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.