Ultrastructural localization of enkephalin and μ-opioid receptors in the rat ventral tegmental area

Garzón, Miguel; Pickel, Virginia M.

doi:10.1016/s0306-4522(02)00249-x

Cited by 29 publications

(19 citation statements)

References 111 publications

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“…As mentioned previously, our results indicate that endogenous enkephalins play an important role in mediating the rewarding properties of nicotine. Enkephalinergic interneurons as well as enkephalinergic inputs from the NAc are present in the VTA (Garzó n and Pickel, 2002). Therefore, we suggest that nicotine could induce, by a direct mechanism or indirectly through glutamate transmission (Isola et al, 2000), a release of endogenous opioid peptides derived from preproenkephalin.…”

Section: Discussionmentioning

confidence: 84%

Nicotine-Induced Antinociception, Rewarding Effects, and Physical Dependence Are Decreased in Mice Lacking the Preproenkephalin Gene

Berrendero¹,

Mendizábal²,

Robledo³

et al. 2005

J. Neurosci.

127

119

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It has been shown previously that the endogenous opioid system may be involved in the behavioral effects of nicotine. In the present study, the participation of endogenous enkephalins on nicotine responses has been investigated by using preproenkephalin knock-out mice. Acute nicotine-induced hypolocomotion remained unaffected in these mice. In contrast, antinociception elicited in the tailimmersion and hot-plate tests by acute nicotine administration was reduced in mutant animals. The rewarding properties of nicotine were then investigated using the place-conditioning paradigm. Nicotine induced a conditioned place preference in wild-type animals, but this effect was absent in knock-out mice. Accordingly, in vivo microdialysis studies revealed that the enhancement in dopamine extracellular levels in the nucleus accumbens induced by nicotine was also reduced in preproenkephalin-deficient mice. Finally, the somatic expression of the nicotine withdrawal syndrome precipitated in nicotine-dependent mice by mecamylamine was significantly attenuated in mutant animals. In summary, the present results indicate that endogenous opioid peptides derived from preproenkephalin are involved in the antinociceptive and rewarding properties of nicotine and participate in the expression of physical nicotine dependence.

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Section: Discussionmentioning

confidence: 84%

Nicotine-Induced Antinociception, Rewarding Effects, and Physical Dependence Are Decreased in Mice Lacking the Preproenkephalin Gene

Berrendero¹,

Mendizábal²,

Robledo³

et al. 2005

J. Neurosci.

127

119

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“…This upregulation of MORs is essential, since genetic MOR knockout mice do not exhibit social defeat stress-induced social avoidance (Komatsu et al, 2011), and MOR knockdown in rat VTA prevents cross-sensitization to amphetamine (Johnston et al, 2011). In the VTA, MORs are expressed by GABA neurons (Sesack and Pickel, 1995; Garzon and Pickel, 2002), which are hyperpolarized in response to MOR stimulation, and act to disinhibit VTA dopamine transmission (Johnson and North, 1992; Bergevin et al, 2002; Vargas-Perez et al, 2009). In fact, enhancement of VTA MOR expression (Nikulina et al, 2005; Nikulina et al, 2008) coincides with social defeat stress-induced cross-sensitization to psychomotor stimulants (Covington and Miczek, 2001; Nikulina et al, 2004; Nikulina et al, 2012), suggesting that GABAergic MORs in the VTA may mediate stress-induced psychomotor sensitization (Figure 2).…”

Section: Vta Bdnf and Stress-induced Vulnerability To Drugs Of Abusementioning

confidence: 99%

Neurotrophins in the ventral tegmental area: Role in social stress, mood disorders and drug abuse

Nikulina¹,

Johnston²,

Wang³

et al. 2014

Neuroscience

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This review discusses the impact of neurotrophins and other trophic factors, including fibroblast growth factor and glial cell line-derived neurotrophic factor, on mood disorders, weight regulation and drug abuse, with an emphasis on stress- and drug-induced changes in the ventral tegmental area (VTA). Neurotrophins, comprising nerve growth factor, brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4/5 play important roles in neuronal plasticity and the development of different psychopathologies. In the VTA, most research has focused on the role of BDNF, because other neurotrophins are not found there in significant quantities. BDNF originating in the VTA provides trophic support to dopamine neurons. The diverse intracellular signaling pathways activated by BDNF may underlie precise physiological functions specific to the VTA. In general, VTA BDNF expression increases after psychostimulant exposures, and enhanced BDNF level in the VTA facilitates psychostimulant effects. The impact of VTA BDNF on the behavioral effects of psychostimulants relies primarily on its action within the mesocorticolimbic circuit. In the case of opiates, VTA BDNF expression and effects seem to be dependent on whether an animal is drug-naïve or has a history of drug use, only the latter of which is related to dopamine mechanisms. Social defeat stress that is continuous in mice or intermittent in rats increases VTA BDNF expression, and is associated with depressive and social avoidance behaviors. Intermittent social defeat stress induces persistent VTA BDNF expression that triggers psychostimulant cross-sensitization. Understanding the cellular and molecular substrates of neurotrophin effects may lead to novel therapeutic approaches for the prevention and treatment of substance use and mood disorders.

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“…By contrast, knockdown of VTA MORs prevented social stress-induced cross-sensitization without blocking amphetamine-induced locomotion. VTA MORs are presynaptically expressed by GABA neurons (Garzon and Pickel, 2002; Sesack and Pickel, 1995), and when activated, reduce GABAergic inhibition of VTA DA neurons (Bergevin et al, 2002; Dacher and Nugent, 2011; Johnson and North, 1992; Trigo et al, 2010; Vargas-Perez et al, 2009) and facilitate response to psychomotor stimulants. Thus, if stimulation of MORs in the VTA indirectly increases VTA DA activity by reducing GABA transmission, then it is likely that knockdown of VTA MORs increases GABA release.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, even acute social defeat stress has been shown to rapidly upregulate MOR mRNA expression in the ventral tegmental area (VTA; Nikulina et al, 1999), while repeated social stress exposure increases VTA MOR mRNA expression for up to 14 days after the last episode (Nikulina et al, 2008). In the VTA MORs are expressed by gamma-aminobutyric acid (GABA) neurons (Garzon and Pickel, 2002; Sesack and Pickel, 1995), which are hyperpolarized in response to MOR stimulation, thus disinhibiting local dopamine (DA) transmission and facilitating response to drugs of abuse (Bergevin et al, 2002; Dacher and Nugent, 2011; Johnson and North, 1992; Vargas-Perez et al, 2009). Rats exposed to repeated social defeat stress, then challenged with an intra-VTA infusion of a MOR-specific agonist exhibited sensitized locomotor activity (Nikulina et al, 2008; Nikulina et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of ventral tegmental area mu-opioid receptors in rats prevents effects of social defeat stress: Implications for amphetamine cross-sensitization, social avoidance, weight regulation and expression of brain-derived neurotrophic factor

et al. 2015

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Social defeat stress causes social avoidance and long-lasting cross-sensitization to psychostimulants, both of which are associated with increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA). Moreover, social stress upregulates VTA mu-opioid receptor (MOR) mRNA. In the VTA, MOR activation inhibits GABA neurons to disinhibit VTA dopamine neurons, thus providing a role for VTA MORs in the regulation of psychostimulant sensitization. The present study determined the effect of lentivirus-mediated MOR knockdown in the VTA on the consequences of intermittent social defeat stress, a salient and profound stressor in humans and rodents. Social stress exposure induced social avoidance and attenuated weight gain in animals with non-manipulated VTA MORs, but both these effects were prevented by VTA MOR knockdown. Rats with non-manipulated VTA MOR expression exhibited cross-sensitization to amphetamine challenge (1.0 mg/kg, i.p.), evidenced by a significant augmentation of locomotion. By contrast, knockdown of VTA MORs prevented stressinduced cross-sensitization without blunting the locomotor-activating effects of amphetamine. At the time point corresponding to amphetamine challenge, immunohistochemical analysis was performed to examine the effect of stress on VTA BDNF expression. Prior stress exposure Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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Ultrastructural localization of enkephalin and μ-opioid receptors in the rat ventral tegmental area

Cited by 29 publications

References 111 publications

Nicotine-Induced Antinociception, Rewarding Effects, and Physical Dependence Are Decreased in Mice Lacking the Preproenkephalin Gene

Nicotine-Induced Antinociception, Rewarding Effects, and Physical Dependence Are Decreased in Mice Lacking the Preproenkephalin Gene

Neurotrophins in the ventral tegmental area: Role in social stress, mood disorders and drug abuse

Knockdown of ventral tegmental area mu-opioid receptors in rats prevents effects of social defeat stress: Implications for amphetamine cross-sensitization, social avoidance, weight regulation and expression of brain-derived neurotrophic factor

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