PMID- 10493769 OWN - NLM STAT- MEDLINE DCOM- 19991014 LR - 20231014 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 19 IP - 19 DP - 1999 Oct 1 TI - Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/Mitogen-activated protein kinase signal transduction cascade. PG - 8685-95 AB - These experiments were designed to assess the role of neurotrophins and the Ras/mitogen-activated protein kinase (MAP) signal transduction cascade in behavioral sensitization to cocaine. The first experiments evaluated the effect of three daily intra-ventral tegmental area (VTA) microinjections of neurotrophin-3 (NT-3) or brain-derived neurotrophic factor (BDNF) on the behavioral-activating effects of a subsequent challenge injection of cocaine in rats. Results indicated that, although NT-3 did not influence behavior across the three microinjection days, animals displayed a sensitized behavioral response to the subsequent cocaine challenge injection. In contrast, BDNF microinjections resulted in a progressive increase in behavioral activity but did not influence the subsequent behavioral response to cocaine. A second series of experiments assessed the effect of inhibiting the MAP kinase signal transduction cascade on the initiation of behavioral sensitization to cocaine. The MAP kinase kinase inhibitor PD98059, or its vehicle, was microinjected into the VTA before three daily cocaine injections. Although PD98059 did not influence the acute behavioral response to cocaine, it blocked sensitization. Finally, the effects of acute and repeated cocaine injections on NT-3 and BDNF mRNA levels in the VTA, substantia nigra, and hippocampus were assessed. Results indicated that an acute cocaine injection resulted in a transient increase in NT-3 mRNA levels in the VTA. Collectively, these results suggest that NT-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/MAP kinase signal transduction system. The present data also indicate that BDNF itself produced a progressive augmentation in behavioral activation with repeated administration. FAU - Pierce, R C AU - Pierce RC AD - Laboratory of Neuropsychopharmacology, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118, USA. FAU - Pierce-Bancroft, A F AU - Pierce-Bancroft AF FAU - Prasad, B M AU - Prasad BM LA - eng GR - DA11168/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (Nerve Growth Factors) RN - 0 (Neurotrophin 3) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - EC 3.6.5.2 (ras Proteins) RN - I5Y540LHVR (Cocaine) RN - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/genetics MH - Calcium-Calmodulin-Dependent Protein Kinases/*metabolism MH - Cocaine/*pharmacology MH - Drug Interactions MH - Enzyme Inhibitors/pharmacology MH - Flavonoids/administration & dosage/pharmacology MH - Hippocampus/drug effects/physiology MH - Male MH - Microinjections MH - Mitogen-Activated Protein Kinase Kinases MH - Nerve Growth Factors/administration & dosage/genetics/*pharmacology MH - Neurotrophin 3 MH - Protein Kinase Inhibitors MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/*drug effects MH - Stereotyped Behavior/*drug effects MH - Substance Withdrawal Syndrome MH - Substantia Nigra/drug effects/*physiology MH - Tegmentum Mesencephali/drug effects/*physiology MH - Transcription, Genetic/drug effects MH - ras Proteins/metabolism PMC - PMC6783001 EDAT- 1999/09/24 00:00 MHDA- 1999/09/24 00:01 PMCR- 2000/04/01 CRDT- 1999/09/24 00:00 PHST- 1999/09/24 00:00 [pubmed] PHST- 1999/09/24 00:01 [medline] PHST- 1999/09/24 00:00 [entrez] PHST- 2000/04/01 00:00 [pmc-release] AID - 3483 [pii] AID - 10.1523/JNEUROSCI.19-19-08685.1999 [doi] PST - ppublish SO - J Neurosci. 1999 Oct 1;19(19):8685-95. doi: 10.1523/JNEUROSCI.19-19-08685.1999.