Transcription and protein synthesis inhibitors reduce the induction of behavioural sensitization to a single morphine exposure and regulate Hsp70 expression in the mouse nucleus accumbens

Abstract

New protein synthesis has been implicated as necessary for long-lasting changes in neuronal function. Behavioural sensitization to a single exposure to addictive drugs is a form of neuroplasticity, but little is known about the importance of new protein synthesis in the underlying mechanism. This study was designed to investigate the effects of the transcription inhibitor actinomycin D (AD) and the protein synthesis inhibitor cycloheximide (CHX) on induction of behavioural sensitization to a single morphine exposure in mice. In combination with behavioural experiments, changes in gene and protein expression in the mouse nucleus accumbens (NAc) were analysed by RT-PCR array and Western blot respectively. Behavioural sensitization was evident in mice pretreated only once with morphine at the doses of 20 and 40 mg/kg, but not 5 and 10 mg/kg. Mice pretreated with morphine (20 mg/kg) and challenged with a lower dose (5 mg/kg) after a period of 4-21 d washout showed sensitized locomotion. At the doses that did not affect locomotion in mice, AD or CHX significantly suppressed hyperactivity induced by acute treatment, but not challenge with morphine, and blocked induction of behavioural sensitization to a single morphine exposure in a dose-related manner. The results from RT-PCR array and Western blot indicated that the changes of Hsp70 expression in the NAc of mice were associated with behavioural sensitization induced by a single morphine exposure. Together, these findings suggest that induction of behavioural sensitization to a single morphine exposure requires new protein synthesis, potentially involving Hsp70 expression in the NAc of mice.

Morphine-induced conditioned place preference and effects of morphine pre-exposure in adolescent and adult male C57BL/6J mice

“…The locomotor-stimulating effects of 32 and 100 mg/kg morphine increased during repeated administration in the first experiment, consistent with other findings of locomotor sensitization after administration of morphine in rats (Vanderschuren et al 2001) and mice (Valjent et al 2010; Luo et al 2011; Koek 2013). These short-term effects of repeated administration of morphine on locomotion were similar in adolescents and adults, confirming and extending previous observations (Koek 2013).…”

Chaperone heat shock protein 70 in nucleus accumbens core: a novel biological target of behavioural sensitization to morphine in rats

“…Traditionally, behavioural sensitization was induced by repeated, intermittent drug exposures. Amazingly, even a single drug exposure, such as an exposure to amphetamine (Robinson et al, 1982;Vanderschuren et al, 1999), cocaine (Kalivas and Alesdatter, 1993), morphine (Vanderschuren et al, 2001;Jing et al, 2011;Luo et al, 2011;Qin et al, 2013) and nicotine (Bhatti et al, 2007) can also evoke behavioural sensitization. Although the extent of behavioural sensitization induced by a single drug exposure is not as profound as that induced by multiple drug exposures, the enduring behavioural and neurochemical consequences of single and repeated drug exposures appear to be highly comparable (Vanderschuren et al, 2001).…”

Comparison of single versus repeated methamphetamine injection induced behavioral sensitization in mice

“…For instance, repeated drug exposure with long intervals is more effective to induce sensitization as compared to chronic exposure to either high and/or escalating dosage with short intervals [17, 23]. Interestingly, even a single exposure to cocaine [5, 7], amphetamine [18, 22] and morphine [6, 10, 21] can produce long-lasting behavioral and neurochemical sensitization.…”

“…Not surprisingly, when the METH dose was further increased to 2 mg/kg, a higher sensitization was observed under both conditions. Previously, it has also been suggested that the mangnitude of sensitization was linearly related to the pretreatment dose in both single [10] or repeated treatment schedules [1] for morphine-induced behavioral sensitization. Kitanaka et al explored the functional alterations of monoaminergic neuronal systems in mice after single and repeated injection of METH, which showed that the degree and direction of modification of the monoaminergic metabolism depend on the treatment (single or repeated) and on the brain regions [8].…”