Scopolamine Administration Modulates Muscarinic, Nicotinic and NMDA Receptor Systems

Falsafi, Soheil Keihan; Deli, Alev; Höger, Harald; Pollak, Arnold; Lubec, Gert

doi:10.1371/journal.pone.0032082

Cited by 81 publications

(50 citation statements)

References 87 publications

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“…impairments, which typically use 100 μg/kg to 3 mg/kg doses of scopolamine (31)(32)(33). Second, the antidepressant-like effects were observed 24 hours after the final 25 μg/kg dose of scopolamine, at a time when the drug had largely been cleared.…”

Section: Figure 6 M1-achr Mediates Cholinergic Stimulation Of Sst Inmentioning

confidence: 99%

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

Wohleb¹,

Wu²,

Gerhard³

et al. 2016

Journal of Clinical Investigation

134

112

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R e s e a R c h a R t i c l e2 4 8 2 jci.org Volume 126 Number 7 July 2016 IntroductionMajor depressive disorder (MDD) is a recurring neuropsychiatric illness that affects up to 17% of the population and causes substantial social and economic burdens (1-4). While some patients respond to existing medications, currently available antidepressants take weeks to months to have an effect, and many patients are considered treatment resistant because they fail to respond to 2 or more antidepressants (5). Recent studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine (ACh) receptor (mAChR) antagonist, and ketamine, an NMDA receptor antagonist, produce rapid antidepressant actions (within hours) and are effective even in treatment-resistant MDD patients (6-8). The rapid antidepressant actions of scopolamine and ketamine are dependent on glutamate release and induction of new spine synapses in the medial prefrontal cortex (mPFC) (9-11), effects that directly target the synaptic pathophysiology of MDD and chronic stress (12-19). However, a major question in the field is, what are the initial cellular targets that mediate the increase in glutamate transmission, leading to increased synapse formation and rapid antidepressant behavior (10, 20, 21)? One hypothesis is that scopolamine blocks muscarinic receptors on GABAergic interneurons, resulting in disinhibition of pyramidal neurons and increased glutamate transmission. Alternatively, scopolamine may act directly on pyramidal neurons to enhance synaptic plasticity and produce antidepressant behavioral responses. Recent studies suggest that the M1-type muscarinic ACh receptor (M1-AChR) subtype may mediate the antidepressant actions of scopolamine (9, 22, 23).M1-AChRs are expressed on both GABAergic interneurons and glutamatergic pyramidal neurons in the mPFC and regulate the activity of both cell types (24)(25)(26).In the present study, we used transgenic mice and viralmediated gene transfer to drive Cre-dependent expression of M1-AChR shRNA in different subtypes of GABA interneurons or glutamate neurons in the mPFC. The results demonstrate that M1-AChR knockdown in GABA interneurons, but not pyramidal neurons, blocks the antidepressant-like response to scopolamine in mouse behavioral models. In addition, we show that knockdown of M1-AChR in somatostatin (SST), but not parvalbumin (PV), interneurons, blocks the actions of scopolamine. These findings reveal that M1-AChRs on SST interneurons in the mPFC are a critical cellular target underlying the rapid antidepressant effects of scopolamine. Results CaMKII+ and GAD + cell type-specific knockdown of M1-AChR in the mPFC. To determine whether glutamatergic pyramidal neurons and GABAergic interneurons in the mPFC express M1-AChR, double immunohistology was conducted with an M1-AChR antibody and Ca 2+ /calmodulin-dependent kinase II (CaMKII; pyramidal cell) or glutamate decarboxylase-67 (GAD67; GABA interneuron) (25). The results show that CaMKII + pyramidal neurons display punctate M1-AChR labeling in the mPF...

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Section: Figure 6 M1-achr Mediates Cholinergic Stimulation Of Sst Inmentioning

confidence: 99%

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

Wohleb¹,

Wu²,

Gerhard³

et al. 2016

Journal of Clinical Investigation

134

112

View full text Add to dashboard Cite

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“…As a standard amnesic drug, scopolamine is frequently used in similar 50 was not established, the therapeutic dose was approximated from a previous study 36 . studies [32][33][34][35] . In this study, scopolamine was successfully substituted by another non-selective muscarinic receptor antagonist -QNB.…”

Section: Discussionmentioning

confidence: 99%

“…This approach enabled long-term observation of anti-cholinergic effects due to the prolonged action of QNB compared to scopolamine 27,36 . To evaluate the pro-cognitive effects of novel compounds, the multiple T-maze test was selected 26,34,37,38 . This behavioural task reflects spatial learning and memory, requiring recollection of spatial information and the construction of a cognitive map, which is considered to be analogous to human episodic memory in animals 39,40 .…”

Section: Discussionmentioning

confidence: 99%

The effects of novel 7-MEOTA-donepezil like hybrids and N-alkylated tacrine analogues in the treatment of quinuclidinyl benzilate-induced behavioural deficits in rats performing the multiple T-maze test

Mišík¹,

Korábečný²,

Nepovimová³

et al. 2015

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Aims. The number of approved drugs for the clinical treatment of Alzheimer disease remains limited. For this reason, there is extensive search for novel therapies. Of these, cholinesterase inhibitors have some proven benefit in slowing the disease progression and still remain the first-line therapeutic approach. In this study, the pro-cognitive effect of four novel tacrine-related inhibitors was evaluated and compared with the standards, tacrine and donepezil. Methods. Wistar rats trained to perform the multiple T-maze were treated intra-peritoneally with the anticholinergic agent 3-quinuclidinyl benzilate (QNB, 2.0 mg/kg), followed 30 min later by another injection containing a therapeutic dose of standard or novel cholinesterase inhibitor. The rats were repeatedly subjected to the multiple T-maze task at several time points following QNB administration (1, 24, 48 and 72 h). The passage time and number of errors were recorded. The inhibitory potential of selected therapeutic doses was assessed in a separate in vivo experiment using a spectrophotometric method. Results. QNB significantly impaired the performance of the rats within 48 h. The four novel cholinesterase inhibitors attenuated the effect of QNB at 1 h, 24 h and 48 h test intervals. The novel compounds resulted in brain cholinesterase inhibition ranging from 5.4 to 11.3 %, and their effect on the QNB-induced deficit recorded in the T-maze performance was comparable to that of the standards or higher at some time points. Conclusion: The best result was achieved with derivative 4, followed by derivatives 2 and 3, suggesting that these compounds could be candidates for the treatment of Alzheimer disease.

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“…Scopolamine appears to be a non-selective muscarinic receptor antagonist; it has been demonstrated that scopolamine has a high selectivity for the muscarinic receptor, although it has also been reported that high doses of scopolamine are also blocking nicotinic receptors [18].…”

Section: Discussionmentioning

confidence: 99%

Effects of Rhodiola rosea extract on passive avoidance tests in rats

Getova

Bakova

2013

Open Medicine

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AbstractThe purpose was to evaluate the effects of extract of Rhodiola rosea on learning and memory processes on rats. The two series of experiments were carried out — on naïve rats and on rats with scopolamine-impaired memory. The passive avoidance tests were performed — step-down and step-through. The latency of reactions in seconds was observed in both tests. Naïve rats treated with the extract in showed the prolongation of latency of reaction of both step-down and step-through passive avoidances compared to the controls. Rats with scopolamine-impaired memory showed shorter latency of reaction in both passive avoidance tests compared to the controls. Rats treated with the extract of Rh. Rosea with scopolamine-impaired memory prolonged the latency in both passive avoidance tests compared to scopolamine group. It was found that the extract of Rh. Rosea improved performance during learning session, short and long memory retrieval tests in naïve rats. Scopolamine impaired the learning and memory retrieval of rats, but Rh. Rosea pretreatment improved performance and turned off the deterioration effect of scopolamine on these brain functions probably by non-specific mechanisms on cholinergic neurons. The studied plant extract can be a candidate for treatment of dementia and other memory disturbances.

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Scopolamine Administration Modulates Muscarinic, Nicotinic and NMDA Receptor Systems

Cited by 81 publications

References 87 publications

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

GABA interneurons mediate the rapid antidepressant-like effects of scopolamine

The effects of novel 7-MEOTA-donepezil like hybrids and N-alkylated tacrine analogues in the treatment of quinuclidinyl benzilate-induced behavioural deficits in rats performing the multiple T-maze test

Effects of Rhodiola rosea extract on passive avoidance tests in rats

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