Abnormal behavior, striatal dopamine turnover and opioid peptide gene expression in histamine‐deficient mice

Abstract

Hypothalamic histaminergic neurons regulate a variety of homeostatic, metabolic and cognitive functions. Recent data have suggested a modulatory role of histamine and histamine receptors in shaping striatal activity and connected the histaminergic system to neuropsychiatric disorders. We characterized exploratory behavior and striatal neurotransmission in mice lacking the histamine producing enzyme histidine decarboxylase (Hdc). The mutant mice showed a distinct behavioral pattern during exploration of novel environment, specifically, increased frequency of rearing seated against the wall, jumping and head/body shakes. This behavioral phenotype was associated with decreased levels of striatal dopamine and serotonin and increased level of dopamine metabolite DOPAC. Gene expression levels of dynorphin and enkephalin, opioids released by medium spiny neurons of striatal direct and indirect pathways respectively, were lower in Hdc mutant mice than in control animals. A low dose of amphetamine led to similar behavioral and biochemical outcomes in both genotypes. Increased striatal dopamine turnover was observed in Hdc KO mice after treatment with dopamine precursor l‐Dopa. Overall, our study suggests a role for striatal dopamine and opioid peptides in formation of distinct behavioral phenotype of Hdc KO mice.

Kappa-opioid receptor-dependent changes in dopamine and anxiety-like or approach-avoidance behavior occur differentially across the nucleus accumbens shell rostro-caudal axis

“…In the caudal NAc shell, KOR activation not only significantly reduced dopamine release, but it also increased rearing behavior in a novel activity chamber and avoidance behavior in a light-dark box, and reduced locomotor activity in both a novel chamber and familiar open field. Increased rearing in a novel environment has been associated with reduced levels of dopamine in the striatum [38] and predicts subsequent high-level ethanol drinking [27]. We postulate that novelty-induced rearing may represent risk-taking or impulsivity.…”

Kappa-opioid receptor-dependent changes in dopamine and affective behavior occur differentially across the nucleus accumbens shell rostro-caudal axis

“…In the caudal NAc shell, KOR activation not only significantly reduced electrically stimulated dopamine release, but also increased rearing behavior in a novel activity chamber and anxiety-like or avoidance behavior in a light-dark box, and reduced locomotor activity in both a novel activity chamber and a familiar open field. Increased rearing in a novel environment has been associated with reduced levels of dopamine in the striatum (Abdurakhmanova et al, 2019) and, in ethanol-naïve rats, predicts subsequent high-level ethanol drinking (Pandey et al, 2019). Thus, we hypothesize that the novelty-induced rearing may represent increased risk-taking or impulsivity.…”

The mouse at the popcorn stage of development

“…Peripherally administered cannabinoid receptor agonists caused cerebellar‐type dysfunctions in motor coordination (Patel & Hillard, 2001) and intra‐cerebellar injections of these agents mimicked cerebellar lesions in pavlovian conditioning (Steinmetz & Freeman, 2020). Dopamine may also interact with glutamate in view of the excessive jumping reported in Glt1 mice deficient in the astrocytic glutamate transporter (Jia et al, 2021) and with histamine in view of the excessive jumping reported in Hdc mice deficient in histamine (Abdurakhmanova et al, 2019), both mentioned above, or else with GABA in view of popcorn‐like jumping in mice injected with high dose levels of the GABA A receptor agonist, alfaxalone (Siriarchavatana et al, 2016). The question therefore arises as to what extent biogenic amines contribute to this behaviour and whether the cerebellum and the basal ganglia are involved.…”

“…Murine strains genetically selected for high and low rearing responses differed in jumping frequency (van Abeelen & Schoones, 1977), in line with the hypothesis that popcorn jumping is associated with other behaviours. Excessive jumping has been described in several null mutants evaluated at various ages, including Glt1 mice deficient in the astrocytic glutamate transporter (Jia et al, 2021), Hdc mice deficient in histidine decarboxylase (Abdurakhmanova et al, 2019) and Shank2 mice deficient in multiple ankyrin repeat domains protein 2 (Won et al, 2012), but whether these models display differences in popcorn jumping from controls remains to be determined.…”