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Table 4 Receptor/Ligand Data Supporting or Refuting Propensity of Clozapine & NDMC to Induce Hypothermia

From: A case report of acute hypothermia during initial inpatient clozapine titration with review of current literature on clozapine-induced temperature dysregulations

Receptor Author, year Conclusions
D1 Ogren SO, 1988 [36]
Salmi P, 1994 [37]
The D1/2 receptor agonist apomorphine and the D2 agonist pergolide induced hypothermia in rats, which was prevented by the use of sulpiride, a D2 antagonist.
Hypothermia produced by clozapine was fully antagonized by the selective D1 receptor antagonist SCH-23390.
D2 Zarrindast MR, 1989 [38]
Boulay D, 1999 [39]
Bromocriptine, a D2 agonist, caused dose-dependent decreases in the core body temperature of mice. This effect was mitigated by pretreatment with sulpiride
The preferential D2/3 receptor agonists 7-OH-DPAT and PD 128907 induced hypothermia in D2 (+/+) mice, but not in D2 knockout mice.
D3 Millan MJ, 1995 [40]
Perachon S, 2000 [41]
Varty GB, 1998 [42]
Similar to (+)-7-OH-DPAT, clozapine dose-dependently elicited hypothermia in rats. The D3-selective antagonist (+/−)-S 11566 blocked clozapine-induced hypothermia.
(+)-7-OH-DPAT was effective in inducing hypothermia in both D3 (+/+) and D3 knockout mice, suggesting the D3 receptor is not responsible for hypothermia.
Raclopride (D2/3 antagonist) blocked (+)-7-OH-DPAT induced hypothermia.
Alpha-1 Boschi G, 1987 [43] Phenothiazines, butyrophenones, and benzamides (alpha-1 antagonists) injected intraperitoneally demonstrated induced-hypothermia, whereas intracerebovascular administration did not. The administration of phenylephrine (alpha-1 agonist) attenuated hypothermia.
5HT1A Gudelsky GA, 1986 [44]
Abdel-Fattah AF, 1995 [45]
Neves G, 2008 [46]
The 5HT1A agonist 8-OH-DPAT induced dose-related decreased in temperature in rats.
Pindolol, a 5HT1A antagonist, suppressed tryptophan (serotonin precursor) induced hypothermia in pargyline-treated mice.
The hypothermia produced by the N-phenylpiperazine derivatives LASSBio-579 and LASSBio-581 was diminished by the 5-HT1A antagonist WAY 100635.
5HT2A/C Yamada J, 1995 [47]
Murphy TJ, 2019 [48]
Gudelsky GA, 1986 [44]
The centrally acting 5HT2A/C agonist I-2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) strongly inhibited haloperidol and chlorpromazine-induced hypothermia.
The selective 5HT2C agonist WAY-163909 inhibited ketamine-induced hypothermia, whereas DOI did not.
MK-212 (5HT2 agonist) induced hyperthermia, while mianserin (5HT2 antagonist) blocked hyperthermia caused by MK-212 in rats.
5HT7 Hedlund PB, 2010 [49]
Naumenko VS, 2011 [50]
LP-211 (5HT7 selective agonist) induced hypothermia in 5HT7 (+/+) mice, but not 5HT7 receptor knockout mice.
The selective 5HT7 receptor antagonist SB 269970 inhibited centrally administered LP-44 (5HT7 agonist) induced hypothermia. Intraperitoneal administration of LP-44 did not induce hypothermia.
M3 Black CE, 2001 [51]
Golding JF, 2018 [52]
M3 antagonism via hyoscine hydrobromide may induce hyperthermia through decreased skin conductance and vasoconstriction, reducing heat loss and sweating.
Neurotensin-1 receptor (NTS-1) Feifel D, 2010 [53] PD149163, a selective, brain-penetrating, NT1 receptor agonist produced hypothermia in rats.