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The Hepatocyte Growth Factor/c-Met Antagonist, Divalinal-Angiotensin IV, Blocks the Acquisition of Methamphetamine Dependent Conditioned Place Preference in Rats.

Wright JW, Wilson WL, Wakeling V, Boydstun AS, Jensen A, Kawas L, Harding JW - Brain Sci (2012)

Bottom Line: The majority of these studies have employed matrix metalloproteinase (MMP) inhibitors to disrupt MMP-induced extracellular matrix molecule dependent synaptic reconfiguration, or GABA receptor agonists.On the other hand, once MA-induced memory consolidation is in place divalinal appears to be ineffective.Mechanistic studies indicated that divalinal is a potent inhibitor of the hepatocyte growth factor (HGF)/c-Met receptor system, and thus it appears that a functional HGF/c-Met system is required for the acquisition of MA-mediated conditioned place preference.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Washington State University, Pullman, WA 99164-4820, USA. wrightjw@wsu.edu.

ABSTRACT
The use of methamphetamine (MA) is increasing in the U.S. and elsewhere around the world. MA's capacity to cause addiction significantly exceeds other psychostimulant drugs, and its use negatively impacts learning and memory. Recently, attempts have been made to interfere with the presumed mechanism(s) underlying the establishment of drug-induced memory consolidation. The majority of these studies have employed matrix metalloproteinase (MMP) inhibitors to disrupt MMP-induced extracellular matrix molecule dependent synaptic reconfiguration, or GABA receptor agonists. The present investigation utilized an angiotensin IV (AngIV) analogue, Divalinal-AngIV (divalinal), to disrupt acquisition of MA-induced dependence in rats as measured using the conditioned place preference paradigm. Results indicate that both acute and chronic intracerebroventricular infusion of divalinal prior to each daily subcutaneous injection of MA prevented acquisition. However, divalinal was unable to prevent MA-induced reinstatement after prior acquisition followed by extinction trials. These results indicate that prevention of MA dependence can be accomplished by blockade of the brain AT4 receptor subtype. On the other hand, once MA-induced memory consolidation is in place divalinal appears to be ineffective. Mechanistic studies indicated that divalinal is a potent inhibitor of the hepatocyte growth factor (HGF)/c-Met receptor system, and thus it appears that a functional HGF/c-Met system is required for the acquisition of MA-mediated conditioned place preference.

No MeSH data available.


Related in: MedlinePlus

Divalinal inhibits hepatocyte growth factor (HGF)-dependent c-Met activation. (A) HEK293 cells were treated for 10 min with HGF ± divalinal at 10−12, 10−10, or 10−8 M. HEK293 cell lysates were immunoblotted with anti-phospho-Met and anti-Met antibodies. Both treatment groups (HGF 20 ng/mL + Dival at 10−10 and 10−8 M) were statistically different from the HGF treated group (* p < 0.05), but were not different from one another or non-treated controls (p > 0.05). Mean ± SEM, N = 3. (B) Western blots for P-Met and total-Met.
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brainsci-02-00298-f005: Divalinal inhibits hepatocyte growth factor (HGF)-dependent c-Met activation. (A) HEK293 cells were treated for 10 min with HGF ± divalinal at 10−12, 10−10, or 10−8 M. HEK293 cell lysates were immunoblotted with anti-phospho-Met and anti-Met antibodies. Both treatment groups (HGF 20 ng/mL + Dival at 10−10 and 10−8 M) were statistically different from the HGF treated group (* p < 0.05), but were not different from one another or non-treated controls (p > 0.05). Mean ± SEM, N = 3. (B) Western blots for P-Met and total-Met.

Mentions: Previous studies conducted in our laboratory indicated that other AT4 receptor antagonists are potent inhibitors of the HGF/c-Met system [33,34,35], so in the present investigation we determined whether divalinal acts to inhibit c-Met signaling. c-Met is a tyrosine kinase-linked growth factor receptor, thus c-Met activation requires a tyrosine residue auto-phosphorylation step that is essential for the eventual recruitment of various SH2 domain signaling proteins. We first evaluated the ability of divalinal to inhibit c-Met tyrosine phosphorylation. As anticipated, divalinal was an effective blocker of HGF-dependent c-Met phosphorylation at 10−10 and 10−8 M (* p < 0.05; Figure 5) but had no effect on total c-Met expression. The divalinal dose of 10−12 M failed to block Met phosphorylation.


The Hepatocyte Growth Factor/c-Met Antagonist, Divalinal-Angiotensin IV, Blocks the Acquisition of Methamphetamine Dependent Conditioned Place Preference in Rats.

Wright JW, Wilson WL, Wakeling V, Boydstun AS, Jensen A, Kawas L, Harding JW - Brain Sci (2012)

Divalinal inhibits hepatocyte growth factor (HGF)-dependent c-Met activation. (A) HEK293 cells were treated for 10 min with HGF ± divalinal at 10−12, 10−10, or 10−8 M. HEK293 cell lysates were immunoblotted with anti-phospho-Met and anti-Met antibodies. Both treatment groups (HGF 20 ng/mL + Dival at 10−10 and 10−8 M) were statistically different from the HGF treated group (* p < 0.05), but were not different from one another or non-treated controls (p > 0.05). Mean ± SEM, N = 3. (B) Western blots for P-Met and total-Met.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061800&req=5

brainsci-02-00298-f005: Divalinal inhibits hepatocyte growth factor (HGF)-dependent c-Met activation. (A) HEK293 cells were treated for 10 min with HGF ± divalinal at 10−12, 10−10, or 10−8 M. HEK293 cell lysates were immunoblotted with anti-phospho-Met and anti-Met antibodies. Both treatment groups (HGF 20 ng/mL + Dival at 10−10 and 10−8 M) were statistically different from the HGF treated group (* p < 0.05), but were not different from one another or non-treated controls (p > 0.05). Mean ± SEM, N = 3. (B) Western blots for P-Met and total-Met.
Mentions: Previous studies conducted in our laboratory indicated that other AT4 receptor antagonists are potent inhibitors of the HGF/c-Met system [33,34,35], so in the present investigation we determined whether divalinal acts to inhibit c-Met signaling. c-Met is a tyrosine kinase-linked growth factor receptor, thus c-Met activation requires a tyrosine residue auto-phosphorylation step that is essential for the eventual recruitment of various SH2 domain signaling proteins. We first evaluated the ability of divalinal to inhibit c-Met tyrosine phosphorylation. As anticipated, divalinal was an effective blocker of HGF-dependent c-Met phosphorylation at 10−10 and 10−8 M (* p < 0.05; Figure 5) but had no effect on total c-Met expression. The divalinal dose of 10−12 M failed to block Met phosphorylation.

Bottom Line: The majority of these studies have employed matrix metalloproteinase (MMP) inhibitors to disrupt MMP-induced extracellular matrix molecule dependent synaptic reconfiguration, or GABA receptor agonists.On the other hand, once MA-induced memory consolidation is in place divalinal appears to be ineffective.Mechanistic studies indicated that divalinal is a potent inhibitor of the hepatocyte growth factor (HGF)/c-Met receptor system, and thus it appears that a functional HGF/c-Met system is required for the acquisition of MA-mediated conditioned place preference.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Washington State University, Pullman, WA 99164-4820, USA. wrightjw@wsu.edu.

ABSTRACT
The use of methamphetamine (MA) is increasing in the U.S. and elsewhere around the world. MA's capacity to cause addiction significantly exceeds other psychostimulant drugs, and its use negatively impacts learning and memory. Recently, attempts have been made to interfere with the presumed mechanism(s) underlying the establishment of drug-induced memory consolidation. The majority of these studies have employed matrix metalloproteinase (MMP) inhibitors to disrupt MMP-induced extracellular matrix molecule dependent synaptic reconfiguration, or GABA receptor agonists. The present investigation utilized an angiotensin IV (AngIV) analogue, Divalinal-AngIV (divalinal), to disrupt acquisition of MA-induced dependence in rats as measured using the conditioned place preference paradigm. Results indicate that both acute and chronic intracerebroventricular infusion of divalinal prior to each daily subcutaneous injection of MA prevented acquisition. However, divalinal was unable to prevent MA-induced reinstatement after prior acquisition followed by extinction trials. These results indicate that prevention of MA dependence can be accomplished by blockade of the brain AT4 receptor subtype. On the other hand, once MA-induced memory consolidation is in place divalinal appears to be ineffective. Mechanistic studies indicated that divalinal is a potent inhibitor of the hepatocyte growth factor (HGF)/c-Met receptor system, and thus it appears that a functional HGF/c-Met system is required for the acquisition of MA-mediated conditioned place preference.

No MeSH data available.


Related in: MedlinePlus