Imaging brain phospholipase A2 activation in awake rats in response to the 5-HT2A/2C agonist (±)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI)

“Plasma was separated from Neuropsychopharmacology arterial blood by centrifugation, and lipids were extracted using the method of Folch et al (1957).”

“One of the three adjacent sections was collected and stained with cresyl violet to identify brain regions with reference to a rat-brain atlas (Paxinos and Watson, 1987).”

“…other drugs effective in schizophrenia, depression, obsessive–compulsive disorder, and neurodegenerative disease are considered to act at serotonin (5-hydroxytryptamine) 5-HT2 receptors (Barnes and Sharp, 1999; Breier, 1995; Ramasubbu et al, 2000; Rauser et al, 2001; Reynolds, 2001; Thase, 2002).”

“One-way ANOVA and Dunnett’s multiple comparison test were used.”

“…distributions of PLA2 activation by DOI and of 5-HT2A receptors could be further examined using DOI and altanserin, a selective 5-HT2A blocker (Hoyer et al, 1995; Leysen et al, 1988; PDSP Drug Database, 2000; Roth et al, 2000), or by studying DOI responses in a 5-HT2Areceptor knockout mouse…”

“The most intense increments in k* in response to DOI (Figure 1, Table 1) were seen in brain regions having high densities of 5-HT2A compared with 5-HT2C binding sites (Cooper et al, 1996; Li et al, 2001; Pazos and Palacios, 1985).”

“Both AA and its eicosanoid metabolites are important second messengers (Shimizu and Wolfe, 1990).”

“…inositol 1,4,5- trisphosphate (IP3) and diacylglycerol as second messengers (Conn and Sanders-Bush, 1986b; Edagawa et al, 2000), or to phospholipase A2 (PLA2) activation, releasing arachidonic acid (AA) from phospholipids (Axelrod, 1995; Berg et al, 1998; Felder et al, 1990; Tournois et al, 1998).”

“DOI are accompanied by a few reductions in rCMRglc (Freo et al, 1991, 1992), which are ascribed to reduced neuronal spike activity (Ashby et al, 1990; Bloom, 1985; Cooper et al, 1996; Freo et al, 1991; Sokoloff, 1999).”

“…of both the (+) and ( ) stereoisomers of DOI are reported to be equivalent at 5-HT2 receptors (Glennon, 1986, 1987; PDSP Drug Database, 2000; Pranzatelli, 1990; Roth et al, 2000), as far as we know the affinities of the two stereoisomers at other receptors coupled to PLA2 have not been examined.”

“Although the affinities of both the (+) and ( ) stereoisomers of DOI are reported to be equivalent at 5-HT2 receptors (Glennon, 1986, 1987; PDSP Drug Database, 2000; Pranzatelli, 1990; Roth et al, 2000), as far as we know the affinities of the two stereoisomers at other receptors coupled to PLA2…”

“…adrenergic a2-antagonist activity as well (Anji et al, 2000; Ashby et al, 1990; Blackshear and Sanders-Bush, 1982; Dijcks et al, 1991; Hoyer et al, 1995; PDSP, 2000; Pranzatelli, 1990; Rocha et al, 1994; Roth and Ciaranello, 1991; Roth et al, 2000; Sanders-Bush et al, 1987; Schreiber et al, 1995).”

“Chronic mianserin is reported not to alter extracellular serotonin levels in rat brain (Kreiss and Lucki, 1995), but is reported to reduce brain densities of 5-HT2A receptors (Berendsen and Broekkamp, 1991; Blackshear and Sanders-Bush, 1982; Essom and Nemeroff, 1996; Frazer et al, 1988; Roth and Ciaranello, 1991) and…”

“…to image brain PLC activation in vivo, whereas PLA2 activation can be imaged by using quantitative autoradiography to measure incorporation into brain of intravenously injected, radiolabeled AA (DeGeorge et al, 1991; Hayakawa et al, 2001; Nariai et al, 1991; Rapoport, 2001; Robinson et al, 1992).”

“5-HT2 receptors are widely distributed in rat brain (Appel et al, 1990; Morilak et al, 1993; Pazos and Palacios, 1985).”

“Recall that PLA2 can be activated when a ligand binds to any of a number of receptor subtypes, including 5-HT2 receptors (Axelrod, 1995; Cooper et al, 1996; Felder et al, 1990).”

“Additionally, 2.5 mg/kg i.p. DOI in rats markedly stimulates the release of corticotropin (ACTH), corticosterone, oxytocin, renin, and prolactin, and activates hypothalamic corticotropin-releasing factor and oxytocin-expressing neurons (Van de Kar et al, 2001).”

“Large changes in [(3)H]AA incorporation into the brain in contrast to small changes in rCMRglc have also been noted in rats administered the muscarinic agonist arecoline or the dopaminergic D2 agonist quinpirol (Hayakawa et al, 2001; Nariai et al, 1991; Orzi et al, 1988; Wooten and Collins, 1981).”

“Its features include an altered mental status, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, and tremor (Mills, 1997; Sternbach, 1991); it is treated by discontinuing serotonergic therapy.”

“…(Ichikawa and Meltzer, 1995), brain extracellular dopamine and noradrenaline concentrations (Gobert and Millan, 1999), and dopamine turnover (Gaggi et al, 1997), and DOI will activate local g-aminobutyric acid (GABA) inputs to serotonergic neurons in the dorsal raphe nucleus (Liu et al, 2000).”

“As noted above, such signaling can occur through activation of PLC or PLA2.”

“We also quantified k* for [(3)H]AA in response to chronically administered mianserin, an atypical tetracyclic antidepressant that has been used as a 5-HT2-receptor antagonist in many animal studies, although having some adrenergic a2-antagonist activity as well (Anji et al, 2000; Ashby et al, 1990; Blackshear and Sand…”

“5-HT2 receptors are widely distributed in rat brain (Appel et al, 1990; Morilak et al, 1993; Pazos and Palacios, 1985).”

“…other drugs effective in schizophrenia, depression, obsessive–compulsive disorder, and neurodegenerative disease are considered to act at serotonin (5-hydroxytryptamine) 5-HT2 receptors (Barnes and Sharp, 1999; Breier, 1995; Ramasubbu et al, 2000; Rauser et al, 2001; Reynolds, 2001; Thase, 2002).”

“DOI can increase amphetamine-induced dopamine release in the brain (Ichikawa and Meltzer, 1995), brain extracellular dopamine and noradrenaline concentrations (Gobert and Millan, 1999), and dopamine turnover (Gaggi et al, 1997), and DOI will activate local g-aminobutyric acid (GABA) inputs to serotonergic neurons in t…”

“…other drugs effective in schizophrenia, depression, obsessive–compulsive disorder, and neurodegenerative disease are considered to act at serotonin (5-hydroxytryptamine) 5-HT2 receptors (Barnes and Sharp, 1999; Breier, 1995; Ramasubbu et al, 2000; Rauser et al, 2001; Reynolds, 2001; Thase, 2002).”

“About 5% of a plasma fatty acid is stripped from albumin as blood passes through the brain (Pardridge and Mietus, 1980).”

“…to image brain PLC activation in vivo, whereas PLA2 activation can be imaged by using quantitative autoradiography to measure incorporation into brain of intravenously injected, radiolabeled AA (DeGeorge et al, 1991; Hayakawa et al, 2001; Nariai et al, 1991; Rapoport, 2001; Robinson et al, 1992).”

“…other drugs effective in schizophrenia, depression, obsessive–compulsive disorder, and neurodegenerative disease are considered to act at serotonin (5-hydroxytryptamine) 5-HT2 receptors (Barnes and Sharp, 1999; Breier, 1995; Ramasubbu et al, 2000; Rauser et al, 2001; Reynolds, 2001; Thase, 2002).”

“The rate of disappearance of labeled AA from brain phospholipids is only 10% per hour (DeGeorge et al, 1989; Rapoport, 2001; Rapoport et al, 2001; Washizaki et al, 1994), which means that we can image tracer incorporation at 20 min without worrying about loss from the phospholipids.”

“…densities than other cortical regions, whereas densities are comparatively low in the caudate-putamen head, globus pallidus, red nuclei, septal nuclei, and most parts of the hippocampus (McKenna et al, 1989; McKenna and Peroutka, 1989), thalamus, hypothalamus, midbrain, brain stem, and spinal cord.”

“The rate of disappearance of labeled AA from brain phospholipids is only 10% per hour (DeGeorge et al, 1989; Rapoport, 2001; Rapoport et al, 2001; Washizaki et al, 1994), which means that we can image tracer incorporation at 20 min without worrying about loss from the phospholipids.”

“PLA2 can also be activated when Ca 2+ enters cells by glutamate acting at N-methyl-d-aspartate (NMDA) receptors or by acetylcholine acting at nicotinic receptors (Brooks et al, 1989; Cooper et al, 1996; Vijayaraghavan et al, 1995).”

“…of both the (+) and ( ) stereoisomers of DOI are reported to be equivalent at 5-HT2 receptors (Glennon, 1986, 1987; PDSP Drug Database, 2000; Pranzatelli, 1990; Roth et al, 2000), as far as we know the affinities of the two stereoisomers at other receptors coupled to PLA2 have not been…”

“Table 2 Continued Neuropsychopharmacology cerebrospinal fluid secretion by increasing phosphorylation of Na+, K+-ATPase by protein kinase C following activation of PLC (Conn and Sanders-Bush, 1986a; Fisone et al, 1995, 1998), or through Ca2+-dependent activation of PLA2 (Kaufman et al, 1995).”

“PLA2 can also be activated when Ca 2+ enters cells by glutamate acting at N-methyl-d-aspartate (NMDA) receptors or by acetylcholine acting at nicotinic receptors (Brooks et al, 1989; Cooper et al, 1996; Vijayaraghavan et al, 1995).”

“DOI can increase amphetamine-induced dopamine release in the brain (Ichikawa and Meltzer, 1995), brain extracellular dopamine and noradrenaline concentrations (Gobert and Millan, 1999), and dopamine turnover (Gaggi et al, 1997), and DOI will activate local g-aminobutyric acid (GABA) inputs to…”

“triphosphate (ATP) consumption (Purdon and Rapoport, 1998; Rapoport, 2001).”

“…other drugs effective in schizophrenia, depression, obsessive–compulsive disorder, and neurodegenerative disease are considered to act at serotonin (5-hydroxytryptamine) 5-HT2 receptors (Barnes and Sharp, 1999; Breier, 1995; Ramasubbu et al, 2000; Rauser et al, 2001; Reynolds, 2001; Thase, 2002).”

“…of k* from rCBF arises because circulating plasma albumin, to which fatty acid is highly bound but from which it can rapidly dissociate (Svenson et al, 1974), acts as an ‘infinite source’ of intravascular tracer for entry into brain (Robinson et al, 1992; Robinson and Rapoport, 1986;…”

“Phosphorylation and interaction of the receptors with membrane G-proteins are altered (Hartman and Northup, 1996; Ozawa et al, 1994; Westphal et al, 1995), and both receptor types are functionally hyposensitive (MazzolaPomietto et al, 1997).”

“…densities than other cortical regions, whereas densities are comparatively low in the caudate-putamen head, globus pallidus, red nuclei, septal nuclei, and most parts of the hippocampus (McKenna et al, 1989; McKenna and Peroutka, 1989), thalamus, hypothalamus, midbrain, brain stem, and spinal cord.”

“Although the affinities of both the (+) and ( ) stereoisomers of DOI are reported to be equivalent at 5-HT2 receptors (Glennon, 1986, 1987; PDSP Drug Database, 2000; Pranzatelli, 1990; Roth et al, 2000), as far as we know the affinities of the two stereoisomers at other receptors coupled to PLA2…”

“As noted above, such signaling can occur through activation of PLC or PLA2.”

“…adrenergic a2-antagonist activity as well (Anji et al, 2000; Ashby et al, 1990; Blackshear and Sanders-Bush, 1982; Dijcks et al, 1991; Hoyer et al, 1995; PDSP, 2000; Pranzatelli, 1990; Rocha et al, 1994; Roth and Ciaranello, 1991; Roth et al, 2000; Sanders-Bush et al, 1987; Schreiber et al, 1995).”

“…to rats of arecoline, a cholinergic agonist that acts at muscarinic M1 receptors coupled to PLA2, increased rCMRglc and rCBF (as well as k*) for labeled AA, without affecting k* for labeled palmitic acid (DeGeorge et al, 1991; Jones et al, 1996; Maiese et al, 1994; Soncrant et al, 1985).”

“The 5-HT2 receptormediated activation of PLC by DOI, which increases phosphatidylinositol turnover and Ca2+ mobilization by IP3, is also reported to be inhibited by chronic mianserin (Conn and Sanders-Bush, 1986b; Wolf and Schutz, 1997).”

“…coupled to PLA2 via membrane G-proteins include cholinergic muscarinic M1 and M3 receptors, dopaminergic D2 receptors, and serotonergic 5-HT2 receptors (Axelrod, 1995; Bayon et al, 1997; Cooper et al, 1996; DeGeorge et al, 1991; Felder et al, 1990; Hayakawa et al, 2001; Vial and Piomelli, 1995).”

“Table 2 Continued Neuropsychopharmacology cerebrospinal fluid secretion by increasing phosphorylation of Na+, K+-ATPase by protein kinase C following activation of PLC (Conn and Sanders-Bush, 1986a; Fisone et al, 1995, 1998), or through Ca2+-dependent activation of PLA2 (Kaufman et al, 1995).”

“…to rats of arecoline, a cholinergic agonist that acts at muscarinic M1 receptors coupled to PLA2, increased rCMRglc and rCBF (as well as k*) for labeled AA, without affecting k* for labeled palmitic acid (DeGeorge et al, 1991; Jones et al, 1996; Maiese et al, 1994; Soncrant et al, 1985).”

“A 5-HT2 syndrome has been described in rats following administration of the 5-HT2A/2C receptor agonist (7 )2,5- dimethoxy-4-iodophenyl-2-aminopropane (DOI) (Glennon, 1986; Johnson et al, 1998; Pranzatelli, 1990; Wettstein et al, 1999).”

“The independence of k* from rCBF arises because circulating plasma albumin, to which fatty acid is highly bound but from which it can rapidly dissociate (Svenson et al, 1974), acts as an ‘infinite source’ of intravascular tracer for entry into brain (Robinson et al, 1992; Robinson and Rapoport, 1986; Washizaki et al,…”

“Large changes in [3H]AA incorporation into the brain in contrast to small changes in rCMRglc have also been noted in rats administered the muscarinic agonist arecoline or the dopaminergic D2 agonist quinpirol (Hayakawa et al, 2001; Nariai et al, 1991; Orzi et al, 1988; Wooten and Collins, 1981).”

“Chronic mianserin is reported not to alter extracellular serotonin levels in rat brain (Kreiss and Lucki, 1995), but is reported to reduce brain densities of 5-HT2A receptors (Berendsen and Broekkamp, 1991; Blackshear and Sanders-Bush, 1982; Essom and Nemeroff, 1996; Frazer et al, 1988; Roth and Ciaranello, 1991) and…”

“…20892, USA, Tel: +1 301 594 3134, Fax: +1 301 402 0074, E-mail: quying@mail.nih.gov Neuropsychopharmacology (2003) 28, 244–252 & 2003 Nature Publishing Group All rights reserved 0893-133X/03 $25.00 www.neuropsychopharmacology.org lated by the hypothalamic–pituitary–adrenal axis (Freo et al, 1992).”

“5-HT2 receptor activation can also inhibit glutamate release from rat cerebellar mossy fibers (Marcoli et al, 2001) and the release of acetylcholine in the hippocampus and neocortex (Feuerstein et al, 1996), which may explain DOI’s inhibition of rCMRglc (Freo et al, 1991, 1992).”

“Recall that PLA2 can be activated when a ligand binds to any of a number of receptor subtypes, including 5-HT2 receptors (Axelrod, 1995; Cooper et al, 1996; Felder et al, 1990).”

“…to image brain PLC activation in vivo, whereas PLA2 activation can be imaged by using quantitative autoradiography to measure incorporation into brain of intravenously injected, radiolabeled AA (DeGeorge et al, 1991; Hayakawa et al, 2001; Nariai et al, 1991; Rapoport, 2001; Robinson et al, 1992).”

“A 5-HT2 syndrome has been described in rats following administration of the 5-HT2A/2C receptor agonist (7 )2,5- dimethoxy-4-iodophenyl-2-aminopropane (DOI) (Glennon, 1986; Johnson et al, 1998; Pranzatelli, 1990; Wettstein et al, 1999).”

“…serotonin levels in rat brain (Kreiss and Lucki, 1995), but is reported to reduce brain densities of 5-HT2A receptors (Berendsen and Broekkamp, 1991; Blackshear and Sanders-Bush, 1982; Essom and Nemeroff, 1996; Frazer et al, 1988; Roth and Ciaranello, 1991) and 5-HT2C receptors (Rocha et al, 1994).”

“…C (PLC) activation, generating inositol 1,4,5- trisphosphate (IP3) and diacylglycerol as second messengers (Conn and Sanders-Bush, 1986b; Edagawa et al, 2000), or to phospholipase A2 (PLA2) activation, releasing arachidonic acid (AA) from phospholipids (Axelrod, 1995; Berg et al, 1998;…”

“…that has been used as a 5-HT2-receptor antagonist in many animal studies, although having some adrenergic a2-antagonist activity as well (Anji et al, 2000; Ashby et al, 1990; Blackshear and Sanders-Bush, 1982; Dijcks et al, 1991; Hoyer et al, 1995; PDSP, 2000; Pranzatelli, 1990; Rocha…”

“…to rats of arecoline, a cholinergic agonist that acts at muscarinic M1 receptors coupled to PLA2, increased rCMRglc and rCBF (as well as k*) for labeled AA, without affecting k* for labeled palmitic acid (DeGeorge et al, 1991; Jones et al, 1996; Maiese et al, 1994; Soncrant et al, 1985).”

“…cases is probably due to mianserin-induced neuroplastic changes, rather than to physical blocking of 5-HT2 receptors by mianserin, as the brain mianserin concentration falls to less than 0.1% of its peak concentration within 24 h after i.p. injection (Dijcks et al, 1991; Sanders-Bush et al, 1987).”

“…to image brain PLC activation in vivo, whereas PLA2 activation can be imaged by using quantitative autoradiography to measure incorporation into brain of intravenously injected, radiolabeled AA (DeGeorge et al, 1991; Hayakawa et al, 2001; Nariai et al, 1991; Rapoport, 2001; Robinson et al, 1992).”

“The remainder, found in the aqueous fraction, represents metabolites arising from comparatively slow b-oxidation (Osmundsen and Hovik, 1988).”

“Chronic mianserin, on the other hand, produces a supersensitivity of adrenergic a2 receptors (Pinder, 1985).”

“…of unlabeled AA from the stereospecifically numbered (sn)-2 position of synaptic brain phospholipids (DeGeorge et al, 1991; Fonlupt et al, 1994; Grange et al, 1998; Jones et al, 1996), independent of changes in regional cerebral blood flow (rCBF) (Chang et al, 1997; DeGeorge et al, 1991;…”

“The increments in k* could be completely blocked by chronic pretreatment with mianserin, a 5-HT2 receptor agonist that has been reported to block the 5-HT2 syndrome and the hyperthermia produced by DOI (Berendsen and Broekkamp, 1991; Mazzola-Pomietto et al, 1997).”

“…adrenergic a2-antagonist activity as well (Anji et al, 2000; Ashby et al, 1990; Blackshear and Sanders-Bush, 1982; Dijcks et al, 1991; Hoyer et al, 1995; PDSP, 2000; Pranzatelli, 1990; Rocha et al, 1994; Roth and Ciaranello, 1991; Roth et al, 2000; Sanders-Bush et al, 1987; Schreiber et al, 1995).”

“…brain (Ichikawa and Meltzer, 1995), brain extracellular dopamine and noradrenaline concentrations (Gobert and Millan, 1999), and dopamine turnover (Gaggi et al, 1997), and DOI will activate local g-aminobutyric acid (GABA) inputs to serotonergic neurons in the dorsal raphe nucleus (Liu et al,…”

“Finally, values for k* for both labeled palmitate and arachidonate were shown to be unaffected by two-fold increments in rCBF induced by hypercapnia in rats and monkeys (Chang et al, 1997; Yamazaki et al, 1994).”

“The robust increments in k* induced by 2.5 mg/kg i.p. DOI are accompanied by a few reductions in rCMRglc (Freo et al, 1991, 1992), which are ascribed to reduced neuronal spike activity (Ashby et al, 1990; Bloom, 1985; Cooper et al, 1996; Freo et al, 1991; Sokoloff, 1999). rCMRglc is a weighted…”

“…PLA2-mediated hydrolysis of unlabeled AA from the stereospecifically numbered (sn)-2 position of synaptic brain phospholipids (DeGeorge et al, 1991; Fonlupt et al, 1994; Grange et al, 1998; Jones et al, 1996), independent of changes in regional cerebral blood flow (rCBF) (Chang et al, 1997;…”

“…cases is probably due to mianserin-induced neuroplastic changes, rather than to physical blocking of 5-HT2 receptors by mianserin, as the brain mianserin concentration falls to less than 0.1% of its peak concentration within 24 h after i.p. injection (Dijcks et al, 1991; Sanders-Bush et al, 1987).”

“…of PLA2 activation by DOI and of 5-HT2A receptors could be further examined using DOI and altanserin, a selective 5-HT2A blocker (Hoyer et al, 1995; Leysen et al, 1988; PDSP Drug Database, 2000; Roth et al, 2000), or by studying DOI responses in a 5-HT2Areceptor knockout mouse (Lira et al, 2001).”

“Finally, we measured k* in response to 2.5 mg/kg i.p. DOI 24 h after mianserin administration (Arvidsson et al, 1986; Berendsen and Broekkamp, 1991; Sanders-Bush et al, 1987), by which time mianserin is known to be largely washed out from the brain (Dijcks et al, 1991; Sanders-Bush et al, 1987).”

“5-HT2 receptor activation can also inhibit glutamate release from rat cerebellar mossy fibers (Marcoli et al, 2001) and the release of acetylcholine in the hippocampus and neocortex (Feuerstein et al, 1996), which may explain DOI’s inhibition of rCMRglc (Freo et al, 1991, 1992).”

“Phosphorylation and interaction of the receptors with membrane G-proteins are altered (Hartman and Northup, 1996; Ozawa et al, 1994; Westphal et al, 1995), and both receptor types are functionally hyposensitive (MazzolaPomietto et al, 1997).”

“…other drugs effective in schizophrenia, depression, obsessive–compulsive disorder, and neurodegenerative disease are considered to act at serotonin (5-hydroxytryptamine) 5-HT2 receptors (Barnes and Sharp, 1999; Breier, 1995; Ramasubbu et al, 2000; Rauser et al, 2001; Reynolds, 2001; Thase, 2002).”

“…cases is probably due to mianserin-induced neuroplastic changes, rather than to physical blocking of 5-HT2 receptors by mianserin, as the brain mianserin concentration falls to less than 0.1% of its peak concentration within 24 h after i.p. injection (Dijcks et al, 1991; Sanders-Bush et al, 1987).”

“Although the significance of this pathway has not been investigated in detail, Qu et al. (2003) found that administration of 2.5 mg/kg DOI to rats led to significantly increased incorporation of [3H]AA in brain membranes.”

“Antipsychotic medications have a high affinity for dopamine D2 and/or serotonin 5-HT2A/C receptors, and both serotonin 5-HT2A/C receptors (Basselin et al., 2005a; Garcia & Kim, 1997; Qu et al., 2003) and dopamine D2 receptors (Basselin et al.”

“4), whereas acutely administered antagonists to M1,3,5 receptors (atropine), D2-like receptors (butaclamol, raclopride) or 5-HT2A/2C receptors (mianserin) did not markedly decrease baseline AA incorporation into the rat brain (Bhattacharjee et al., 2008; DeGeorge et al., 1991; Hayakawa et al., 2001; Qu et al., 2003).”

“…rats given drugs that act at receptors coupled a G-protein to PLA2 (Basselin et al, 2005a, b, 2003; Bhattacharjee et al, 2005; DeGeorge et al, 1991; Qu et al, 2003)Fcholinergic muscarinic M1,3,5, dopaminergic D2-like and serotonergic 5-HT2A/2C receptors (Axelrod, 1995; Bayon et al, 1997; Felder et…”

“…dose (1.5 mg/kg) than we previously used in rats (2.5 mg/kg) (Qu et al. 2003a) to reduce the extent of secondary activation, and the pattern of k* responses to 1.5 mg/kg DOI in SERT+/+ mice was comparable to the pattern following 1.0–2.5 mg/kg DOI in rats (Basselin et al. 2005; Qu et al. 2003a).”

“Through stimulation of the 5-HT2A receptor, psychedelics activate intracellular signaling pathways such as PLC, PLA, and Src [138, 139].”

“…(D1 and D2) and a1adrenergic receptors under different experimental conditions (Bymaster et al. 1996; Kapur and Remington 2001), many of which are coupled to cPLA2 activation and AA release (Vial and Piomelli 1995; Berg et al. 1998; Qu et al. 2003; Bhattacharjee et al. 2007; Rapoport et al. 2009).”

“…the sn-2 position of membrane phospholipids; additionally, there may be some downstream increases in k* via the activation of any of a number of receptor subtypes coupled to PLA2 (DeGeorge et al. 1991; Hayakawa et al. 2001; Qu et al. 2003; Rapoport 2003; Robinson et al. 1992; Weichel et al. 1999).”

“In-vitro studies show that 5HT2 receptors are coupled via G proteins to PLA2 activation (Axelrod, 1990 ; Felder et al. 1990 ; Qu et al. 2003) and it has been reported that fluoxetine treatment results in an increase in cytosolic PLA2 enzyme protein levels and activity in the rat brain (Rao et al.”

“…regional effects of other sensory stimuli as well as of drug induced neuroreceptor activation (Basselin et al., 2006a,b; Bhattacharjee et al., 2005; Qu et al., 2003a) in human subjects, under normal conditions and in diseases where neurotransmission via AA likely is disturbed (Hayakawa et al.,…”

“…for serotonergic drugs, as chronic LiCl administration has been reported to reduce the convulsant threshold to DOI (Williams and Jope 1995), an agonist to PLA2-coupled 5-HT2A/2C receptors (Felder et al. 1990; Qu et al. 2003) and to enhance DOI-induced locomotor activity (Moorman and Leslie 1998).”

“The former images PLA2-mediated signal transduction via AA in cell bodies or dendrites, whereas the latter reflects the energyconsuming firing of axonal terminals of these cell bodies (Qu et al, 2003; Rapoport, 2003; Sokoloff, 1999).”

“It may be relevant that blockade of phospholipase A2 (PLA2)-coupled serotonin 5-HT2A/C (Qu et al., 2003) and dopamine D2 (Myers et al., 2001) receptors, which are blocked by atypical antipsychotic medications, down-regulate PUFA turnover in rat brain.”

“The in vivo fatty acid method to image brain PLA2 signaling has been described elsewhere (DeGeorge et al, 1991; Hayakawa et al, 2001; Qu et al, 2003).”

“We have elaborated a method to image this AA signaling process in unanesthetized rodents (DeGeorge et al. 1991; Robinson et al. 1992; Rapoport 2001; Rapoport et al. 2001; Basselin et al. 2003; Qu et al. 2003; Rapoport 2003; Basselin et al. 2005a,b; Bhattacharjee et al. 2005).”

“5-HT2 receptors can activate phospholipase A2 via G-protein coupling, releasing ARA from phospholipids (50), which can modulate signal transduction, transcription, neuronal activity, apoptosis, and other brain processes (51).”

“…view of prior data demonstrating that the 5-HT2A/2C receptor can be coupled to PLA2 and regulate membrane DHA and AA turnover (Garcia and Kim, 1997; Qu et al., 2003), reductions in serotonin turnover in the rat PFC in the present study may be anticipated to alter 5-HT2A/2C receptor-mediated DHA…”

“…et al. 2006), suggests that D2 receptor-mediated signaling via AA contributes little to the basal value of k*. Blocking cholinergic muscarinic M1,3,5 or serotonergic 5-HT2A/2C receptors coupled to cPLA2 also had no effect on baseline values of k* (DeGeorge et al. 1991; Qu et al. 2003).”

“It remains to be seen whether the AA signal following activation of other receptors coupled to cPLA2, such as dopaminergic D2-like [7], serotonergic 5-HT2A/2C [55], and glutamatergic Nmethyl-D-aspartate receptors [3], also represent selective COX-2 mediated AA loss.”

“These receptors, like D2-receptors, can be coupled to cPLA2 to release AA from membrane phospholipid (Berg et al., 1998; Garcia and Kim, 1997; Kurrasch-Orbaugh et al., 2003; Qu et al., 2003).”

“Nicotine reduces arachidonate signal L Chang et al increased k* for AA in unanesthetized rats (Basselin et al, 2006a, b; Bhattacharjee et al, 2005; Qu et al, 2003).”