Application of gabapentinoids and novel compounds for the treatment of benzodiazepine dependence: the glutamatergic model

Warlick, Halford; Leon, Lexie; Patel, Rudresh; Filoramo, Stefanie; Knipe, Ryan; Joubran, Ernesto; Levy, Arkene; Nguyen, Hoang; Rey, José A

doi:10.1007/s11033-022-08110-9

Cited by 3 publications

(2 citation statements)

References 104 publications

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“…According to this account, adaptive influences develop when neural systems are subjected to prolonged suppression and rebound when, on drug removal, these oppositional influences no longer meet resistance [23]. Thus, rebound increases in neurotransmission are reported in response to discontinued administration of other psychotropic drugs; for example, a rebound increase in excitatory transmission is associated with alcohol and benzodiazepine withdrawal [21, 24] whereas opiate withdrawal is associated with elevated noradrenergic activity [22]. Variation in the symptoms of withdrawal from these different classes of psychotropic drugs likely reflects the different neurotransmitter systems involved [23].…”

Section: Discussionmentioning

confidence: 99%

“…Although changes in 5-HT metabolism/synthesis do not always model 5-HT release [19,20], these early findings with fluoxetine and citalopram are suggestive of a rebound increase in 5-HT function over days following discontinuation. Notably, evidence of rebound increases in neural function have been observed after withdrawal from various psychotropic drugs including morphine, benzodiazepines and alcohol [21][22][23][24], suggesting potential parallels between the mechanisms of cessation of treatment with these different psychotropic drugs.…”

Section: Introductionmentioning

confidence: 99%

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Rebound activation of 5-HT neurons following SSRI discontinuation

Collins,

Gullino,

Ozdemir

et al. 2023

Preprint

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Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset, disabling discontinuation syndrome the mechanism of which is surprisingly little investigated. Here we determined the effect on 5-HT neurochemistry of discontinuation from the SSRI paroxetine. Paroxetine was administered repeatedly to mice (once daily, 12 days versus saline controls) and then either continued or discontinued for up to 5 days. Whereas tissue levels of 5-HT and/or its metabolite 5-HIAA tended to decrease during continuous paroxetine, levels increased above controls after discontinuation, notably in the hippocampus. In microdialysis experiments continuous paroxetine elevated hippocampal extracellular 5 HT and this effect fell to saline control levels on discontinuation. However, depolarisation (high potassium)-evoked 5-HT release was reduced by continuous paroxetine but increased above controls post-discontinuation. Extracellular hippocampal 5-HIAA also decreased during continuous paroxetine and increased above controls post-discontinuation. Next, immunohistochemistry experiments found that paroxetine discontinuation increased Fos expression in midbrain 5-HT neurons, adding further evidence for a hyperexcitable 5-HT system. The latter effect was recapitulated by 5-HT1A receptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT1A autoreceptors following paroxetine discontinuation. Finally, in behavioural experiments paroxetine discontinuation increased anxiety-like behaviour, which partially correlated in time with the measures of increased 5-HT function. In summary, this study finds that SSRI discontinuation triggers a rebound activation of 5-HT neurons across a range of experiments. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rebound activation of 5-HT neurons following SSRI discontinuation

Collins,

Gullino,

Ozdemir

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Mechanisms of SSRI Therapy and Discontinuation

Sharp,

Collins

2023

Current Topics in Behavioral Neurosciences

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Rebound activation of 5-HT neurons following SSRI discontinuation

Collins,

Gullino,

Ozdemir

et al. 2024

Neuropsychopharmacol.

View full text Add to dashboard Cite

Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset and disabling discontinuation syndrome, the mechanism of which is surprisingly little investigated. Here we determined the effect on 5-HT neurochemistry of discontinuation from the SSRI paroxetine. Paroxetine was administered repeatedly to mice (once daily, 12 days versus saline controls) and then either continued or discontinued for up to 5 days. Whereas brain tissue levels of 5-HT and/or its metabolite 5-HIAA tended to decrease during continuous paroxetine, levels increased above controls after discontinuation, notably in hippocampus. In microdialysis experiments continuous paroxetine elevated hippocampal extracellular 5-HT and this effect fell to saline control levels on discontinuation. However, depolarisation (high potassium)-evoked 5-HT release was reduced by continuous paroxetine but increased above controls post-discontinuation. Extracellular hippocampal 5-HIAA also decreased during continuous paroxetine and increased above controls post-discontinuation. Next, immunohistochemistry experiments found that paroxetine discontinuation increased c-Fos expression in midbrain 5-HT (TPH2 positive) neurons, adding further evidence for a hyperexcitable 5-HT system. The latter effect was recapitulated by 5-HT1A receptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT1A autoreceptors following paroxetine discontinuation. Finally, in behavioural experiments paroxetine discontinuation increased anxiety-like behaviour, which partially correlated in time with the measures of increased 5-HT function. In summary, this study reports evidence that, across a range of experiments, SSRI discontinuation triggers a rebound activation of 5-HT neurons. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.

show abstract

Application of gabapentinoids and novel compounds for the treatment of benzodiazepine dependence: the glutamatergic model

Cited by 3 publications

References 104 publications

Rebound activation of 5-HT neurons following SSRI discontinuation

Rebound activation of 5-HT neurons following SSRI discontinuation

Mechanisms of SSRI Therapy and Discontinuation

Rebound activation of 5-HT neurons following SSRI discontinuation

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