Cocaine- and amphetamine-regulated transcript peptide (CART) induced reward behavior is mediated via Gi/o dependent phosphorylation of PKA/ERK/CREB pathway

Amita R Somalwar; Amit G Choudhary; Pravesh R Sharma; Nagalakshmi B; Sneha Sagarkar; Amul J Sakharkar; Nishikant K Subhedar; Dadasaheb M Kokare

doi:10.1016/j.bbr.2018.03.035

Cocaine- and amphetamine-regulated transcript peptide (CART) induced reward behavior is mediated via G_i/o dependent phosphorylation of PKA/ERK/CREB pathway

Behav Brain Res. 2018 Aug 1:348:9-21. doi: 10.1016/j.bbr.2018.03.035. Epub 2018 Mar 23.

Authors

Amita R Somalwar¹, Amit G Choudhary¹, Pravesh R Sharma¹, Nagalakshmi B², Sneha Sagarkar², Amul J Sakharkar², Nishikant K Subhedar³, Dadasaheb M Kokare⁴

Affiliations

¹ Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, 440 033, India.
² Department of Biotechnology, Savitribai Phule Pune University, Pune, 411 007, India.
³ Indian Institute of Science Education and Research (IISER), Dr. Homi Bhabha Road, Pune, 411 008, India.
⁴ Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, 440 033, India. Electronic address: kokaredada@yahoo.com.

PMID: 29580892
DOI: 10.1016/j.bbr.2018.03.035

Abstract

Although the role of cocaine- and amphetamine-regulated transcript peptide (CART) in modulating the mesolimbic reward pathway has been suggested, underlying cellular mechanisms have not been elucidated. Herein, we investigate the involvement of G_i/o dependent protein kinase A (PKA)/extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) signaling in CART induced reward behavior. The rat was implanted with a stimulating electrode targeted at the lateral hypothalamus (LH)-medial forebrain bundle (MFB) and conditioned to intracranial self-stimulation (ICSS) in an operant chamber. Intracerebroventricular (icv) administration of CART (55-102) dose-dependently lowered ICSS threshold suggesting reward promoting action, however, pretreatment with subeffective doses of G_i/o inhibitor (pertussis toxin, PTX) or PKA inhibitor (Rp-cAMPS) or ERK inhibitor (U0126) via icv route, attenuated CART mediated reward experience. Operant conditioned rats showed increased pCREB levels in the nucleus accumbens shell (AcbSh), ventral tegmental area (VTA) and hypothalamic paraventricular nucleus (PVN). Infusion of CART (icv) in the conditioned rats augmented the population of pCREB positive cells in the AcbSh, VTA and PVN areas, but not in the arcuate nucleus (ARC). Pretreatment with U0126 significantly decreased CART induced pCREB activation in the AcbSh and VTA, but not in PVN and ARC. ICSS or CART induced CREB mRNA expression in Acb and VTA was attenuated by U0126. We suggest that recruitment of G_i/o dependent PKA/ERK/CREB phosphorylation signaling in Acb and VTA might play an important role in CART induced reward behavior.

Keywords: CART; CREB; ERK; G(i/o); Intracranial self-stimulation; Reward.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Conditioning, Operant / drug effects
Cyclic AMP Response Element-Binding Protein / metabolism
Cyclic AMP-Dependent Protein Kinases / metabolism
Hypothalamic Area, Lateral / physiology
MAP Kinase Signaling System / physiology
Male
Medial Forebrain Bundle / physiology
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Nerve Tissue Proteins / physiology*
Nucleus Accumbens / drug effects
Peptides / metabolism
Peptides / pharmacology
Phosphorylation / drug effects
Rats
Rats, Wistar
Reward
Self Stimulation / drug effects
Signal Transduction / drug effects
Ventral Tegmental Area / drug effects

Substances

Cyclic AMP Response Element-Binding Protein
Nerve Tissue Proteins
Peptides
cocaine- and amphetamine-regulated transcript protein
Cyclic AMP-Dependent Protein Kinases