Histamine H3 Receptor Agonists Decrease Hypothalamic Histamine Levels and Increase Stereotypical Biting in Mice Challenged with Methamphetamine

Abstract

The effects of the histamine H3 receptor agonists (R)-α-methylhistamine, imetit and immepip on methamphetamine (METH)-induced stereotypical behavior were examined in mice. The administration of METH (10 mg/kg, i.p.) to male ddY mice induced behaviors including persistent locomotion and stereotypical behaviors, which were classified into four categories: stereotypical head-bobbing (1.9%), circling (1.7%), sniffing (14.3%), and biting (82.1%). Pretreatment with (R)-α-methylhistamine (3 and 10 mg/kg, i.p.) significantly decreased stereotypical sniffing, but increased stereotypical biting induced by METH, in a dose-dependent manner. This effect of (R)-α-methylhistamine on behavior was mimicked by imetit or immepip (brain-penetrating selective histamine H3 receptor agonists; 10 mg/kg, i.p. for each drug). Hypothalamic histamine levels 1 h after METH challenge were significantly increased in mice pretreated with saline. These increases in histamine levels were significantly decreased by pretreatment with histamine H3 receptor agonists, effects which would appear to underlie the shift from METH-induced stereotypical sniffing to biting.

Molecular Landscape of Tourette’s Disorder

“…Moreover, the histamine precursor histidine was shown to promote astrocyte migration and provide neuroprotection through HRH2 [ 276 ]. Histidine and HNMT inhibitors also ameliorated methamphetamine-induced stereotyped behavior and behavioral sensitization in rodent models, while HDC inhibitors and HRH2 antagonists enhanced this behavior [ 277 , 278 , 279 , 280 , 281 , 282 , 283 ]. As histamine does not cross the BBB [ 284 ], a potential strategy to increase the brain levels of histamine—that could then bind and signal through HRH2—would be to provide additional histidine through the diet.…”

Brain Histamine N-Methyltransferase as a Possible Target of Treatment for Methamphetamine Overdose

“…In addition, pretreatment with histamine H 3 receptor (autoreceptor) agonists such as (R)-a-methylhistamine, imetit, and immepip decreased hypothalamic histamine levels and increased the frequency of METH-induced stereotypical biting. 86 Moreover, it was noted that there was a very strong negative correlation (r = -0.918, P , 0.001) between the frequency of METH-induced stereotypical biting and hypothalamic histamine levels, suggesting that activation of brain histaminergic system may suppress high-dose behavioral effects of METH, and might consequently reduce high-dose effects associated with the progression to drug dependence and acute overdose. 87…”

Brain Histamine N-Methyltransferase as a Possible Target of Treatment for Methamphetamine Overdose

“…In addition, pretreatment with histamine H 3 receptor (autoreceptor) agonists such as ( R )-α-methylhistamine, imetit, and immepip decreased hypothalamic histamine levels and increased the frequency of METH-induced stereotypical biting. 86 Moreover, it was noted that there was a very strong negative correlation ( r = –0.918, P < 0.001) between the frequency of METH-induced stereotypical biting and hypothalamic histamine levels, suggesting that activation of brain histaminergic system may suppress high-dose behavioral effects of METH, and might consequently reduce high-dose effects associated with the progression to drug dependence and acute overdose. 87…”