Differential regulation of Ca²⁺ signals in dopamine neurons : a potential mechanism for neuroadaptive changes underlying drug addiction
Abstract
A key adaptive change in the brain reward circuitry during the
development of drug addiction is augmented dopamine (DA) release in response
to addictive drugs. Potentiated glutamatergic synaptic transmission onto
midbrain DA neurons has been suggested to be one of the cellular mechanisms
mediating this change. Intracellular Ca2+ ([Ca2+
]i) rise associated with
postsynaptic bursts of action potentials (APs) and metabotropic glutamate
receptor (mGluR) activation has been implicated in the induction of long-term
potentiation (LTP) and long-term depression (LTD), respectively, of glutamate
transmission in DA neurons. In this dissertation, we found a unique mechanism
that differentially regulates these two opposing Ca2+ signals. We performed
patch-clamp recordings from DA neurons in acutely cut brain slices, and showed
that tonic activation of metabotropic neurotransmitter receptors (such as mGluRs,
α1 adrenergic receptors, and muscarinic acetylcholine receptors), attained by
weak, sustained (~1 sec) synaptic stimulation or bath application of selective
agonists, augmented AP-induced Ca2+ transients while inhibiting Ca2+ signals
elicited by strong, transient activation of mGluRs. This differential regulation is
mediated by increased intracellular inositol 1,4,5-triphosphate (IP3) levels, since it
was blocked by IP3 receptor antagonist heparin and reproduced by photolytic
application of IP3. We further showed that AP-induced Ca2+ transients were
regulated by the firing context of dopamine neurons. Evoking APs repetitively at
low frequency (2 Hz) mimicking the basal firing of DA neurons caused
inactivation of IP3 receptors and inhibited AP-induced Ca2+ transients. IP3
facilitation of single AP-induced Ca2+ signals was completely abolished during
the AP train, while facilitation of Ca2+ signals triggered by bursts of APs (5 spikes
at 20 Hz) was attenuated by less than half, indicating that increased IP3 level
selectively amplifies Ca2+ signals associated with bursts but not single APs in a
tonicly firing neuron. Finally, we obtained evidence suggesting that
psychostimulant amphetamine may augment burst-induced Ca2+ signals via both
depression of basal firing and production of IP3. We propose that the differential
Ca2+ regulation mechanisms described in this dissertation may induce a shift in
the balance of plasticity toward burst-dependent LTP in DA neurons and may
contribute to the development of drug addiction.
Department
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