Research ReportHistamine-dependent behavioral response to methamphetamine in 12-month-old male mice
Research highlights
► MA increased activity in the elevated zero maze the shock-startle. ► MA increased activity and measures of anxiety more in Hdc−/− than Hdc+/+ mice. ► MA had opposite effects on performance of Hdc−/− and Hdc+/+ mice in the zero maze. ► MA similarly increased the shock-startle response in Hdc−/− and Hdc+/+ mice.
Introduction
According to the National Institute on Drug Abuse (NIDA), the prevalence of methamphetamine (MA) abuse is problematic across the United States (Maxwell, 2005). MA is a schedule II drug; it is a white, odorless and bitter-tasting crystalline powder most commonly smoked or taken orally. This addictive stimulant leads to several side effects including insomnia, irritability, and increased anxiety (Anglin et al., 2000, Brecht et al., 2004, Ernst et al., 2000, Sulzer et al., 2005). Certain individuals appear to be more susceptible to the side effects associated with first-time and repeated MA use (Cruickshank and Dyer, 2009). Due to high rates of polydrug use and environmental exposures associated with MA production and use, these effects are hard to study in controlled experiments with humans. Therefore, rodent models are used to examine potential physiological or genetic modulators that may explain different responses to MA use.
Animal studies have established that there are dose-dependent responses to acute and repeated MA administration at 1 mg/kg, resulting in increased locomotion and stereotypic behavior (Brien et al., 1978, Itzhak, 1997, Milesi-Halle et al., 2005). Most commonly, 3- to 6-month-old mice have been used in animal studies of MA-induced behavioral changes (Fukushima et al., 2007, Watanabe and Yanai, 2001). Age-dependent analyses indicate that 6-month-old mice display the highest sensitivity to MA at first administration and the lowest sensitivity after repeated administration compared to younger mice (Kuribara et al., 1996). Little is known about the potential effects of MA in 12-month-old mice. As age also appears to modulate MA-related neuronal effects (Sabol et al., 2000), more studies are needed in older mice in order to further understand the mechanisms of response.
Histamine (HA) is produced in the posterior hypothalamus (Miklos and Kovacs, 2003, Panula et al., 1984, Panula et al., 1989), where histidine decarboxylase (HDC) converts l-histidine to HA (Ohtsu et al., 2001). HA is distributed through an extensive network of fibers projecting to various regions of the central nervous system, including the cerebral cortex, amygdala, and hippocampus (Brown et al., 2001, Haas and Panula, 2003, Nakamura et al., 2004). Neuronal HA functions as a neurotransmitter through three post-synaptic (H1, H2, and H4) receptors and one pre-synaptic (H3) receptor (Hill et al., 1997). The H3 receptor (H3R) functions as a negative feedback; i.e., stimulation of H3R inhibits HA release. HA has been shown to regulate the effects of MA in the rat brain (Ito et al., 1996, Ito et al., 1997a, Ito et al., 1997b). In addition, repeated administration of MA increases HDC activity in the striatum and cortex in rats and HA levels peak at 60 min post-injection (Ito et al., 1996). In mice, MA leads to the release of HA in various brain regions, including the cortex and striatum, with peak HA levels at 60 min post-injection (Dai et al., 2004). In male mice younger than 5 months of age, HA and its precursor, l-histidine, inhibit MA-induced stereotyped behavior and behavioral sensitization to MA. These effects are blocked in the presence of H1 or H2 receptor antagonists (Kitanaka et al., 2007, Kitanaka et al., 2010, Onodera et al., 1998). Antagonism of the H3R enhances MA-induced stereotypic hyperactivity in young male mice (Munzar et al., 1998, Okuda et al., 2009, Toyota et al., 2002). To study the effects of long-term HA deficiency, HDC targeted ES cell-mediated gene knockouts (Hdc−/−) mice were produced that have only minimal levels of HA remaining in their organs due to diet and/or HA-producing bacteria in the gut (Ohtsu et al., 2001). Young (less than 3 months old) male Hdc−/− mice, which have little or no neuronal HA (Ohtsu et al., 2001), show enhanced MA-induced locomotor activity and behavioral sensitization at 60 min post-injection (Kubota et al., 2002). These data support a strong association between MA and HA in young mice, but it is unclear whether such an association also exists in older mice.
Both young and old male Hdc−/− mice are more anxious than wild-type (Hdc+/+) mice with heightened sensitivity in younger mice (Acevedo et al., 2006, Dere et al., 2003, Dere et al., 2004). In addition, when comparing Hdc−/− mice to their wild-type counterparts, the former display age-dependent impairments in object recognition, spatial memory retention in water-maze probe trials and memory retention in the passive avoidance test (Acevedo et al., 2006). Therefore, age should be considered as a factor when examining the response to drugs such as MA that may impair cognitive ability. Currently, there are no studies on the effects of MA in Hdc−/− mice older than 6 months.
The aim of this study was to determine the effects of acute and repeated MA administration on behavioral performance in the open field and elevated zero-maze and the shock-startle response in 12-month-old Hdc+/+ and Hdc−/− mice.
Section snippets
Body weight
At 12 months of age, mice were injected daily with MA (1 mg/kg) or saline (SA). During the injection period, there were no effects of MA on body weights of the mice (Table 1).
MA-related open-field behavior of 12-month-old Hdc+/+ mice
The effect of daily MA or SA administration on open-field behavior in Hdc+/+ mice was assessed 30 min and 60 min post-injection. A repeated measures (REM) analysis of variance (ANOVA) for time-by-treatment effects across days was conducted for all open field measures. There was an overall effect of treatment for active time (F
Discussion
As MA use is of growing concern, understanding the initial response to the drug may help in understanding why only some individuals become addicted to it. There are many factors to consider including age and genetic predisposition. This study examined older mice (12-month-old) to compare to previous studies in <6-month-old mice (Brien et al., 1978, Fukushima et al., 2007, Itzhak, 1997, Kuribara et al., 1996, Milesi-Halle et al., 2005, Watanabe and Yanai, 2001). Not every individual develops the
Animals
Homozygous mice lacking exons 6–8 and part of exon 9 of the HDC gene (Hdc−/−) male mice, generated as described (Ohtsu et al., 2001) using homozygous mating, were backcrossed onto the C57Bl6/J (Hdc+/+) background for six generations. The mice were 12 months old at the time of testing. The mice were kept on a 12:12 h light/dark schedule (lights on at 6 AM) with chow (PicoLab Rodent Diet 20, #5053; PMI Nutrition International, St. Louis, MO) and water given ad libitum. To maintain stable weights,
Acknowledgments
This work was supported by a pilot project funded by the Methamphetamine Abuse Research Center of OHSU (1P50DA018165), an Oregon State Tartar fellowship and NIDA training grant (T32 DA07262). We would like to thank Timothy Pfankuch for his assistance with the behavioral testing. We thank Dr. Hiroshi Ohtsu for generously providing histidine decarboxylase (HDC) deficient and wild-type mice.
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2020, Neuroscience LettersCitation Excerpt :Such a genotype difference in rotation could indicate a difference in lesion extent [18]; however, no difference was found in TH-positive immunostaining remaining in the SNc. The present behavioral observation is in line with some previous studies using unlesioned mice: methamphetamine has been reported to induce more locomotor activity in HDC KO than wildtype mice [19,20]. However, other studies have observed attenuated [21] or unchanged [22] amphetamine-induced motor activity in unlesioned HDC KO mice.
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Current Address: Departments of Physiology, Pharmacology and Toxicology, Psychology Program, Ponce School of Medicine and Health Science, Ponce, Puerto Rico 00732.