Cognitive rigidity and BDNF-mediated frontostriatal glutamate neuroadaptations during spontaneous nicotine withdrawal

Robert D. Cole, Matty Zimmerman, Anastasia Matchanova, Munir Gunes Kutlu, Thomas J. Gould, Vinay Parikh

Research output: Contribution to journalArticle

Abstract

Cognitive flexibility is the ability to switch strategic responses adaptively in changing environments. Cognitive rigidity imposed by neural circuit adaptations during nicotine abstinence may foster maladaptive nicotine taking in addicts. We systematically examined the effects of spontaneous withdrawal in mice exposed to either nicotine (6.3 or 18 mg/kg/day) or saline for 14 days on cognitive flexibility using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity in these circuits, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Mice undergoing nicotine withdrawal required more trials to attain strategy-switching criterion. Error analysis show that animals withdrawn from both nicotine doses committed higher perseverative errors, which correlated with measures of anxiety. However, animals treated with the higher nicotine dose also displayed more strategy maintenance errors that remained independent of negative affect. BDNF mRNA expression increased in the medial prefrontal cortex (mPFC) following nicotine withdrawal. Surprisingly, BDNF protein declined in mPFC but was elevated in dorsal striatum (DS). DS BDNF protein positively correlated with perseverative and maintenance errors, suggesting mPFC-DS overflow of BDNF during withdrawal. BDNF-evoked glutamate release and synapsin phosphorylation was attenuated within DS synapses, but enhanced in the nucleus accumbens, suggesting a dichotomous role of BDNF signaling in striatal regions. Taken together, these data suggest that spontaneous nicotine withdrawal impairs distinct components of cognitive set-shifting and these deficits may be linked to BDNF-mediated alterations in glutamate signaling dynamics in discrete frontostriatal circuits.

Original languageEnglish (US)
JournalNeuropsychopharmacology
DOIs
StateAccepted/In press - Jan 1 2019

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Brain-Derived Neurotrophic Factor
Nicotine
Glutamic Acid
Prefrontal Cortex
Nerve Growth Factors
Maintenance
Synapsins
Corpus Striatum
Aptitude
Nucleus Accumbens
Synapses
Anxiety
Phosphorylation
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Cole, Robert D. ; Zimmerman, Matty ; Matchanova, Anastasia ; Kutlu, Munir Gunes ; Gould, Thomas J. ; Parikh, Vinay. / Cognitive rigidity and BDNF-mediated frontostriatal glutamate neuroadaptations during spontaneous nicotine withdrawal. In: Neuropsychopharmacology. 2019.
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Cognitive rigidity and BDNF-mediated frontostriatal glutamate neuroadaptations during spontaneous nicotine withdrawal. / Cole, Robert D.; Zimmerman, Matty; Matchanova, Anastasia; Kutlu, Munir Gunes; Gould, Thomas J.; Parikh, Vinay.

In: Neuropsychopharmacology, 01.01.2019.

Research output: Contribution to journalArticle

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