In recent years, GABAB receptor agonist has received a considerable research interest for its extensive therapeutic implications associated with alcohol dependence , cocaine abuse [20, 29], nicotine [30, 31] and opiates addiction [32–34]. An involvement of GABAB receptor agonist in modulating dopaminergic effects related to opiates abuse have been reported by several previous studies [18, 34, 35], which is encouraging to consider the possibility that GABAB receptor agonist could play an important role in opiates addiction.
Baclofen, a potent GABAB receptor agonist was determined to attenuate morphine discriminative stimulus effects , inhibit morphine withdrawal signs [36, 37] and decreased morphine-induced hyperactivity in mice . However, its potential role in morphine sensitization in rats still remains to investigate further. From this perspective, in the present work, we determined to evaluate that the effect of baclofen on the development and expression of morphine-induced behavioral sensitization. In addition, extracellular DA release in NAc was also detected.
Baclofen reversed the behavioral sensitization to morphine in rats had been reported . However, in our study, we systemically evaluated the effect of baclofen on development and expression of morphine sensitization and dopamine release in NA in rats. The main finding of the present work is that repeated baclofen administration during 4-day consecutive morphine administration and 3-day withdrawal period inhibits the acquisition and expression of morphine sensitization and dopamine release in the shell of NAc, which are consistent with previous reports that the shell of NAc plays a critical role in the behavioral sensitization [27, 40].
Repeated administration of opiates can lead to increased locomotor activity which is called behavioral sensitization [41–44]. It has been widely recognized that behavioral sensitization plays an important role in drug addiction such as relapse [45, 46], compulsive drug-seeking [47–49]. Based on the crucial role of behavioral sensitization in drug addiction, it is necessary to investigate the effect of baclofen on morphine-induced behavioral sensitization which can also provide new insights into the understanding of potential mechanism underlying the morphine dependence. The present study confirmed that repeated morphine administration for 4 days in rat produces an increase in locomotion activity in response to an acute challenge of morphine following 3 days of withdrawal period, which was in agreement with preliminary studies [26, 50], suggesting the development of locomotion sensitization. Furthermore, our current findings showed that chronic treatment with different doses of baclofen significantly inhibited the development of behavioral sensitization induced by morphine. In addition, acute treatment of only high dose of baclofen has effect on morphine sensitization. The present study provides the evidence that the increased GABA release is really suppressed morphine-induced sensitization which suggested the possibility that GABA transmission plays a key role in sensitization.
There are substantial findings revealed that mesolimbic DAergic pathway might be involved in modulating behavioral sensitization , especially the nucleus accumbens which receives DAergic projection arising from DA neurons in the ventral tegmental area (VTA) [11, 13, 14, 52]. To detect the possible mechanism contribute to the inhibition of baclofen on behavioral sensitization following repeated exposure to morphine, we assessed the effect of baclofen on extracellular DA release in NAc. Results showed that, after 3 days withdrawal following repeated morphine administration, morphine challenge significantly increased extracellular DA release in NAc, consistent with the previous report . It is also found that pretreatment with baclofen significantly prevents enhancement of extracellular DA release in NAc induced by morphine challenge.
The NAc includes a medioventral shell region and a dorsolateral core region and receive dopaminergic and GABAergic projections from the VTA and other regions . Previous studies had shown that GABAB receptor activation in the VTA reduced the synaptic dopamine release in the NAc [7, 53]. Therefore, Activation of GABAB receptors localized on dopaminergic neurons in the VTA might be involved in the effect of baclofen in our study which attenuated both the development and expression of morphine sensitization and dopamine release in the shell of NAc. Moreover, GABAB receptors have been found in the NAc and other region. The effect of baclofen on acquisition and expression of morphine sensitization might be also induced by GABAB receptor activation in the shell of NAc.