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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.