Administration of BDNF in the ventral tegmental area produces a switch from a nicotine‐non‐dependent D1R‐mediated motivational state to a nicotine‐dependent‐like D2R‐mediated motivational state

Abstract

Brain‐derived neurotrophic factor (BDNF) has been implicated in the transition from a non‐dependent motivational state to a drug‐dependent and drug‐withdrawn motivational state. Chronic nicotine can increase BDNF in the rodent brain and is associated with smoking severity in humans; however, it is unknown whether this increased BDNF is linked functionally to the switch from a nicotine‐non‐dependent to a nicotine‐dependent state. We used a place conditioning paradigm to measure the conditioned responses to nicotine, showing that a dose of acute nicotine that non‐dependent male mice find aversive is found rewarding in chronic nicotine‐treated mice experiencing withdrawal. A single BDNF injection in the ventral tegmental area (in the absence of chronic nicotine treatment) caused mice to behave as if they were nicotine dependent and in withdrawal, switching the neurobiological substrate mediating the conditioned motivational effects from dopamine D1 receptors to D2 receptors. Quantification of gene expression of BDNF and its receptor, tropomyosin‐receptor‐kinase B (TrkB), revealed an increase in TrkB mRNA but not BDNF mRNA in the VTA in nicotine‐dependent and nicotine‐withdrawn mice. These results suggest that BDNF signalling in the VTA is a critical neurobiological substrate for the transition to nicotine dependence. The modulation of BDNF signalling may be a promising new pharmacological avenue for the treatment of addictive behaviour.

Acute and chronic effects by nicotine on striatal neurotransmission and synaptic plasticity in the female rat brain

“…This finding is in agreement with previous studies performed on male rats, showing that nicotine acutely depresses the frequency but not amplitude of spontaneous excitatory post synaptic currents in medium spiny neurons in the DLS ( Licheri et al, 2018 ). The exact mechanisms underlying nicotine-induced neuroplasticity in the striatum is not fully understood, but dopamine D2 receptor signaling appears to mediate the down-stream effects of nAChR activation ( Licheri et al, 2018 ; Grieder et al, 2022 ). Dopamine D2 receptors are also critical for induction of nicotine-induced conditioned place preference (CPP) in mice ( Wilar et al, 2019 ), and the improving effect of nicotine on stress-induced memory impairment ( Keshavarzian et al, 2018 ).…”

Paternal Cocaine-Seeking Motivation Defines Offspring's Vulnerability to Addiction by Down-Regulation of GABAergic GABRG3 in the Ventral Tegmental Area

“…However, the factors contributing to these behavioral differences remain unclear. During the development of compulsive drug-seeking behavior associated with addictive drugs, from drug dependence to withdrawal and relapse, drug-seeking motivation gradually intensi es, leading to a series of neuroplasticity changes in the midbrain limbic reward circuit [13][14][15][16][17] . It is widely believed that the ventral tegmental area (VTA) is primarily responsible for dopamine release and motivation regulation, playing a pivotal role in reward sensation and motivation reinforcement during the development of addictive behaviors [18][19][20][21][22] .…”