Altering behavioral responses and dopamine transporter protein with antisense peptide nucleic acids

Tyler-McMahon, BM Stewart, JA Jackson, J Bitner, MD Fauq, A McCormick, DJ Richelson, E

Bm. Tyler-mcmahon et al., Altering behavioral responses and dopamine transporter protein with antisense peptide nucleic acids, BIOCH PHARM, 62(7), 2001, pp. 929-932

20

INGLESE

Article

Pharmacology & Toxicology

BIOCHEMICAL PHARMACOLOGY

0006-2952 → ACNP

62

7

2001

929 - 932

ISI

0006-2952(20011001)62:7<929:ABRADT>2.0.ZU;2-E

The dopamine transporter (DAT) plays a role in locomotion and is an obligat ory target for amphetamines. We designed and synthesized an antisense pepti de nucleic acid (PNA) to rat DAT to examine the effect of this antisense mo lecule on locomotion and on responsiveness to amphetamines. Rats were injec ted intraperitoneally daily for 9 days with either saline, an antisense DAT PNA, a scrambled DAT PNA, or a mismatch DAT PNA. On days 7 and 9 after ini tial motility measurements were taken, the animals were challenged with 10 mg/kg of amphetamine and scored for motility. On day 7, there was no signif icant difference between the baseline levels of activity of any of the grou ps or their responses to amphetamine. On day 9, the antisense PNA-treated r ats showed a statistically significant increase in their resting motility ( P < 0.01). When these rats were challenged with amphetamine, motility of th e saline-, scrambled PNA-, and mismatch PNA-treated animals showed increase s of 31-, 36-, and 20-fold, respectively, while the antisense PNA-treated a nimals showed increases of only 3.4-fold (P < 0.01). ELISA results revealed a 32% decrease in striatal DAT in antisense PNA-treated rats compared with the saline, scrambled PNA, and mismatch PNA controls (P < 0.001). These re sults extend our previous findings that brain proteins can be knocked down in a specific manner by antisense molecules administered extracranially. Ad ditionally, these results suggest some novel approaches for the treatment o f diseases dependent upon the function of the dopamine. transporter. (C) 20 01 Elsevier Science Inc. All rights reserved.