Selective inhibition of phosphodiesterase 7 enzymes reduces motivation for nicotine use through modulation of mesolimbic dopaminergic transmission

Ciccocioppo, Roberto; Guglielmo, Giordano de; Li, Hong Wu; Melis, Miriam; Caffino, Lucia; Shen, Quienwei; Domi, Ana; Fumagalli, Fabio; Demopulos, Gregory; Gaitanaris, George A.

doi:10.1523/jneurosci.3180-20.2021

Cited by 3 publications

(2 citation statements)

References 80 publications

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“…Electrophysiological studies support synaptic potentiation of nAc excitatory synapses where prolonged abstinence following cocaine, enhances AMPAR-dependent synaptic strength with both increases in mEPSC amplitude and AMPA/NMDA ratio ( Kourrich et al, 2007 ; Ortinski et al, 2012 ). Our findings suggest a possibly common AMPAR nAcS metaplasticity during forced abstinence for both nicotine and cocaine beyond the other evidences of shared molecular effects within the accumbens of these two drugs of abuse ( Di Chiara and Imperato, 1988 ; Pich et al, 1997 ; McClung et al, 2004 ; Ciccocioppo et al, 2021 ). Importantly negative affective states, generally experienced during late nicotine withdrawal, are characterized by increased AMPA receptor expression in nAcS selectively in dopamine D1 MSNs ( Pignatelli et al, 2021 ) In addition, cocaine abstinence has been shown to selectively increase the rectification of AMPA receptor-mediated currents in nAcS dopamine D1 receptor expressing MSNs ( Inbar et al, 2022 ).…”

Section: Discussionmentioning

confidence: 57%

Nicotine but not saline self-administering or yoked control conditions produces sustained neuroadaptations in the accumbens shell

Domi

Lucente

Cadeddu

et al. 2023

Front. Mol. Neurosci.

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IntroductionUsing yoked animals as the control when monitoring operant drug-self-administration is considered the golden standard. However, instrumental learning per se recruits several neurocircuits that may produce distinct or overlapping neuroadaptations with drugs of abuse. The aim of this project was to assess if contingent responding for nicotine or saline in the presence of a light stimulus as a conditioned reinforcer is associated with sustained neurophysiological adaptations in the nucleus accumbens shell (nAcS), a brain region repeatedly associated with reward related behaviors.MethodsTo this end, nicotine-or saline-administrating rats and yoked-saline stimulus-unpaired training conditions were assessed in operant boxes over four consecutive weeks. After four additional weeks of home cage forced abstinence and subsequent cue reinforced responding under extinction conditions, ex vivo electrophysiology was performed in the nAcS medium spiny neurons (MSNs).ResultsWhole cell recordings conducted in voltage and current-clamp mode showed that excitatory synapses in the nAcS were altered after prolonged forced abstinence from nicotine self-administration. We observed an increase in sEPSC amplitude in animals with a history of contingent nicotine SA potentially indicating higher excitability of accumbal MSNs, which was further supported by current clamp recordings. Interestingly no sustained neuroadaptations were elicited in saline exposed rats from nicotine associated visual cues compared to the yoked controls.ConclusionThe data presented here indicate that nicotine self-administration produces sustained neuroadaptations in the nAcS while operant responding driven by nicotine visual stimuli has no long-term effects on MSNs in nAcS.

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Section: Discussionmentioning

confidence: 57%

Nicotine but not saline self-administering or yoked control conditions produces sustained neuroadaptations in the accumbens shell

Domi

Lucente

Cadeddu

et al. 2023

Front. Mol. Neurosci.

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“…4.2.5. Phosphodiesterase 7 PDE7 is another isoenzyme with specific affinity for cAMP, as shown by the effect of selective inhibitors significantly elevating cAMP levels in the CNS [163]. PDE7 has two known isoforms, PDE7A and PDE7B, each with distinct tissue distribution and subcellular localization.…”

Section: Phosphodiesterasementioning

confidence: 99%

Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia

Kochoian,

Bure,

Papa

2023

Cells

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A large body of work during the past several decades has been focused on therapeutic strategies to control L-DOPA-induced dyskinesias (LIDs), common motor complications of long-term L-DOPA therapy in Parkinson’s disease (PD). Yet, LIDs remain a clinical challenge for the management of patients with advanced disease. Glutamatergic dysregulation of striatal projection neurons (SPNs) appears to be a key contributor to altered motor responses to L-DOPA. Targeting striatal hyperactivity at the glutamatergic neurotransmission level led to significant preclinical and clinical trials of a variety of antiglutamatergic agents. In fact, the only FDA-approved treatment for LIDs is amantadine, a drug with NMDAR antagonistic actions. Still, novel agents with improved pharmacological profiles are needed for LID therapy. Recently other therapeutic targets to reduce dysregulated SPN activity at the signal transduction level have emerged. In particular, mechanisms regulating the levels of cyclic nucleotides play a major role in the transduction of dopamine signals in SPNs. The phosphodiesterases (PDEs), a large family of enzymes that degrade cyclic nucleotides in a specific manner, are of special interest. We will review the research for antiglutamatergic and PDE inhibition strategies in view of the future development of novel LID therapies.

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Identification of genes and pathways associated with sex in Non-smoking lung cancer population

Wang

Cheng

2022

Gene

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Selective inhibition of phosphodiesterase 7 enzymes reduces motivation for nicotine use through modulation of mesolimbic dopaminergic transmission

Abstract: Selective inhibition of phosphodiesterase 7 enzymes reduces motivation for nicotine use through modulation of mesolimbic dopaminergic transmission

Cited by 3 publications

References 80 publications

Nicotine but not saline self-administering or yoked control conditions produces sustained neuroadaptations in the accumbens shell

Nicotine but not saline self-administering or yoked control conditions produces sustained neuroadaptations in the accumbens shell

Targeting Striatal Glutamate and Phosphodiesterases to Control L-DOPA-Induced Dyskinesia

Identification of genes and pathways associated with sex in Non-smoking lung cancer population

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