Methamphetamine, amphetamine, MDMA ('ecstasy'), MDA and mCPP modulate electrical and cholinergic input in PC12 cells.

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Dopamine (DA) transporter reversal is a primary mechanism for increased DA levels by drugs of abuse.
• Drug-induced modulation of exocytotic DA release via electrical and neurochemical inputs may also contribute to DA level changes.

Purpose of the Study:

• To investigate the effects of methamphetamine, amphetamine, MDMA, MDA, and mCPP on electrical and cholinergic inputs.
• To measure drug-induced changes in basal, depolarization-, and acetylcholine (ACh)-evoked intracellular calcium concentrations ([Ca(2+)](i)) in a dopaminergic model.

Main Methods:

• Utilized a dopaminergic cell model (PC12 cells) and Fura 2 calcium imaging.
• Measured basal, depolarization-evoked, and ACh-evoked [Ca(2+)](i) in the presence of various drug concentrations (1-1000 μM).

Main Results:

• All tested drugs significantly inhibited ACh-evoked [Ca(2+)](i) increases, with nearly complete abolition at 1mM.
• High concentrations of MDMA and mCPP increased basal [Ca(2+)](i) after ACh stimulation; low amphetamine concentrations potentiated ACh-evoked [Ca(2+)](i) increases.
• Depolarization-evoked [Ca(2+)](i) increases were inhibited by high drug concentrations, but drugs were less potent than on cholinergic input. mCPP showed the highest potency across endpoints.

Conclusions:

• High drug concentrations reduce stimulation-evoked [Ca(2+)](i) increases, likely decreasing dopaminergic output by inhibiting electrical and cholinergic inputs.
• Elevated basal [Ca(2+)](i) by MDMA/mCPP and potentiated ACh-evoked [Ca(2+)](i) by amphetamines can contribute to increased DA levels.
• Meta-chlorophenylpiperazine (mCPP) is the most potent drug among those tested for the investigated neurochemical endpoints.