Research ReportSeptal nuclei critically mediate the development of behavioral sensitization to a single morphine injection in rats
Highlights
► Rats pretreated with a single morphine injection exhibited behavioral sensitization. ► Bilateral lesions of septal nuclei attenuated the development of sensitization. ► Septal lesions had no significant effects on the expression of sensitization. ► CPP to morphine remained intact in rats with septal lesions. ► Antinociceptive effects of morphine did not change in rats with septal lesions.
Introduction
The well documented manifestation of behavioral sensitization is the enhanced locomotor response to a subsequent injection following pre-exposure to addictive drugs (Chae et al., 2004, Damianopoulos and Carey, 1993). This behavioral demonstration of drug induced neuroplasticity is thought to be related to the increased susceptibility to drug reward and relapse (Matsuyama et al., 2011, Robinson and Berridge, 1993, Vanderschuren and Kalivas, 2000, Vezina and Leyton, 2009). We and others have recently demonstrated that even a single exposure to morphine is sufficient to induce long-lasting behavioral changes in rats, a finding that could shed fresh light on the process of neural sensitization at behavioral level (Bloise et al., 2007, Luo et al., 2010a, Vanderschuren et al., 2001).
In human addicts, the neural substrates underlying neural sensitization are also considered to be related to relapse and other drug-induced psychosis (Li and Wolf, 1997). This correlate has attracted increasing attention in delineating the anatomical substrates of behavioral sensitization induced by addictive drugs. Locomotor sensitization has long been thought to reflect a long-lasting form of neuroplasticity in some neural circuits in the brain, including nucleus accumbens (NAc), ventral tegmental area (VTA), basolateral amygdala, prefrontal cortex (PFC) and the hippocampus (Degoulet et al., 2008, Mickiewicz et al., 2010, Wolf, 2002).
Since 1950s when Olds and Milner first observed that rats actively pressed a lever to emit an electric stimulation through electrodes implanted into septal nuclei (Olds and Milner, 1954), septal region has been increasingly recognized as a critical brain region that is involved in reinforcement (Cazala et al., 1998, Prado Alcala et al., 1984). Septal nuclei hold intimate connections to reinforcement related brain regions, such as VTA and NAc, and are implicated in morphine, amphetamine, and phencyclidine abuse (Sheehan et al., 2004). Furthermore, septal nuclei are considered as a “pacemaker” of the hippocampus which is critically involved in the neuroplasticity of behavioral sensitization induced by morphine (Allen and Crawford, 1984, Brazhnik and Vinogradova, 1986, Farahmandfar et al., 2011, Miller and Groves, 1977). Septal region receives and outputs major information from and to hippocampus as well as the mesolimbic system, including VTA and indirectly NAc. Thus, the mesolimbic dopaminergic projections interact with the septo-hippocampal cholinergic information in situ and therefore may be involved in the regulation of the rewarding behaviors (Felten and Jozefowicz, 2003, Gong et al., 1995, Nair and Gonzalez-Lima, 1999). In the present study, we tested the hypothesis that septal nuclei were critically involved in morphine-induced behavioral sensitization. Septal nuclei lesions were applied to examine whether this manipulation impacted the development and expression of a single morphine treatment induced behavioral sensitization. In addition, in order to understand the selectivity of the observed effects of septal nuclei ablation on behavioral sensitization, parallel studies were conducted, including conditioned place preference test (CPP) and tail flick test. CPP is widely used for the assessment of the rewarding property of drugs (Bardo and Bevins, 2000, O'Dell and Khroyan, 2009) and was used in the current study to examine the impact of septal lesion on associative learning related to contextual cue and morphine (differential conditioning with morphine and vehicle and choice test). In this regard, although the context plays an important role in the development and expression of behavioral sensitization (Robinson and Berridge, 2003), sensitization is in essence a non-associative learning process (Sanchis-Segura and Spanagel, 2006).
Section snippets
Experiment 1 — a single morphine injection induced behavioral sensitization in rats
Fig. 1 shows the acute effects of morphine injection on locomotor activity in rats. We observed that low or intermediate doses of morphine (1, 3, 10 mg/kg) induced hyperactivity peaked at different time-points within 240 min, while the highest dose of morphine (30 mg/kg) showed an initial depressant effect that reverted to hyperactivity from approximately 3 h after treatment. The inset (Fig. 1) compared the total distance traveled by rats in 4 h [F (4, 30) = 5.996, p < 0.01], indicating an enhancement
Discussion
The present study provides several interesting findings for our understanding of the neural substrates contributing to behavioral sensitization. First, a single injection with morphine was sufficient to induce behavioral sensitization in rats. Second, lesions of septal nuclei before the development phase completely eliminated the establishment of behavioral sensitization in rats pretreated with morphine. Such an effect disappeared when the lesions were carried out after morphine pretreatment.
Animals
Male Sprague–Dawley (SD) rats, initially weighing 180–200 g, were obtained from the Center of Laboratory Animal Science, Academy of Military Medical Sciences, Beijing, China. The animals were housed in groups of four to five in clear plastic cages with free access to water and food in a room that was kept at a constant temperature (22 ± 2 °C) and humidity (50 ± 20%) and on a 12/12 h light/dark cycle (light on at 08:00 h). Rats were allowed at least 5 days of habituation before the start of the
Acknowledgments
This study was supported by the National Nature Science Foundation of China, no. 30870894, the National Basic Research Program of China, no. 2009CB522000, and the National Key Technology R&D Program in the 12th Five Year Plan of China, no. 2011BAK04B08. AJL is a Principal Research Fellow supported by the National Health & Medical Research Council (Australia).
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