Amphetamine Action Revisited: A Critical Role For Dopamine Cell Membrane Excitability
2019-08-06T00:00:00Z (GMT) by
Amphetamine (AMPH) is thought to increase extracellular dopamine concentrations in the nucleus accumbens (NAc) primarily through action at dopamine terminals. Characterized as a dopamine releaser in in vitro studies, AMPH invades the presynaptic terminal via the dopamine transporter (DAT), compromises vesicular packaging, and increases extracellular dopamine through reverse transport. As such, AMPH activates nonexocytotic dopamine release and eliminates the ability of dopamine neurons to phasically signal through exocytotic release. Yet, AMPH increases the frequency of phasic dopamine release events (dopamine transients) in vivo, a signaling pattern inconsistent with reverse transport. Thus, these dissertation studies seek to determine the extent to which AMPH-induced increases in NAc dopamine and hyperlocomotion target phasic dopamine release signaled by neural activity at the dopamine cell bodies in the ventral tegmental area (VTA). While the reverse transport model predicts nonexocytotic dopamine activation occurs independent of VTA neural activity, I predicted that inhibition of VTA dopamine activation would attenuate AMPH-induced increases in NAc dopamine transients and hyperlocomotion. Inhibitory chemogenetic designer receptors exclusively activated by designer drug (DREADD) was used to gain suppressive control of VTA dopamine neuron firing activity, and systemic administration of the DREADD ligand, clozapine-n-oxide (CNO) suppressed electrically evoked phasic dopamine release. Similar to recent work in behaving rats, AMPH (2.5 mg/kg, IP) increased both electrically evoked dopamine release as well as spontaneous dopamine transient frequency in the NAc. These effects were significantly reduced with CNO pretreatment (1 mg/kg, IP) relative to vehicle, results consistent with the idea that AMPH activates exocytotic dopamine release in behaving rats. Furthermore, we have observed a suppression in AMPH-induced hyperlocomotion with systemic CNO. Taken together, these results corroborate in vivo-based conclusions supporting VTA dopamine cell body activity as a critical target for AMPH action.