Cross-Talk between Dopaminergic and Noradrenergic Systems in the Rat Ventral Tegmental Area, Locus Ceruleus, and Dorsal Hippocampus

Abstract

A decreased central dopaminergic and/or noradrenergic transmission is believed to be involved in the pathophysiology of depression. It is known that dopamine (DA) neurons in the ventral tegmental area (VTA) and norepinephrine (NE) neurons in the locus ceruleus (LC) are autoregulated by somatodendritic D 2 -like and ␣ 2 -adrenoceptors, respectively. Complementing these autoreceptor-mediated inhibitory feedbacks, anatomical and functional studies have established a role for noradrenergic inputs in regulating dopaminergic activity, and reciprocally. In the present study, a microiontophoretic approach was used to characterize the postsynaptic catecholamine heteroreceptors involved in such regulations. In the VTA, the application of DA and NE significantly reduced the firing activity of DA neurons. In addition to a role for D 2 -like receptors in the inhibitory effects of both catecholamines, it was demonstrated that the ␣ 2 -adrenoceptor antagonist idazoxan dampened the DA-and NE-induced attenuations of DA neuronal activity, indicating that both of these receptors are involved in the responsiveness of VTA DA neurons to catecholamines. In the LC, the effectiveness of iontophoretically applied NE and DA to suppress NE neuronal firing was blocked by idazoxan but not by the D 2 -like receptor antagonist raclopride, which suggested that only ␣ 2 -adrenoceptors were involved. In the dorsal hippocampus, a forebrain region having a sparse dopaminergic innervation but receiving a dense noradrenergic input, the suppressant effects of DA and NE on pyramidal neurons were attenuated by idazoxan but not by raclopride. The suppressant effect of DA was prolonged by administration of the selective NE reuptake inhibitor desipramine and, to lesser extent, of the selective DA reuptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)-piperazine (GBR12909), suggesting that both the NE and DA transporters were involved in DA uptake in the hippocampus. These findings might help in designing new antidepressant strategies aimed at enhancing DA and NE neurotransmission.The catecholamines neurotransmitters dopamine (DA) and norepinephrine (NE) are believed to be involved in psychiatric disorders, and a better knowledge of the reciprocal interactions between these two systems should improve our understanding of the pathophysiology and treatment of mood disorders. Anatomical evidence indicates that noradrenergic neurons of the locus ceruleus (LC) send projections to the ventral tegmental area (VTA) in the vicinity of DA neuron cell bodies (Simon et al., 1979). Several subtypes of ␣-adrenergic receptors have been identified in the VTA (Lee et al., 1998), raising the possibility that NE inputs play a role in modulating DA neuronal activity. Consistent with this assumption, it was recently demonstrated that a selective lesion of LC NE neurons increases the mean firing activity of DA neurons by 70% and their burst activity by almost 50%, thus revealing a net inhibitory effect of NE in the VTA (Guiard et al., 2008). In con...

Evidence for Noncanonical Neurotransmitter Activation: Norepinephrine as a Dopamine D2-Like Receptor Agonist

“…Adenylyl cyclase inhibition 1 6 0.2 76 6 10 G-protein activation (Gi1) 12 6 2 2 4 6 2 b Arrestin-2 recruitment 687 6 247 15 6 1 small separation between the potencies of norepinephrine and dopamine for a2AR and D 2 -like receptors (20-fold), verifying D 2 -like receptors as potential signal transducers for norepinephrine. With our findings on relative potencies, the previously reported so-called cross reactivity phenomenon between dopamine and norepinephrine (Guiard et al, 2008;Gonzalez et al, 2012a;Lei, 2014) can now be better explained at the receptor-effector levels and considered as likely biologically occurring events. Furthermore, dopamine and norepinephrine concentrations in prefrontal cortex are comparable (Koob et al, 1975;Blank et al, 1979;Li et al, 1998), suggesting that actions of norepinephrine at cortical D 2 -like receptors are likely functionally significant.…”

A Switch in the Neuromodulatory Effects of Dopamine in the Oval Bed Nucleus of the Stria Terminalis Associated with Cocaine Self-Administration in Rats

“…5, Table 1). These data suggest that the effect of DA on excitatory synaptic transmission is mediated by ␣2R (Zhang et al, 1999;Cornil et al, 2002;Zhang and Ordway, 2003;Cornil and Ball, 2008;Guiard et al, 2008;Krawczyk et al, 2011) and that ␣2Rs are not functionally altered with operant responding for either a pharmacological or natural reward.…”

Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal

“…Dopaminergic signaling in the BLA, which is necessary for the acquisition of fear-potentiated startle (Nader and LeDoux, 1999;Greba and Kokkinidis, 2000;Greba et al, 2001;Fadok et al, 2009), may also trigger extended amygdala activity. Following opiate exposure, dopamine levels rise and fall in portions of the extended amygdala (Di Chiara and Imperato, 1988;Acquas and Di Chiara, 1992;Spanagel et al, 1992;Wise et al, 1995;Carboni et al, 2000), possibly triggering the release of corticotropin-releasing factor and norepinephrine (Guiard et al, 2008;Kash et al, 2008).…”