Behavioral and neurochemical profile of MK-801 adult zebrafish model: Forebrain β2-adrenoceptors contribute to social withdrawal and anxiety-like behavior

Abstract

Deficits in social communication and interaction are core clinical symptoms characterizing multiple neuropsychiatric conditions, including autism spectrum disorder (ASD) and schizophrenia. Interestingly, elevated anxiety levels are a common comorbid psychopathology characterizing individuals with aberrant social behavior. Despite recent progress, the underlying neurobiological mechanisms that link anxiety with social withdrawal remain poorly understood. The present study developed a zebrafish pharmacological model displaying social withdrawal behavior, following a 3-h exposure to 4 μΜ (+)-MK-801, a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, for 7 days. Interestingly, MK-801-treated zebrafish displayed elevated anxiety levels along with higher frequency of stereotypical behaviors, rendering this zebrafish model appropriate to unravel a possible link of catecholaminergic and ASD-like phenotypes. MK-801-treated zebrafish showed increased telencephalic protein expression of metabotropic glutamate 5 receptor (mGluR5), dopamine transporter (DAT) and β₂-adrenergic receptors (β₂-ARs), supporting the presence of excitation/inhibition imbalance along with altered dopaminergic and noradrenergic activity. Interestingly, β₂-ARs expression, was differentially regulated across the Social Decision-Making (SDM) network nodes, exhibiting increased levels in ventral telencephalic area (Vv), a key-area integrating reward and social circuits but decreased expression in dorso-medial telencephalic area (Dm) and anterior tuberal nucleus (ATN). Moreover, the co-localization of β₂-ARs with elements of GABAergic and glutamatergic systems, as well as with GAP-43, a protein indicating increased brain plasticity potential, support the key-role of β₂-ARs in the MK-801 zebrafish social dysfunctions. Our results highlight the importance of the catecholaminergic neurotransmission in the manifestation of ASD-like behavior, representing a site of potential interventions for amelioration of ASD-like symptoms.

Keywords: Autism-like phenotype; Catecholaminergic; Dopamine transporter; Metabotropic glutamate 5 receptor (mGluR5); Social withdrawal; β(2)-adrenergic receptors.