Selective Activation of Striatal NGF-TrkA/p75NTR/ MAPK Intracellular Signaling in Rats That Show Suppression of Methamphetamine Intake 30 Days following Drug Abstinence

Featured Paper of the Month – September 2018.

Methamphetamine addiction is a public health threat throughout the world. Investigators in Dr. Cadet’s laboratory in the intramural program have developed a rat model of methamphetamine addiction that includes one of the psychiatric criteria used to make that diagnosis in humans. In that model, they used footshocks to represent adverse consequences that are present during the clinical course of addiction. Contingent footshocks helped the investigators to identify some rats (addicted) that continue to press a lever to get methamphetamine whereas other rats (non-addicted) suppress or stop their taking of methamphetamine in the presence of these adverse consequences. The investigators wanted to know if there were chemicals that could help them understand why these animals behaved differently in the presence of these shocks. They focused their attention on some chemicals called trophic factors including brain derived neurotrophic factor (BDNF) that are thought to regulate drug taking by rats. Because one area of the brain called dorsal striatum is involved in habit forming similar to the habits observed in patients who abuse drugs, the researchers measured the expression of some of these factors in that brain structure. They found that BDNF protein levels were similarly increased in the striatum in both groups of rats. However, another trophic factor called nerve growth factor (NGF) showed greater increases in the non-addicted rats. They also found that the receptor for NGF, called TrkA, is only activated in the non-addicted animals. Another important receptor for NGF called p75NTR is also only activated in the non-addicted rats. Importantly, proteins that are usually activated in cells that are stimulated by NGF were also activated only in the striatum of the non-addicted animals. These observations indicate that stimulation of NGF and other NGF-dependent proteins play a role in the suppression of methamphetamine taking by the non-addicted rats. These data also suggest that there is a need to develop medications that can activate NGF-dependent mechanisms that might benefit patients who are addicted to methamphetamine.

Publication Information

Torres, Oscar V; Jayanthi, Subramaniam; McCoy, Michael T; Cadet, Jean Lud

Selective Activation of Striatal NGF-TrkA/p75NTR/MAPK Intracellular Signaling in Rats That Show Suppression of Methamphetamine Intake 30 Days following Drug Abstinence. Journal Article

In: Int J Neuropsychopharmacol, vol. 21, no. 3, pp. 281–290, 2018, ISSN: 1469-5111 (Electronic); 1461-1457 (Linking).

Abstract | Links

@article{Torres:2018aa,

title = {Selective Activation of Striatal NGF-TrkA/p75NTR/MAPK Intracellular Signaling in Rats That Show Suppression of Methamphetamine Intake 30 Days following Drug Abstinence.},

author = {Oscar V Torres and Subramaniam Jayanthi and Michael T McCoy and Jean Lud Cadet},

url = {https://www.ncbi.nlm.nih.gov/pubmed/29165617},

doi = {10.1093/ijnp/pyx105},

issn = {1469-5111 (Electronic); 1461-1457 (Linking)},

year  = {2018},

date = {2018-03-01},

journal = {Int J Neuropsychopharmacol},

volume = {21},

number = {3},

pages = {281--290},

address = {Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, Baltimore, Maryland.},

abstract = {Background: The continuing epidemic of methamphetamine addiction has prompted research aimed at understanding striatal dysfunctions potentially associated with long-term methamphetamine use. Methods: Here, we investigated transcriptional and translational alterations in the expression of neurotrophic factors in the rat striatum at 30 days following methamphetamine self-administration and footshock punishment. Male Sprague-Dawley rats were trained to self-administer methamphetamine (0.1 mg/kg/injection, i.v.) or saline during twenty-two 9-hour sessions. Subsequently, rats were subjected to incremental footshocks for 13 additional methamphetamine self-administration sessions. This paradigm led to the identification of rats with shock-resistant and shock-sensitive phenotypes. Thirty days following the last footshock session, the dorsal striatum was dissected and processed for gene expression and protein analyses. Results: PCR arrays revealed significant differences in neurotrophins and their receptors between the 2 phenotypes. Brain-derived neurotrophic factor and nerve growth factor protein levels were increased in the dorsal striatum of both shock-resistant and shock-sensitive rats. However, neurotrophic receptor tyrosine kinase 1 phosphorylation and nerve growth factor receptor protein expression were increased only in the shock-sensitive phenotype. Moreover, shock-sensitive rats showed increased abundance of several phosphorylated proteins known to participate in Ras/Raf/MEK/ERK signaling cascade including cRaf, ERK1/2, MSK1, and CREB. Conclusions: These findings support the notion that animals with distinct phenotypes for methamphetamine intake in the presence of adverse consequences also display differential changes in an intracellular signaling cascade activated by nerve growth factor-TrkA/p75NTR interactions. Thus, the development of pharmacological agents that can activate nerve growth factor-dependent pathways may be a promising therapeutic approach to combat methamphetamine addiction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

Background: The continuing epidemic of methamphetamine addiction has prompted research aimed at understanding striatal dysfunctions potentially associated with long-term methamphetamine use. Methods: Here, we investigated transcriptional and translational alterations in the expression of neurotrophic factors in the rat striatum at 30 days following methamphetamine self-administration and footshock punishment. Male Sprague-Dawley rats were trained to self-administer methamphetamine (0.1 mg/kg/injection, i.v.) or saline during twenty-two 9-hour sessions. Subsequently, rats were subjected to incremental footshocks for 13 additional methamphetamine self-administration sessions. This paradigm led to the identification of rats with shock-resistant and shock-sensitive phenotypes. Thirty days following the last footshock session, the dorsal striatum was dissected and processed for gene expression and protein analyses. Results: PCR arrays revealed significant differences in neurotrophins and their receptors between the 2 phenotypes. Brain-derived neurotrophic factor and nerve growth factor protein levels were increased in the dorsal striatum of both shock-resistant and shock-sensitive rats. However, neurotrophic receptor tyrosine kinase 1 phosphorylation and nerve growth factor receptor protein expression were increased only in the shock-sensitive phenotype. Moreover, shock-sensitive rats showed increased abundance of several phosphorylated proteins known to participate in Ras/Raf/MEK/ERK signaling cascade including cRaf, ERK1/2, MSK1, and CREB. Conclusions: These findings support the notion that animals with distinct phenotypes for methamphetamine intake in the presence of adverse consequences also display differential changes in an intracellular signaling cascade activated by nerve growth factor-TrkA/p75NTR interactions. Thus, the development of pharmacological agents that can activate nerve growth factor-dependent pathways may be a promising therapeutic approach to combat methamphetamine addiction.