Excitatory drive onto dopaminergic neurons in the rostral linear nucleus is enhanced by norepinephrine in an α1 adrenergic receptor-dependent manner

Abstract

Dopaminergic innervation of the extended amygdala regulates anxiety-like behavior and stress responsivity. A portion of this dopamine input arises from dopamine neurons located in the ventral lateral periaqueductal gray (vlPAG) and rostral (RLi) and caudal linear nuclei of the raphe (CLi). These neurons receive substantial norepinephrine input, which may prime them for involvement in stress responses. Using a mouse line that expresses eGFP under control of the tyrosine hydroxylase promoter, we explored the physiology and responsiveness to norepinephrine of these neurons. We find that RLi dopamine neurons differ from VTA dopamine neurons with respect to membrane resistance, capacitance and the hyperpolarization-activated current, Ih. Further, we found that norepinephrine increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) on RLi dopamine neurons. This effect was mediated through the α1 adrenergic receptor (AR), as the actions of norepinephrine were mimicked by the α1-AR agonist methoxamine and blocked by the α1-AR antagonist prazosin. This action of norepinephrine on sEPSCs was transient, as it did not persist in the presence of prazosin. Methoxamine also increased the frequency of miniature EPSCs, indicating that the α1-AR action on glutamatergic transmission likely has a presynaptic mechanism. There was also a modest decrease in sEPSC frequency with the application of the α2-AR agonist UK-14,304. These studies illustrate a potential mechanism through which norepinephrine could recruit the activity of this population of dopaminergic neurons.

Specificity and impact of adrenergic projections to the midbrain dopamine system

“…Contrary to the effect of inhibitory postsynaptic currents, activation of α1 adrenoceptors increased presynaptic glutamate release. Phenylephrine increased the amplitude of evoked and frequency of spontaneous AMPA excitatory postsynaptic currents (Velasquez-Martinez et al, 2012; Williams et al, 2014). Taken together, the presynaptic α1 actions are in accordance to an activation of DA neurons favoring glutamate over GABA inputs.…”

“…Clonidine and UK14304, both α 2 agonist, decreased the frequency of spontaneous and miniature EPSCs (Jimenez-Rivera et al, 2012; Williams et al, 2014). Conversely, both clonidine and UK14304 increased spontaneous IPSCs (Cathala et al, 2002).…”

Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling

“…), facilitation of excitatory glutamatergic drive onto VTA DA neurons through the recruitment of intracellular plasticity mechanisms (Williams et al . ), alteration of release probability of glutamate versus GABA from afferent terminals innervating the VTA (Velásquez‐Martinez et al . ; Velásquez‐Martínez et al .…”

“…; Williams et al . ; Mejias‐Aponte ). However, contrary to expectations, intra‐VTA α 2 ‐AR blockade was able to robustly inhibit evoked phasic DA release, suggesting a different mechanism.…”

Alcohol preference and consumption are controlled by the caudal linear nucleus in alcohol‐preferring rats

“…The CLi receives serotonergic inputs from the dorsal raphe region and noradrenergic inputs from the locus coeruleus and brainstem centres (Halliday & Tork, 1989;Mejias-Aponte et al, 2009). Stimulation of 5-HT 2C and 5-HT 2A receptors, as well as a 1adrenoreceptors localized on CLi dopamine neurons increased firing rate of dopamine neurons (Nocjar et al, 2002;Bubar et al, 2011;Williams et al, 2014). The low CLi activity in na€ ıve AA rats could therefore be hypothesized to reflect diminished serotonergic and/or noradrenergic tone, whereas alcohol-induced activation could be related to stimulation of serotonergic and noradrenergic transmission, which increases brain activity in the projection areas of CLi dopamine neurons, for example in the nucleus accumbens shell seen in the present data.…”