THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: G protein‐coupled receptors

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In mammals, a central circadian clock, located in the suprachiasmatic nuclei (SCN) of the hypothalamus, tunes the innate circadian physiological rhythms to the ambient 24 h light–dark cycle to invigorate and optimize the internal temporal order. The SCN‐activated, light‐inhibited production of melatonin conveys the message of darkness to the clock and induces night‐state physiological functions, for example, sleep/wake blood pressure and metabolism. Clinically meaningful effects of melatonin treatment have been demonstrated in placebo‐controlled trials in humans, particularly in disorders associated with diminished or misaligned melatonin rhythms, for example, circadian rhythm‐related sleep disorders, jet lag and shift work, insomnia in children with neurodevelopmental disorders, poor (non‐restorative) sleep quality, non‐dipping nocturnal blood pressure (nocturnal hypertension) and Alzheimer's disease (AD). The diminished production of melatonin at the very early stages of AD, the role of melatonin in the restorative value of sleep (perceived sleep quality) and its sleep‐anticipating effects resulting in attenuated activation of certain brain networks are gaining a new perspective as the role of poor sleep quality in the build‐up of β amyloid, particularly in the precuneus, is unravelled. As a result of the recently discovered relationship between circadian clock, sleep and neurodegeneration, new prospects of using melatonin for early intervention, to promote healthy physical and mental ageing, are of prime interest in view of the emerging link to the aetiology of Alzheimer's disease.Linked ArticlesThis article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc

Section: Discussionmentioning

confidence: 99%

New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation

Zisapel

2018

567

350

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharma-cology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al, 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 (Alexander et al, 2017a,b,c). …”

Section: Methodsmentioning

confidence: 99%

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Khan

Shekh‐Ahmad²,

Khalil³

et al. 2018

Background and PurposeA non‐psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy. To elucidate the mechanisms by which CBD exerts its anti‐seizure effects, we investigated its effects at synaptic connections and on the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin (PV)‐expressing and adapting, cholecystokinin (CCK)‐expressing interneurons. We also investigated whether in vivo treatment with CBD altered the fate of CCK and PV interneurons using immunohistochemistry.Experimental ApproachElectrophysiological intracellular whole‐cell recordings combined with neuroanatomy were performed in acute brain slices of rat temporal lobe epilepsy in in vivo (induced by kainic acid) and in vitro (induced by Mg2+‐free solution) epileptic seizure models. For immunohistochemistry experiments, CBD was administered in vivo (100 mg·kg−1) at zero time and 90 min post status epilepticus, induced with kainic acid.Key ResultsBath application of CBD (10 μM) dampened excitability at unitary synapses between pyramidal cells but enhanced inhibitory synaptic potentials elicited by fast spiking and adapting interneurons at postsynaptic pyramidal cells. Furthermore, CBD restored impaired membrane excitability of PV, CCK and pyramidal cells in a cell type‐specific manner. These neuroprotective effects of CBD were corroborated by immunohistochemistry experiments that revealed a significant reduction in atrophy and death of PV‐ and CCK‐expressing interneurons after CBD treatment.Conclusions and ImplicationsOur data suggest that CBD restores excitability and morphological impairments in epileptic models to pre‐epilepsy control levels through multiple mechanisms to reinstate normal network function.

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al, 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 (Alexander et al, 2017a,b,c,d). …”

Section: Methodsmentioning

confidence: 99%

Targeting the dopamine D₁ receptor or its downstream signalling by inhibiting phosphodiesterase‐1 improves cognitive performance

Pekcec

Schülert

Stierstorfer

et al. 2018

Background and PurposeInsufficient prefrontal dopamine 1 (D1) receptor signalling has been linked to cognitive dysfunction in several psychiatric conditions. Because the PDE1 isoform B (PDE1B) is postulated to regulate D1 receptor‐dependent signal transduction, in this study we aimed to elucidate the role of PDE1 in cognitive processes reliant on D1 receptor function.Experimental ApproachCognitive performance of the D1 receptor agonist, SKF38393, was studied in the T‐maze continuous alternation task and 5‐choice serial reaction time task. D1 receptor/PDE1B double‐immunohistochemistry was performed using human and rat prefrontal brain sections. The pharmacological activity of the PDE1 inhibitor, ITI‐214, was assessed by measuring the increase in cAMP/cGMP in prefrontal brain tissue and its effect on working memory performance. Mechanistic studies on the modulation of prefrontal neuronal transmission by SKF38393 and ITI‐214 were performed using extracellular recordings in brain slices.Key ResultsSKF38393 improved working memory and attentional performance in rodents. D1 receptor/PDE1B co‐expression was verified in both human and rat prefrontal brain sections. The pharmacological activity of ITI‐214 on its target, PDE1, was demonstrated by its ability to increase prefrontal cAMP/cGMP. In addition, ITI‐214 improved working memory performance. Both SKF38393 and ITI‐214 facilitated neuronal transmission in prefrontal brain slices.Conclusion and ImplicationsWe hypothesize that PDE1 inhibition improves working memory performance by increasing prefrontal synaptic transmission and/or postsynaptic D1 receptor signalling, by modulating prefrontal downstream second messenger levels. These data, therefore, support the use of PDE1 inhibitors as a potential approach for the treatment of cognitive dysfunction.