G-protein coupled receptors and synaptic plasticity in sleep deprivation

Table 1 Comparative features of long term potentiation and long term depression and their implications in sleep and associated functions

	Prominent brain regions	Receptors involved	Induction	Maintenance	Association with sleep	Functional significance
LTP: Strengthening of synaptic transmission due to a transient high frequency stimulation of the synapses	Cerebellum, hippocampus, cerebral cortex	Ionotropic: NMDARs, AMPARs	Requires activation of both pre- and post-synaptic neurons at the same time for glutamate to fully activate the NMDA receptors [51].	Secondary activation of receptors like AMPARs by glutamate needed for maintenance of LTP[51].	Active nature of LTP likely associated with active state of sleep.	Enhances synaptic response as well as neuronal excitability.
		Metabotropic: Group I mGluRs	Ionotropic induction requires activation of NMDARs by glutamate released from pre-synaptic neurons for higher Ca2+ influx in the post-synaptic neuron [51].	Requires activation of intermediate protein kinases like CaMKIV, protein kinase M-ζ, PKA etc. by high Ca2+ concentration to release membrane obscured AMPARs[56].	More commonly linked with REM sleep associated cellular and molecular modulation of synaptic plasticity[57].	Involved in memory consolidation and learning: Strengthened synapses promote long-term memory storage[58]; Promotes associative and spatial learning[59]; Involved in motor learning and task reperformance[60,61].
			Metabotropic induction works via an increase in intracellular Ca2+ release through mGluR activated phospholipase C and synthesis of secondary messengers IP3 and DAG[54,55].
LTD: Weakening of the synaptic strength due to a relatively low frequency stimulation of the synapses	Cerebellum, hippocampus, cerebral cortex	Ionotropic: NMDARs	Activation of pre-synaptic neuron sufficient to trigger a moderate response of NMDA receptors and does not require both synapses to be activated at the same time[51].	Deactivation of AMPARs involved in maintenance of LTD[131].	Suppressive nature of LTD more likely to be associated with quiescent state of sleep.	Interferes with LTP thereby providing a counteractive balance to prevent hyperexcitability of neurons[52].
		Metabotropic: GPCRs like mGlu1Rs, mGlu5Rs, GABA-B	Ionotropic induction requires moderate activation of NMDA receptors by glutamate for Ca2+ influx in post-synaptic neuron which is lower than that for LTP induction[52].	Requires activation of intermediate protein phosphatases like protein phosphatase 1, 2 and calcineurin by low Ca2+ concentration to inhibit the release of membrane obscured AMPARs[53].	More commonly linked with SWS associated cellular and molecular modulation of synaptic plasticity[64].	Involved in memory consolidation and learning: Weakened state of synapses implicated in forgetting old memories in order to make space for new ones [65]; Involved in novelty acquisition and spatial learning[66].
			Metabotropic induction through mGlu1Rs and mGlu5Rs causes endocytosis of the expressed AMPARs and/or a decrease in phospholipase C via reduced adenylyl cyclase activity[62].
			Enhancement of GABA-B mediated inhibitory effects may result in LTD[63].

GABA-B: Gamma-amino butyric acid-B; NMDA: N-methyl-D-aspartate; SWS: Slow wave sleep; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; LTP: Long term potentiation; LTD: long term depression; mGlu: Metabotropic glutamate; 5-HT: 5-hydroxytryptamine.

Table 2 Changes in synaptic plasticity, learning and sleep associated with antipsychotic, antidepressant and anxiolytic drug therapy

Class of drugs	Drug examples		Target GPCRs	Mechanism of action	Therapeutic application	Possible association with synaptic plasticity and learning	Implications in sleep and associated functions
Antipsychotics	1st generation / typical antipsychotic drugs	Chlorpromazine	DA D1/D2/D3, 5-HT2A, Histamine H1, α1-Adrenergic, Muscarinic receptors.	1 Acts as an antagonist by blocking post-synaptic DA D2 receptors.	1 In the treatment of psychotic disorders like schizophrenia, bipolar disorder, acute mania, dementia, etc.	1 Synaptic plasticity: Acute treatment with haloperidol can impair induction of LTP but not its maintenance in rabbit hippocampus. Chronic treatment with haloperidol suggested to enhance LTP in corticostriatal brain slices of rats[174,175].	1 Associated with sedation and often promote sleep inducing effects.
		Haloperidol		2 Can also block serotoninergic, histaminergic, cholinergic and noradrenergic receptors[173].	2 Reduce psychosis symptoms like hallucinations and delusion.	3 Learning Functions: Haloperidol and Chlorpromazine can impair spatial learning in rats[176, 177].	(1) Haloperidol, loxapine and mesoridazine increase REM sleep latency. Withdrawal of drug causes significant disruption of sleep with reduced REM and total sleep;
		Loxapine					(2) No significant effect on SWS[178-180];
		Mesoridazine					(3) Chlorpromazine enhances SWS along with a dose dependent effect on REM sleep - lower doses increasing and higher doses reducing or having no effect on REM sleep[181].
	2nd generation /atypical antipsychotic drugs	Clozapine	DA D2, 5-HT2A, 2C receptors	1 Antagonistic effects by blocking 5-HT2A/2C receptors and agonistic effects by promoting 5-HT1A receptor mediated actions.	1 In the treatment of psychotic disorders like schizophrenia, bipolar disorder, acute mania, dementia etc.	1 Synaptic Plasticity: Without tetanization, acute clozapine administration induces LTP in rabbit hippocampus[184]. Chronic treatment with clozapine impairs LTP in rat prelimbic cortex[185]; Acute administration of risperidone impairs LTP in rabbit hippocampus. LTP induction post tetanization takes places in rat hippocampus upon chronic treatment with olanzapine[186,187].	1 Associated with an increase in the total amount of sleep but show an uneven trend in their stage specific effects.
		Risperidone		2 Transiently block DA D2 receptors[182].	2 Reduce psychosis symptoms like hallucinations and delusion, disordered thinking, social withdrawal etc.	2 Learning Functions: Clozapine and olanzapine impair memory retrieval in mice[188] while risperidone improves learning and memory processing in humans[189].	(1) Clozapine increases REM sleep density and improves NREM sleep. However, its effect on SWS is inconsistent[180];
		Olanzapine
	3rd Generation antipsychotic drugs	Aripiprazole	DA D2 receptors	1 Partial agonist of DA D2 and 5-HT1A receptors and an antagonist of 5-HT2A receptors.			(2) Olanzapine improves SWS as well as REM sleep latency. Risperidone increases SWS but reduces REM sleep[180,190,191].
				2 DA D2 antagonist in the mesolimbic pathway[183].
Antidepressants and anxiolytics		Fluoxetine	5-HT-1A receptors	1 Blocks the serotonin reuptake and increases serotonin action via 5-HT1A receptors.	In the treatment of depression, obsessive control disorders, eating disorders, substance use disorders etc.	1 Synaptic Plasticity: (1) Acute treatment with fluoxetine before stressful stimuli indicated to suppress stress induced LTD in CA1 region of rat hippocampus[194];	1 Associated with uneven side effects on sleep like somnolence, sedation and insomnia.
				2 Suggested to cause reversible internalization of 5-HT1A auto -receptors[192].		(2) Chronic fluoxetine treatment enhances neurogenesis dependent LTP in mice hippocampal granule cells and also upregulates Brain-Derived Neurotrophic Factor-LTP associated genes. Acute treatment showed no such upregulation[195,196];	(1) Fluoxetine reduces overall sleep continuity with a reduction in REM sleep but increases REM latency. It either increases or has no effect on SWS[197];
		Mirtazapine	5-HT1 and 2 receptors, α2-adrenergic receptors	1 Blocks 5-HT2 receptors in order to increase 5-HT1 mediated transmission.		(3) Acute treatment of vortioxetine enhances LTP in the CA1 region of rat hippocampus by increasing pyramidal cell output[199];of memory processing[207,208];	(2) Mirtazapine increases sleep continuity and SWS but does not affect REM sleep[197];
				2 Antagonist of α2-adrenergic receptors to increase adrenergic neurotransmission[193].		(4) Acute treatment of buspirone as an agonist of 5-HT1A results in the reversal of LTP in a time -dependent manner in rat hippocampal slices[202];	(3) Vortioxetine causes a reduction in REM sleep but increases its latency. It’s effects on SWS are unclear[197];
		Vortioxetine	5-HT1A, 1B, 1D, 5-HT7 receptors.	Antagonist of 5-HT1D and H-HT7 receptors and a partial agonist of 5-HT1A and 1B receptors[198].	In the treatment of Major Depressive Disorder.	(5) Acute treatment of baclofen induces GABA-B receptor mediated LTD enhancement of a glutamate-evoked current in the cerebellar cortical neurons. It also enhances mGluR1-coupled intracellular Ca2+ release[63].	(4) Vilazodone causes sleep disturbances with a decrease in REM sleep and an increase in wakefulness and SWS[209];
		Vilazodone	5-HT1A receptors	Blocks the serotonin reuptake inhibitor and also acts as a partial agonist of 5-HT1A receptor and stimulates it[200].		2 Learning Functions: (1) Fluoxetine reverses memory impairment in rats and enhances memory processing in mice[203,204]. Chronic use of mirtazapine and vortioxetine improve cognitive functions in humans[205,206,208,209];	(5) Buspirone increases REM sleep density and latency[210];
		Buspirone	5-HT1A, DA D2 auto receptors	Partial agonist of 5-HT1A receptor and antagonist of DA D2 auto receptors with low affinity[201].	For treating of Generalized Anxiety Disorder and side effects of Parkinson’s and Alzheimer’s disease.	(2) Buspirone and baclofen are implicated in the impairment of memory processing[207,208].	(6) Baclofen prolongs total sleep time with an increase in duration for REM sleep and SWS[211].
		Baclofen	GABA-B receptors	GABA-B agonist to increase inhibitory signals[172].	Suggested use in treating depression and anxiety as well as a muscle relaxant.

LTP: Long term potentiation; LTD: long term depression; SWS: Slow wave sleep; 5-HT: 5-hydroxytryptamine; GABA-B: Gamma-amino butyric acid-B.