Research reportProtective effects of cholecystokinin-8 on methamphetamine-induced behavioral changes and dopaminergic neurodegeneration in mice
Introduction
Abuse of methamphetamine (METH) is an extremely serious and growing global problem. Long-term abuse of METH may result in memory loss, aggression, psychotic symptoms and potential heart and brain damage [1], [2], [3]. Rodents administered single or repeated METH treatments serve as an animal model for METH abuse in humans, as they present abnormal behaviors including hyperlocomotion and repetitive and compulsive behavior [4]. Systemic administration of METH to rodents induces increased locomotor activity and behavioral sensitization, and these are replaced by stereotypic behavior and hyperthermia at higher doses [5], [6], [7]. Once initiated, the stereotypic behavior induced by METH can persist for several hours, depending on the dose [8]. It was hypothesized that the action of METH on the dopamine (DA) neuronal system may contribute to the augmentation of psychostimulant use [9], [10]. Studies have demonstrated that METH is neurotoxic to striatal DA terminals, exemplified by a significant reduction in striatal DA and tyrosine hydroxylase (TH). In addition, dopamine transporter (DAT), an integral membrane protein that removes dopamine from the synaptic cleft and deposits it into surrounding cells, significantly decreased in both METH-treated animals and abuser [2], [7], [11].
However, the precise mechanisms by which METH elicits neurotoxic effects are still being elucidated. A number of studies have shown that METH-induced neurotoxicity involve the interaction of several neurotransmitters, neuropeptides, and neurotrophic factors. Cholecystokinin (CCK), a gut–brain peptide, exerts a wide range of biological activities in the gastrointestinal tract and central nervous system (CNS). It was initially isolated from the porcine duodenum as a 33 amino acid peptide [12] and acts via the CCK1 and CCK2 receptor subtypes. A number of biologically active molecular variants were subsequently described, and the most abundant peptide present in the brain was shown to be CCK-8: Asp-Tyr (SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2 [13], [14], [15]. CCK-8 is involved in the regulation of feeding, pain perception, and learning and memory and possibly in the pathogenesis of anxiety and psychosis [16], [17], [18], [19], [20]. It modulates the release of several neurotransmitters, such as DA and gamma-aminobutyric acid (GABA), and possibly acts as a neurotransmitter/modulator [21], [22]. A subpopulation of the dopaminergic neurons in the ventral tegmental area (VTA) projecting to the nucleus accumbens (NAc) contains CCK as a co-transmitter. Changes in the activity of the DA system have been observed in pharmacological studies conducted on CCK receptor-deficient mice. The targeted genetic suppression of CCK2 receptors has been shown to increase the sensitivity of pre- and post-synaptic D2 receptors. Loonam et al. found that CCK regulated neurochemical responses to METH in the striatum [23], [24]. Additionally, there are reports on the role of CCK in DA-mediated behaviors, with different subregions of the NAc involved in different effects on DA-mediated locomotor activity [25]. Moreover, our previous results have shown that CCK-8 has anti-oxidative stress and anti-inflammatory effects [26], [27]. In addition, it produced neuroprotective effects in neuronal injury models. These data show that CCK-8 exhibits a pharmaco-therapeutic potential for treating METH-induced neurotoxicity in CNS.
The present study aimed to evaluate the effects of CCK-8 on METH-induced behavioral changes, including hyperlocomotion, behavioral sensitization, and stereotypical behavior. Furthermore, the effects of CCK-8 on high doses of METH-induced hyperthermia and dopamine neurotoxicity were investigated.
Section snippets
Animals
Male C57BL/6 mice, initially weighing 18–20 g, were purchased from Beijing Vital River Laboratory Animal Technology Co. Ltd., China. The animals were housed in a climate-controlled environment. Constant temperature (21 ± 2 °C), humidity (approximately 60%) and a 12 h light/dark cycle (lights on at 7:00 am) were maintained. Food and water were available ad libitum. All experiments were conducted according to the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory
Animal exclusion
The group sizes were unequal due to the loss of the cannula, injection leakage, or poor locomotor activity. A total of 18 out of 235 mice were not included in the statistical analyses due to the mislocation of the cannulae. A total of 41 mice were excluded because of cannula surgery failure or poor general activity. In total, 270 animals were evaluable.
Effects of CCK-8 on single METH administration induced hyper-locomotion in mice
As shown in Fig. 2, a dose of 1 mg/kg (i.p.) METH before testing produced a significant hyper-locomotion compared with the baseline locomotion in
Discussions
In all METH-treated groups, significant hypo-locomotion, behavioral sensitization, hyperthermia and stereotypic behavior were established. The present study shows that CCK-8 has protective effects against behavioral and histological changes induced by low and high doses of METH in mice. CCK-8 significantly attenuated the hypo-locomotion induced by a single low dose (1 mg/kg) of METH. Pre-treatment with CCK-8 significantly inhibited the development and expression of METH-induced behavioral
Acknowledgments
All authors contributed to the writing of the manuscript and approved the final version. This study was financially supported in part by the National Natural Science Foundation of China (nos. 81302618,81471822), the Training funds for Talent Project in Hebei Province (no. LJRC005), and the Natural Science Foundation of Hebei Province (nos. H2013206157, H2014206275).
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These authors contributed equally to this work.