Research ReportPeripheral electrical stimulation reversed the cell size reduction and increased BDNF level in the ventral tegmental area in chronic morphine-treated rats
Introduction
The mesolimbic dopamine system (MLDS) has been known as the neural substrate involved in opiate reinforcement and addiction (Koob et al., 1992, Shippenberg et al., 1993). It includes the dopaminergic neurons located in the VTA and their anterior projections to the limbic forebrain, for example, the nucleus accumbens (NAc) and the frontal cortex (Volkow and Li, 2005). Chronic administration of morphine produces a number of adaptive changes in the MLDS: a hypofunction of the dopaminergic neurons of the VTA (Diana et al., 1995, Bonci and Williams, 1997, Manzoni and Williams, 1999, Diana et al., 1999), a decrease of the content of neurofilament proteins (intermediate filament proteins specific to neurons) (Beitner-Johnson et al., 1992, Garcia-Sevilla et al., 2004), an impairment of the axonal transport in the VTA-NAc pathway (Beitner-Johnson and Nestler, 1993) and a reduction of the dopaminergic cell size in the VTA (Spiga et al., 2003, Sklair-Tavron et al., 1996). These modifications represent the opiate-induced neuronal plastic changes, which are believed to contribute to opiate addiction (Nestler, 2004, Nestler, 1997).
Previous results have shown that PES can suppress both morphine withdrawal syndrome (Liu et al., 2005, Han and Zhang, 1993) and morphine-induced CPP expression in rats (Shi et al., 2003, Shi et al., 2004, Chen et al., 2005), as well as heroin craving in the addicts (Zhang et al., 2000, Zhong et al., 2006). It seemed important to study whether PES can reverse chronic morphine-induced neuronal plasticity changes in the MLDS as above mentions. Thus, the first aim of the present study was to investigate if PES can accelerate the recovery of dopaminergic cell size reduction in the VTA induced by chronic morphine administration.
The morphological changes in the VTA dopaminergic neurons induced by chronic morphine exposure may indicate neural injury. In this context, neurotrophic factors could play a role in the prevention or protection of long-term changes in responses to the drug exposure. Indeed, direct infusion of brain-derived neurotrophic factor (BDNF) or related neurotrophins into the VTA can block morphine-induced biochemical and morphological changes in this brain region (Berhow et al., 1995, Sklair-Tavron et al., 1996). Moreover, in vivo study revealed that BDNF protected dopaminergic neurons in the substantia nigra against toxic effects of 6-hydroxydopamine ions (Baquet et al., 2005, Zheng et al., 2005) and stimulated their neuronal activity (Shen et al., 1994). Taken together, these results suggest that BDNF may implicate in regulating neuronal plasticity in the CNS (Shen et al., 1994, Gaiddon et al., 1996). Liang et al. (2002) has reported that 100 Hz PES increased the abundance of BDNF mRNA in the VTA and substantia nigra in a rat model of Parkinson's disease. And our second aim in the present study was to determine whether PES can increase the endogenous BDNF pathway along with the recovery of damaged dopaminergic neurons in the VTA of chronic morphine-treated rats. Nerve Growth Factor (NGF) was used as a control growth factor, since NGF was known not to be related with morphine-induced neuronal plasticity (Berhow et al., 1995).
Section snippets
Repeated 100 Hz PES accelerated the morphological recovery of the VTA dopaminergic neurons damaged by chronic morphine treatment
TH immunohistochemical staining was performed and the morphological changes of dopaminergic neurons in the VTA were measured as described in Experimental procedures. As shown in Fig. 1, chronic morphine treatment decreased the size of dopaminergic neurons in the VTA. The neuronal areas decreased by 34.5%, 17.8% and 44.0% respectively, 3 h, 24 h and 14 days after the last morphine injection compared to NS control groups (see Experimental procedures for the animal grouping). A two-way ANOVA for
Discussion
In the present study, we found for the first time that multiple 100 Hz PES could accelerate the recovery of morphine-induced morphological changes of dopaminergic neurons in the VTA. Our results showed that the cell size reduction induced by chronic morphine administration lasted for at least 14 days after morphine abstinence, which is consistent with the earlier studies (Sklair-Tavron et al., 1996, Spiga et al., 2003, Kalivas and Nakamura, 1999). The cell size of VTA dopaminergic neuron in
Subjects
Male Sprague–Dawley rats, weighing 180–220 g at the beginning of the experiment, were obtained from the Institute of Animal Research, Chinese Academy of Sciences, Beijing. They were housed four per chamber, in a standard 12:12-h light/dark cycle (light on at 07:00) with food and water ad libitum.
The room temperature was maintained at 22 ± 1 °C. The rats were habituated to the environment and handled daily for 5 days before the experiment. The experimental procedures were approved by the Committee
Acknowledgments
This work was supported by the National Basic Research Programme of China (2003-CB515407) and the center of excellence grant (P01 AT-002038-01A1) from NIH, USA.
References (53)
- et al.
Influence of neurotrophic factors on morphine- and cocaine-induced biochemical changes in the mesolimbic dopamine system
Neuroscience
(1995) - et al.
Neural substrates of opiate reinforcement
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(1983) - et al.
Repeated 2 Hz peripheral electrical stimulations suppress morphine-induced CPP and improve spatial memory ability in rats
Exp. Neurol.
(2005) - et al.
Neurofilament proteins and cAMP pathway in brains of mu-, delta- or kappa-opioid receptor gene knock-out mice: effects of chronic morphine administration
Neuropharmacology
(2004) - et al.
Suppression of morphine abstinence syndrome by body electroacupuncture of different frequencies in rats
Drug Alcohol Depend.
(1993) - et al.
Neural systems for behavioral activation and reward
Curr. Opin. Neurobiol.
(1999) - et al.
Neural substrates of opiate withdrawal
Trends Neurosci.
(1992) - et al.
Long-term high-frequency electro-acupuncture stimulation prevents neuronal degeneration and up-regulates BDNF mRNA in the substantia nigra and ventral tegmental area following medial forebrain bundle axotomy
Brain Res. Mol. Brain Res.
(2002) - et al.
Electroacupuncture attenuates morphine withdrawal signs and c-Fos expression in the central nucleus of the amygdala in freely moving rats
Brain Res.
(2005) Repeated episodic exposure to ethanol affects neurotrophin content in the forebrain of the mature rat
Exp. Neurol.
(2004)
Molecular mechanisms of opiate and cocaine addiction
Curr. Opin. Neurobiol.
Historical review: molecular and cellular mechanisms of opiate and cocaine addiction
Trends Pharmacol. Sci.
The neurotrophin hypothesis for synaptic plasticity
Trends Neurosci.
Differential effect of short-term REM sleep deprivation on NGF and BDNF protein levels in the rat brain
Brain Res.
Brain opioid-receptors are involved in mediating peripheral electric stimulation-induced inhibition of morphine conditioned place preference in rats
Brain Res.
Repeated peripheral electrical stimulations suppress both morphine-induced CPP and reinstatement of extinguished CPP in rats: accelerated expression of PPE and PPD mRNA in NAc implicated
Brain Res. Mol. Brain Res.
Electroacupuncture: mechanisms and clinical application
Biol. Psychiatry
Opiate reward: sites and substrates
Neurosci. Biobehav. Rev.
Suppression of morphine withdrawal by electroacupuncture in rats: dynorphin and kappa-opioid receptor implicated
Brain Res.
Different expression of brain-derived neurotrophic factor in the nucleus accumbens of alcohol-preferring (P) and -nonpreferring (NP) rats
Brain Res.
Delayed gene therapy of glial cell line-derived neurotrophic factor is efficacious in a rat model of Parkinson's disease
Brain Res. Mol. Brain Res.
Activity-dependent release of endogenous brain-derived neurotrophic factor from primary sensory neurons detected by ELISA in situ
J. Neurosci.
Brain-derived neurotrophic factor is required for the establishment of the proper number of dopaminergic neurons in the substantia nigra pars compacta
J. Neurosci.
Morphine and cocaine exert common chronic actions on tyrosine hydroxylase in dopaminergic brain reward regions
J. Neurochem.
Chronic morphine impairs axoplasmic transport in the rat mesolimbic dopamine system
Neuroreport
Neurofilament proteins and the mesolimbic dopamine system: common regulation by chronic morphine and chronic cocaine in the rat ventral tegmental area
J. Neurosci.
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