Control of midbrain dopaminergic neurons by opioids.

摘要

Dopaminergic neurons of the ventral tegmental area (VTA) play a critical role in motivation and reinforcement of goal-directed behaviors. Excitation of these neurons has been implicated in the addictive process initiated by drugs such as morphine that act at the mu-opioid (MOP) receptor. In contrast, kappa-opioid (KOP) receptor activation in the VTA produces motivational actions opposite to those elicited by MOP receptor activation. The neural mechanism underlying this opposition, however, has not been investigated. VTA neurons have been categorized previously as principal, secondary, or tertiary on the basis of electrophysiological and pharmacological characteristics. In this thesis, post- and presynaptic actions of KOPs and MOPs in the VTA were investigated using whole-cell patch-clamp recordings.; In studies of the postsynaptic actions of opioids in VTA, I observed that a selective KOP receptor agonist (U69593, 1 μM) directly inhibits a subset of principal and tertiary, but not secondary, neurons. This KOP receptor-mediated inhibition occurs via activation of a G-protein-coupled inwardly rectifying potassium channel. Significantly, KOP receptor-mediated inhibition was limited to tyrosine hydroxylase immunoreactive, and thus dopaminergic, neurons. In addition, a subset of principal neurons was both disinhibited by a selective MOP receptor agonist ([D-Ala 2, N-Me-Phe4, Gly-ol 5]-enkephalin) (3 μM) and directly inhibited by U69593.; Presynaptic MOP and KOP control of glutamate release onto the different classes of VTA neurons has not been systematically studied. To address this issue I measured excitatory postsynaptic currents (EPSCs) in VTA-containing brain slices. I confirmed that MOP agonists inhibit glutamate release onto principal and secondary cells, and discovered a similar effect in tertiary cells. I also found that U69593 produces a small reduction in EPSC amplitude in principal neurons, and a robust inhibition of EPSCs in secondary and tertiary neurons.; The postysynaptic results reported here provide a cellular mechanism for the opposing behavioral effects of KOP and MOP receptor agonists. In addition, the presynaptic actions of MOP and KOP agonists provide a mechanism for opioid control of specific inputs to each VTA cell class. Together, these data provide information essential to our understanding of how KOPs regulate the motivational effects of both natural rewards and addictive drugs.