Histamine H3 receptor agonists decrease hypothalamic histamine levels and increase stereotypical biting in mice challenged with methamphetamine

Abstract

The effects of the histamine H(3) 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 H(3) 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 H(3) receptor agonists, effects which would appear to underlie the shift from METH-induced stereotypical sniffing to biting.

Fig. 1

Frequencies of stereotypy after a single administration of methamphetamine in mice pretreated with (R)-α-methylhistamine or vehicle. Values are shown as the mean ± SEM (n = 8). METH: methamphetamine (10 mg/kg, i.p.); 3MHA: 3 mg/kg (i.p.) (R)-α-methylhistamine; 10MHA: 10 mg/kg (i.p.) (R)-α-methylhistamine; Sal: saline (vehicle).

Fig. 2

Different types of stereotypical behavior in response to saline or methamphetamine in mice pretreated with (R)-α-methylhistamine or vehicle. Values are shown as the mean ± SEM (n = 8). N.D., not detected. METH: methamphetamine (10 mg/kg, i.p.). *P < 0.05, compared with the Saline challenge group (open column; Bonferroni/Dunn test). †P < 0.05, compared with the METH challenge group pretreated with 0 mg/kg (R)-α-methylhistamine (Bonferroni/Dunn test). ‡P < 0.05, compared with the METH challenge group pretreated with 3 mg/kg (R)-α-methylhistamine (Bonferroni/Dunn test).

Fig. 3

Frequencies of stereotypy after a single administration of methamphetamine in mice pretreated with 10 mg/kg imetit, 10 mg/kg immepip, or vehicle. Values are shown as the mean ± SEM (n = 6). METH: methamphetamine (10 mg/kg, i.p.); Sal: saline (vehicle). *P < 0.05, compared with corresponding group pretreated with saline or imetit.

Fig. 4

Different types of stereotypical behavior in response to saline or methamphetamine in mice pretreated with 10 mg/kg imetit, 10 mg/kg immepip, or vehicle. Values are shown as the mean ± SEM (n = 6). N.D., not detected. METH: methamphetamine (10 mg/kg, i.p.). *P < 0.05, compared with the Saline challenge group (open column; Bonferroni/Dunn test). †P < 0.05, compared with the METH challenge group pretreated with saline (Bonferroni/Dunn test).

Fig. 5

Hypothalamic histamine (A) and N^τ-methylhistamine content (B) in mice pretreated with 3 and 10 mg/kg (R)-α-methylhistamine. Values are shown as the mean ± SEM (n = 8). METH: methamphetamine (10 mg/kg, i.p.). **P < 0.01, compared with corresponding saline-challenged mice (Fischer’s PLSD test). †P < 0.05, compared with saline-pretreated subjects (Fischer’s PLSD test).

Fig. 6

Hypothalamic histamine (A) and N^τ-methylhistamine content (B) in mice pretreated with 10 mg/kg imetit and immepip. Values are shown as the mean ± SEM (n = 6). METH: methamphetamine (10 mg/kg, i.p.). **P < 0.01, compared with corresponding saline-challenged mice (Fischer’s PLSD test). †P < 0.05, †††P < 0.001, compared with saline-pretreated subjects (Fischer’s PLSD test).