^{3

5}, María Aránzazu Goicolea⁹, Pedro Grandes^{7

8

10}, Joan Sallés^{3

4

5}

Affiliations

¹ Department of Physiology, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.
² Bioaraba, Dispositivos Móviles para el Control de Enfermedades Crónicas, Vitoria-Gasteiz, Spain.
³ Department of Pharmacology, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.
⁴ Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain.
⁵ Bioaraba, Neurofarmacología Celular y Molecular, Vitoria-Gasteiz, Spain.
⁶ Department of Neurosciences, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.
⁷ Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain.
⁸ Achucarro Basque Center for Neuroscience, Science Park of the University of the Basque Country (UPV/EHU), Leioa, Spain.
⁹ Department of Analytical Chemistry, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.
¹⁰ Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.

Abstract

The present study describes a detailed neuroanatomical distribution map of the cannabinoid type 1 (CB₁) receptor, along with the biochemical characterization of the expression and functional coupling to their cognate G _i/o proteins in the medial prefrontal cortex (mPCx) of the obese Zucker rats. The CB₁ receptor density was higher in the prelimbic (PL) and infralimbic (IL) subregions of the mPCx of obese Zucker rats relative to their lean littermates which was associated with a higher percentage of CB₁ receptor immunopositive excitatory presynaptic terminals in PL and IL. Also, a higher expression of CB₁ receptors and WIN55,212-2-stimulated [³⁵S]GTPγS binding was observed in the mPCx but not in the neocortex (NCx) and hippocampus of obese rats. Low-frequency stimulation in layers II/III of the mPCx induced CB₁ receptor-dependent long-term synaptic plasticity in IL of area obese Zucker but not lean rats. Overall, the elevated 2-AG levels, up-regulation of CB₁ receptors, and increased agonist-stimulated [³⁵S]GTPγS binding strongly suggest that hyperactivity of the endocannabinoid signaling takes place at the glutamatergic terminals of the mPCx in the obese Zucker rat. These findings could endorse the importance of the CB₁ receptors located in the mPCx in the development of obesity in Zucker rats.

Keywords: 2-AG levels; CB1 receptor; Gi/o proteins; excitatory synapses; glutamatergic terminals; long-term potentiation; medial prefrontal cortex; obese Zucker rat.