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  • br Acknowledgment br Introduction Positive and


    Introduction Positive and negative reinforcement are known as the two pivotal components in various models of drug dependence. Compulsive drug seeking behavior results from both the euphoric effects of drug use (positive reinforcement) and the unpleasant withdrawal signs following cessation of drug taking (negative reinforcement). Previous studies have shown that locus coeruleus (LC) nucleus, bilaterally located along the ventrolateral side of the fourth ventricle (1,2), is involved in development of opiate dependence (3,4). LC is the main noradrenergic 5-Methoxy-UTP structure and contains a homogenous population of neurons which highly express µ-opioid receptors (5). LC neurons spontaneously fire at the frequency of 0.5-5 Hz and various factors could affect the level of discharge rate in these neurons (6). Also, LC plays a key role in modulating various physiological functions including drug dependence through adjusting the firing rate (7,8). It has been shown that both acute and long-term morphine exposure affect the cellular and molecular mechanisms within the LC neurons (5,9,10). Acute opioid administration significantly suppresses the spontaneous discharge rate of LC (11) Following long-term administration, although the frequency of discharge rate is brought back to the control level (11), LC neurons undergo remarkable intracellular changes compared to the untreated cells. In this regard, it has been demonstrated that these neurons elicit a more significant hyperactivity following naloxone-precipitated opioid withdrawal (12). Aside from the opioid effects, the intrinsic and extrinsic excitatory factors have also been shown to increase the spontaneous discharge rate in LC neurons. For example, lateral hypothalamus sends widespread orexinergic inputs to LC region (13,14). Orexin neuropeptides (orexin-A and orexin-B) mediate a wide variety of physiological processes ([15], [16], [17], [18], [19], [20]). Two types of orexin receptors have been identified throughout the brain (OX1R and OX2R). Of these, OX1R is highly expressed in LC neurons (21,22). The activity of orexinergic afferents in this brain region is involved in development of dependence to opioid effects (23). Also, several lines of studies have independently reported the involvement of orexin and glutamate receptors in morphine dependence ([24], [25], [26]). However, the interaction between the activity of orexinergic system and glutamatergic neurons provides a more profound understanding and mechanistic insight towards the situation (Tose et al. 2009). This interaction has been shown to play a role in expression of behavioral manifestations associated with opioid dependence (27). It has been reported that 50% of orexinergic neurons express vesicular glutamate transporter (VGLUT) mRNA (28). Also, Orexin-A can modulate glutamatergic transmission by both pre- and post-synaptic mechanisms (29). Borgland et al., have demonstrated that orexin neuropeptides can enhance the expression of N-methyl-D-aspartate (NMDA) receptors (30). Moreover, intracerebroventricular (i.c.v.) administration of orexin-A increases glutamate release from LC neurons (31,32). Several lines of evidence support the involvement of coerulear glutamatergic activity in development of opioid dependence. For example, intra-LC microinjection of NMDA receptor antagonists have been shown to attenuate opioid dependence in rats (33). Consistently, superfusion of glutamate on LC neurons results in significant increase in spontaneous firing rate (34). Regarding the role of both orexin and glutamate in modulating the firing rate of LC neurons, the present study was designed to investigate the modulatory effects of orexin and glutamate on firing discharge of LC neurons in both naïve and morphine dependent rats.
    Materials and methods
    Discussion Among various neural networks underlying development of dependence to opioid effects, orexinergic projections from hypothalamus to the locus coeruleus (LC) have been widely studied during the last decade (38). Although, an extensive body of evidence supports the excitatory effect of orexin on LC neurons (39), the precise cellular mechanisms still remains to be unveiled. Regarding the significant role of glutamate on cellular mechanisms of orexin effects, the present study was designed to investigate the interaction between the effect of orexin-A and glutamate in LC neurons of morphine dependent rats. To achieve this, acutely prepared brain slices containing LC neurons were superfused by orexin (group 1), glutamate (group 2) and orexin plus glutamate (group 3) for 5 min in both morphine dependent and non-dependent animals.