Elsevier

Brain Research

Volume 1182, 28 November 2007, Pages 90-98
Brain Research

Research Report
Peripheral electrical stimulation reversed the cell size reduction and increased BDNF level in the ventral tegmental area in chronic morphine-treated rats

https://doi.org/10.1016/j.brainres.2007.08.086Get rights and content

Abstract

Chronic morphine administration induces functional and morphological alterations in the mesolimbic dopamine system (MLDS), which is believed to be the neurobiological substrate of opiate addiction. Our previous studies have demonstrated that peripheral electrical stimulation (PES) can suppress morphine withdrawal syndrome and morphine-induced conditioned place preference (CPP) in rats. The present study was designed to investigate if PES could reverse the cell size reduction induced by chronic morphine treatment in the ventral tegmental area (VTA), which is an important area of the MLDS. Immunohistochemical observations showed that the cell size of dopaminergic neurons in the VTA reduced significantly in the chronic morphine-treated rats with a concomitant decrease in the number of BDNF-positive cells compared to the saline-treated rats. A much milder morphological change, accompanying with an increased number of BDNF-positive cells, was observed in dopaminergic neurons in the rats that received repeated 100 Hz PES after morphine withdrawal. In another experiment, enzyme-linked immunosorbent assay (ELISA) reconfirmed a significant up-regulation of BDNF protein level in the VTA in the rats received 100 Hz PES after morphine abstinence. These results indicate that PES could facilitate the morphological recovery of the VTA dopaminergic cells damaged by chronic morphine treatment and up-regulate the BDNF protein level in the VTA. Activation of endogenous BDNF by PES may play a role in the recovery of the injured dopaminergic neurons in the morphine addictive 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.

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