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Altering behavioral responses and dopamine transporter protein with antisense peptide nucleic acids
B M Tyler-McMahon1, J A Stewart, J Jackson
1Neuropsychopharmacology, Mayo Clinic, Birdsall Medical Research Building, 4500 San Pablo Rd., Jacksonville, FL 32224, USA. mcmahon.beth@mayo.edu
Biochemical Pharmacology
|September 7, 2001
Summary
Antisense peptide nucleic acid (PNA) targeting the dopamine transporter (DAT) significantly reduced amphetamine-induced locomotion in rats. This study demonstrates effective extracranial knockdown of brain proteins, suggesting new therapeutic avenues for DAT-related disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- The dopamine transporter (DAT) is crucial for regulating locomotion and is a primary target for amphetamines.
- Antisense molecules offer a potential strategy for targeted gene silencing.
Purpose of the Study:
- To investigate the effect of an antisense peptide nucleic acid (PNA) targeting rat DAT on locomotion and amphetamine response.
- To assess the feasibility of extracranial administration of antisense molecules for brain protein knockdown.
Main Methods:
- Rats received daily intraperitoneal injections of saline, antisense DAT PNA, scrambled DAT PNA, or mismatch DAT PNA for 9 days.
- Locomotor activity was measured at baseline and after amphetamine challenge (10 mg/kg) on days 7 and 9.
- Dopamine transporter levels in the striatum were quantified using ELISA.
Main Results:
- On day 9, antisense PNA-treated rats exhibited significantly increased resting motility (P < 0.01).
- Amphetamine challenge resulted in a blunted locomotor response in antisense PNA-treated rats (3.4-fold increase) compared to controls (20-36 fold increase; P < 0.01).
- ELISA confirmed a 32% reduction in striatal DAT levels in antisense PNA-treated rats (P < 0.001).
Conclusions:
- Extracranial administration of antisense PNA effectively and specifically reduces target brain protein levels (DAT).
- Targeting DAT with antisense PNA significantly alters locomotor activity and reduces responsiveness to amphetamines.
- These findings support novel therapeutic strategies for conditions involving dopamine transporter dysfunction.