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M5 Muscarinic Receptors Mediate Striatal Dopamine Activation by Ventral Tegmental Morphine and Pedunculopontine Stimulation in Mice  [PDF]
Stephan Steidl, Anthony D. Miller, Charles D. Blaha, John S. Yeomans
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027538
Abstract: Opiates, like other addictive drugs, elevate forebrain dopamine levels and are thought to do so mainly by inhibiting GABA neurons near the ventral tegmental area (VTA), in turn leading to a disinhibition of dopamine neurons. However, cholinergic inputs from the laterodorsal (LDT) and pedunculopontine (PPT) tegmental nucleus to the VTA and substantia nigra (SN) importantly contribute, as either LDT or PPT lesions strongly attenuate morphine-induced forebrain dopamine elevations. Pharmacological blockade of muscarinic acetylcholine receptors in the VTA or SN has similar effects. M5 muscarinic receptors are the only muscarinic receptor subtype associated with VTA and SN dopamine neurons. Here we tested the contribution of M5 muscarinic receptors to morphine-induced dopamine elevations by measuring nucleus accumbens dopamine efflux in response to intra-VTA morphine infusion using in vivo chronoamperometry. Intra-VTA morphine increased nucleus accumbens dopamine efflux in urethane-anesthetized wildtype mice starting at 10 min after infusion. These increases were absent in M5 knockout mice and were similarly blocked by pre-treatment with VTA scopolamine in wildtype mice. Furthermore, in wildtype mice electrical stimulation of the PPT evoked an initial, short-lasting increase in striatal dopamine efflux, followed 5 min later by a second prolonged increase in dopamine efflux. In M5 knockout mice, or following systemic pre-treatment with scopolamine in wildtype mice, the prolonged increase in striatal dopamine efflux was absent. The time course of increased accumbal dopamine efflux in wildtype mice following VTA morphine was consistent with both the prolonged M5-mediated excitation of striatal dopamine efflux following PPT electrical stimulation and accumbal dopamine efflux following LDT electrical stimulation. Therefore, M5 receptors appear critical for prolonged PPT excitation of dopamine efflux and for dopamine efflux induced by intra-VTA morphine.
Repeated Exposure to Methamphetamine, Cocaine or Morphine Induces Augmentation of Dopamine Release in Rat Mesocorticolimbic Slice Co-Cultures  [PDF]
Takayuki Nakagawa,Yuichi Suzuki,Kazuki Nagayasu,Maiko Kitaichi,Hisashi Shirakawa,Shuji Kaneko
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0024865
Abstract: Repeated intermittent exposure to psychostimulants and morphine leads to progressive augmentation of its locomotor activating effects in rodents. Accumulating evidence suggests the critical involvement of the mesocorticolimbic dopaminergic neurons, which project from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex, in the behavioral sensitization. Here, we examined the acute and chronic effects of psychostimulants and morphine on dopamine release in a reconstructed mesocorticolimbic system comprised of a rat triple organotypic slice co-culture of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex regions. Tyrosine hydroxylase-positive cell bodies were localized in the ventral tegmental area, and their neurites projected to the nucleus accumbens and medial prefrontal cortex regions. Acute treatment with methamphetamine (0.1–1000 μM), cocaine (0.1–300 μM) or morphine (0.1–100 μM) for 30 min increased extracellular dopamine levels in a concentration-dependent manner, while 3,4-methylenedioxyamphetamine (0.1–1000 μM) had little effect. Following repeated exposure to methamphetamine (10 μM) for 30 min every day for 6 days, the dopamine release gradually increased during the 30-min treatment. The augmentation of dopamine release was maintained even after the withdrawal of methamphetamine for 7 days. Similar augmentation was observed by repeated exposure to cocaine (1–300 μM) or morphine (10 and 100 μM). Furthermore, methamphetamine-induced augmentation of dopamine release was prevented by an NMDA receptor antagonist, MK-801 (10 μM), and was not observed in double slice co-cultures that excluded the medial prefrontal cortex slice. These results suggest that repeated psychostimulant- or morphine-induced augmentation of dopamine release, i.e. dopaminergic sensitization, was reproduced in a rat triple organotypic slice co-cultures. In addition, the slice co-culture system revealed that the NMDA receptors and the medial prefrontal cortex play an essential role in the dopaminergic sensitization. This in vitro sensitization model provides a unique approach for studying mechanisms underlying behavioral sensitization to drugs of abuse.
Role of Corticotropin-Releasing Factor (CRF) Receptor-1 on the Catecholaminergic Response to Morphine Withdrawal in the Nucleus Accumbens (NAc)  [PDF]
Pilar Almela, Javier Navarro-Zaragoza, Juan-Antonio García-Carmona, Lucía Mora, Juana Hidalgo, María-Victoria Milanés, María-Luisa Laorden
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047089
Abstract: Stress induces the release of the peptide corticotropin-releasing factor (CRF) into the ventral tegmental area (VTA), and also increases dopamine (DA) levels in brain regions receiving dense VTA input. Since the role of stress in drug addiction is well established, the present study examined the possible involvement of CRF1 receptor in the interaction between morphine withdrawal and catecholaminergic pathways in the reward system. The effects of naloxone-precipitated morphine withdrawal on signs of withdrawal, hypothalamo-pituitary-adrenocortical (HPA) axis activity, dopamine (DA) and noradrenaline (NA) turnover in the nucleus accumbens (NAc) and activation of VTA dopaminergic neurons, were investigated in rats pretreated with vehicle or CP-154,526 (selective CRF1R antagonist). CP-154,526 attenuated the increases in body weight loss and suppressed some of withdrawal signs. Pretreatment with CRF1 receptor antagonist resulted in no significant modification of the increased NA turnover at NAc or plasma corticosterone levels that were seen during morphine withdrawal. However, blockade of CRF1 receptor significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin (ACTH) levels, DA turnover and TH phosphorylation at Ser40 in the NAc. In addition, CP-154,526 reduced the number of TH containing neurons expressing c-Fos in the VTA after naloxone-precipitated morphine withdrawal. Altogether, these results support the idea that VTA dopaminergic neurons are activated in response to naloxone-precipitated morphine withdrawal and suggest that CRF1 receptors are involved in the activation of dopaminergic pathways which project to NAc.
High-Frequency Stimulation of Nucleus Accumbens Changes in Dopaminergic Reward Circuit  [PDF]
Na Yan, Ning Chen, Honghua Zhu, Jianguo Zhang, Moira Sim, Yu Ma, Wei Wang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079318
Abstract: Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is a potential remedial therapy for drug craving and relapse, but the mechanism is poorly understood. We investigated changes in neurotransmitter levels during high frequency stimulation (HFS) of the unilateral NAc on morphine-induced rats. Sixty adult Wistar rats were randomized into five groups: the control group (administration of saline), the morphine-only group (systematic administration of morphine without electrode implantation), the morphine-sham-stimulation group (systematic administration of morphine with electrode implantation but not given stimulation), the morphine-stimulation group (systematic administration of morphine with electrode implantation and stimulation) and the saline-stimulation group (administration of saline with electrode implantation and stimulation). The stimulation electrode was stereotaxically implanted into the core of unilateral NAc and microdialysis probes were unilaterally lowered into the ipsilateral ventral tegmental area (VTA), NAc, and ventral pallidum (VP). Samples from microdialysis probes in the ipsilateral VTA, NAc, and VP were analyzed for glutamate (Glu) and γ-aminobutyric acid (GABA) by high-performance liquid chromatography (HPLC). The levels of Glu were increased in the ipsilateral NAc and VP of morphine-only group versus control group, whereas Glu levels were not significantly changed in the ipsilateral VTA. Furthermore, the levels of GABA decreased significantly in the ipsilateral NAc, VP, and VTA of morphine-only group when compared with control group. The profiles of increased Glu and reduced GABA in morphine-induced rats suggest that the presence of increased excitatory neurotransmission in these brain regions. The concentrations of the Glu significantly decreased while the levels of GABA increased in ipsilateral VTA, NAc, and VP in the morphine-stimulation group compared with the morphine-only group. No significant changes were seen in the morphine-sham stimulation group compared with the morphine-only group. These findings indicated that unilateral NAc stimulation inhibits the morphine-induced rats associated hyperactivation of excitatory neurotransmission in the mesocorticolimbic reward circuit.
The gamma-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens
Zhenyu Fu, Hongfa Yang, Yuqiang Xiao, Gang Zhao, Haiyan Huang
Behavioral and Brain Functions , 2012, DOI: 10.1186/1744-9081-8-20
Abstract: We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo.The present study demonstrated that morphine challenge (3?mg/kg, s.c.) obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5?mg/kg) significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3?days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge.Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse.Repeated morphine administration can induce the neurochemical effects including mainly protein components and neurotransmission adaptations in the brain, which results in behavioral response underlying opioid dependence [1]. There are abundant reports have shown that locomotion sensitization has been suggested to mimic the brain changes that occur in the human addict [1-3], so it is intriguing animal model used to study neural mechanisms related to opioid dependence [4,5]. Morphine administration can produce a robust enhancement of locomotor activity in mice [6,7]. However, it induced dramatically an initial decrease and then an increase in locomotor activity in rats [1,8]. Hence, investigation of sensitization in rats may be interesting to better understand the potential mechanisms resulting in opioid dependence.There are increasing findings have demons
Single dose of morphine produced a prolonged effect on dopamine neuron activities
Die Zhang, Hai Zhang, Guo-zhang Jin, Kehong Zhang, Xuechu Zhen
Molecular Pain , 2008, DOI: 10.1186/1744-8069-4-57
Abstract: Acute morphine treatment significantly increased not only the firing rate and firing population but also the power of slow oscillation of DA neurons in na?ve rats. These changes lasted at least for 3 days following the morphine treatment. During this period of time, responses of the DA neurons to subsequent morphine challenge were diminished. We further demonstrated a transient desensitization of opiate receptors as monitored by GTPγS binding to G-proteins. The present study provided first direct evidence for the temporal changes in the VTA DA neuron activities and opiate receptors desensitization.Prolonged VTA DA neuron activation and opiate receptors desensitization followed single morphine exposure may underlie the development of dependence and tolerance that may associate with the acute analgesic tolerance and acute addiction of morphine.Dopamine (DA) neurons in the ventral tegmental area (VTA) project primarily to the nucleus accumbens and the prefrontal cortex, forming the mesocorticolimbic system [1-3]. Like other drugs of abuse, morphine influence DA neurotransmission directly or indirectly[4,5]. Positive reinforcement of drugs of abuse is believed to be mediated through the activation of the mesocorticolimbic DA system[6]. Repeated exposure to morphine induce substantial adaptive changes in cellular and synaptic functions in the mesocorticolimbic DA system [7,8]. These adaptations are believed to play a critical role in the development of tolerance and dependence [9,10].Clinical and experimental evidences have revealed that a single exposure to morphine could induce rapid tolerance and dependence that may associate with acute addiction and analgesic tolerance [11-14]. Increased firing activity of VTA DA neurons in response to acute morphine administration has been reported [15-17]. However, the long-lasting effect and the time course (onset, duration, and dissipation) on the activity of VTA DA neurons and how this change may contribute to the single morphin
Concomitant Release of Ventral Tegmental Acetylcholine and Accumbal Dopamine by Ghrelin in Rats  [PDF]
Elisabet Jerlhag, Anna Carin Janson, Susanna Waters, J?rgen A. Engel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049557
Abstract: Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg) to the dopaminergic cells of the ventral tegmental area (VTA) and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.). Ghrelin receptors (GHS-R1A) are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg) to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating.
Alterations in Phosphorylated CREB Expression in Different Brain Regions following Short- and Long-Term Morphine Exposure: Relationship to Food Intake  [PDF]
Xiuhai Ren,Kabirullah Lutfy,Michael Mangubat,Monica G. Ferrini,Martin L. Lee,Yanjun Liu,Theodore C. Friedman
Journal of Obesity , 2013, DOI: 10.1155/2013/764742
Abstract: Background. Activation of the cyclic adenosine monophosphate (cAMP)/phosphorylated CREB (P-CREB) system in different brain regions has been implicated in mediating opioid tolerance and dependence, while alteration of this system in the lateral hypothalamus (LH) has been suggested to have a role in food intake and body weight. Methods. Given that opioids regulate food intake, we measured P-CREB in different brain regions in mice exposed to morphine treatments designed to induce different degrees of tolerance and dependence. Results. We found that a single morphine injection or daily morphine injections for 8 days did not influence P-CREB levels, while the escalating dose of morphine regimen raised P-CREB levels only in the ventral tegmental area (VTA). Chronic morphine pellet implantation for 7 days raised P-CREB levels in the LH, VTA, and dorsomedial nucleus of the hypothalamus (DM) but not in the nucleus accumbens and amygdala. Increased P-CREB levels in LH, VTA, and DM following 7-day treatment with morphine pellets and increased P-CREB levels in the VTA following escalating doses of morphine were associated with decreased food intake and body weight. Conclusion. The morphine regulation of P-CREB may explain some of the physiological sequelae of opioid exposure including altered food intake and body weight. 1. Introduction Drug addiction is a complex state induced by repeated drug exposure and characterized by compulsive drug-seeking and drug-taking behaviors, despite adverse consequences associated with such behaviors. The processes leading to addiction following drug use and abuse are manifested by adaptations in numerous neuronal circuits in the central nervous system and lead to dependence, tolerance/sensitization, and reinforcement/reward [1]. Opioids and other drugs of abuse affect several intracellular messenger systems that are implicated in the addiction process. The most studied of these is CREB, a transcription factor responsive to cAMP that is activated by phosphorylation at serine residue 133 by cAMP-dependent protein kinase A (PKA). Changes in the phosphorylation of CREB result in changes in transcription of genes that are dependent on activation of their CREs that are cis-acting enhancer elements on promoters of various genes [2, 3]. CREB is found in most tissues examined, with high levels in the brain [4] and is thought to be an important mediator in substance abuse [5, 6]. In many brain regions, acute administration of μ-opioid receptor agonists leads to the inhibition of adenylate cyclase with a resultant decrease in cAMP-dependent
Identification of Rat Ventral Tegmental Area GABAergic Neurons  [PDF]
Elyssa B. Margolis, Brian Toy, Patricia Himmels, Marisela Morales, Howard L. Fields
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042365
Abstract: The canonical two neuron model of opioid reward posits that mu opioid receptor (MOR) activation produces reward by disinhibiting midbrain ventral tegmental area (VTA) dopamine neurons through inhibition of local GABAergic interneurons. Although indirect evidence supports the neural circuit postulated by this model, its validity has been called into question by growing evidence for VTA neuronal heterogeneity and the recent demonstration that MOR agonists inhibit GABAergic terminals in the VTA arising from extrinsic neurons. In addition, VTA MOR reward can be dopamine-independent. To directly test the assumption that MOR activation directly inhibits local GABAergic neurons, we investigated the properties of rat VTA GABA neurons directly identified with either immunocytochemistry for GABA or GAD65/67, or in situ hybridization for GAD65/67 mRNA. Utilizing co-labeling with an antibody for the neural marker NeuN and in situ hybridization against GAD65/67, we found that 23±3% of VTA neurons are GAD65/67(+). In contrast to the assumptions of the two neuron model, VTA GABAergic neurons are heterogeneous, both physiologically and pharmacologically. Importantly, only 7/13 confirmed VTA GABA neurons were inhibited by the MOR selective agonist DAMGO. Interestingly, all confirmed VTA GABA neurons were insensitive to the GABAB receptor agonist baclofen (0/6 inhibited), while all confirmed dopamine neurons were inhibited (19/19). The heterogeneity of opioid responses we found in VTA GABAergic neurons, and the fact that GABA terminals arising from neurons outside the VTA are inhibited by MOR agonists, make further studies essential to determine the local circuit mechanisms underlying VTA MOR reward.
TRPC4 ion channel protein is selectively expressed in a subpopulation of dopamine neurons in the ventral tegmental area  [PDF]
Kurt R. Illig,Kristin C. Rasmus,Andrew L. Varnell,Eric M. Ostertag,William D. Klipec,Donald C. Cooper
Quantitative Biology , 2012, DOI: 10.1038/npre.2011.6577.1
Abstract: The nonselective cation channel TRPC4 has been shown to be present in high abundance in the corticolimbic regions of the brain and play a pivotal role in modulating cellular excitability due to their involvement in intracellular Ca2+ regulation. Recently we reported their involvement in socialization and regulating anxiety-like behaviors in rats. Given the important role for dopamine in modulating emotions involved in social anxiety we investigated whether TRPC4 protein and mRNA was found on dopaminergic neurons of the ventral tegmental area (VTA). Using emulsion autoradiography we found that TRPC4 mRNA is indeed present in the VTA and the substantia nigra. Additionally, immunohistochemistry verified it's presence on a subpopulation of dopamine neurons in the VTA. We confirmed these findings by testing Trpc4 knock-out rats in addition to wild-type animals. This novel finding suggests that TRPC4 plays a pivotal role in regulating dopamine release in a sub-population of neurons that may modulate emotional and cognitive responses in social situations.
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