Deprenyl treatment attenuates long-term pre- and post-synaptic changes evoked by chronic methamphetamine.
Deprenyl, used clinically in Parkinson's disease, has multiple pharmacological effects which make it a good candidate to treat neurotoxicity. Thus, we investigated deprenyl's ability to attenuate methamphetamine-induced dopamine neurotoxicity. We also examined deprenyl's effect in changing markers associated with psychostimulant sensitization. A potential therapeutic effect on either pathological domain would be a boon in developing novel treatments for methamphetamine abuse. Adult male Sprague-Dawley rats were split into 6 groups. Three groups received a 7-day saline minipump with saline, 0.05 or 0.25 mg/kg SC deprenyl injections given for 10 days before, during and 5 days after the 7-day saline minipump implant. Similarly, 3 groups received methamphetamine pumps (25 mg/kg/day) with escalating daily injections of methamphetamine (0-6 mg/kg) in addition to the minipump treatment. These rats also received saline, 0.05 or 0.25 mg/kg deprenyl injections given before, during and the 7-day minipump treatment. Rats were killed on day 28 of withdrawal and brain samples taken. HPLC analysis for dopamine and 3,4-Dihydroxy-Phenylacetic Acid (DOPAC) revealed a loss of dopamine in the caudate and accumbens which was partially reversed by high dose deprenyl. Tyrosine hydroxylase immunostaining in the midbrain was unaffected by methamphetamine, suggesting that dopamine neurotoxicity was localized to the caudate. Western blot analysis of the caudate after methamphetamine revealed little change in Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid (AMPA) GluR1 or N-Methyl-d-Aspartate (NMDA) NR2B subunits, or their phosphorylation state. However, methamphetamine increased levels of GluR1 and its phosphorylation state in the prefrontal cortex (PFC), and these increases were attenuated by deprenyl. Methamphetamine also increased levels of PFC NR2B subunit, but these increases were not attenuated by deprenyl. We suggest that deprenyl may be effective in reducing the neurotoxic effects of methamphetamine and may also attenuate changes in prefrontal AMPA receptor function, presumably more associated with addiction rather than neurotoxicity.
Davidson
Colin
C
Department of Psychiatry and Behavioral Sciences, Box 3870, Duke University Medical Center, Durham, NC 27710, USA. colda@duke.edu
Chen
Qiang
Q
Zhang
Xiuwn
X
Xiong
Xueying
X
Lazarus
Cindy
C
Lee
Tong H
TH
Ellinwood
Everett H
EH
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D007120:Immunochemistry; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D012642:Selegiline / Q000008:administration & dosage / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000378:metabolism
D015102:3,4-Dihydroxyphenylacetic Acid; D000978:Antiparkinson Agents; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors; D008694:Methamphetamine; D018091:Receptors, AMPA; D012642:Selegiline; D014446:Tyrosine 3-Monooxygenase