Noradrenergic modulation of the hyperpolarization-activated cation current (Ih) in dopamine neurons of the ventral tegmental area

Abstract

Alterations in the state of excitability of midbrain dopamine (DA) neurons from the ventral tegmental area (VTA) may underlay changes in the synaptic plasticity of the mesocorticolimbic system. Here, we investigated norepinephrine's (NE) regulation of VTA DA cell excitability by modulation of the hyperpolarization-activated cation current, I h in whole cell recordings. Current clamp recordings show that NE (40 µM) hyperpolarizes spontaneously firing VTA DA cells (11.23 ±4 mV; n = 8). In voltage clamp, NE (40 µM) induces an outward current (100 ± 24 pA; n = 8) at − 60 mV that reverses at about the Nernst potential for potassium (−106 mV). In addition, NE (40 µM) increases the membrane cord conductance (179 ± 42%; n = 10) and reduces I h amplitude (68 ± 3% of control at −120 mV; n = 10). The noradrenergic alpha-1 antagonist prazosin (40 µM; n = 5) or the alpha-2 antagonist yohimbine (40 µM; n = 5) did not block NE effects. All NE-evoked events were blocked by the D 2 antagonists sulpiride (1 µM) and eticlopride (100 nM) and no significant reduction of I h took place in the presence of the potassium channel blocker BaCl 2 (300 µM). Therefore, it is concluded that NE inhibition of I h was due to an increase in membrane conductance by a non-specific activation of D 2 receptors that induce an outward potassium current and not a result of a second messenger system acting on h-channels. The results also suggest that I h channels are mainly located at dendrites of VTA DA cells and thus their inhibition may facilitate the transition from single spike firing to burst firing and vice versa.

The Effects of Locus Coeruleus and Norepinephrine in Methamphetamine Toxicity

“…This occurs through the activation of D2 DA receptors, which work as inhibitory autoreceptors on midbrain DA neurons (Fig. 4A ) [139]. It is thus not surprising that in the absence of NE, the firing rate of these neurons is enhanced and the effects of METH on the mesolimbic (and mesostriatal) system are potentiated (Fig.…”

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels in the regulation of midbrain dopamine systems

“…During AHP after a burst firing, the membrane potential is likely to be more negative than -70 mV and thus activates HCN channels, which leads to a reduction in amplitude and duration of AHP. It has been reported in VTA DA neurons that neurotransmitters such as serotonin [60] and norepinephrine [50] reduced Ih, leading to an enhancement of the amplitude and duration of AHP after bursting and a reduction of neuronal excitability. The activation of HCN channels and the down-regulation of DA neuron excitability would filter off lots of synaptic inputs and further inhibit the burst firing DA neurons that depends on the excitatory afferent inputs [12] .…”

“…In addition, a recent study implicated that HCN channels are mainly located at the dendrites of VTA DA neurons in comparison to the soma, which has been speculated to preferentially influence the burst firing of VTA DA neurons [50] . However, there still lack of direct evidences for the somatodendritic spatial gradient of HCN channels in VTA DA neurons and more detailed investigations are needed in the future.…”

“…HCN channels as modulatory targets for the activity modulation of DA neurons HCN channels are targets for many neurotransmitters and drugs for modulating the activity of DA cells [34,50,60,62,63] . As discussed in the previous section, the activity of HCN channels is sensitive to many factors, such as cAMP, PIP 2 and protein kinase, thus any alteration in the activity of postsynaptic receptors are very likely to induce changes in the function of HCN channels, further influencing the activity of DA neurons.…”

“…For example, serotonin dramatically inhibited HCN channels in VTA DA cells through activation of 5-HT 2A receptors and such an effect may be involved in the serotonin-induced potentiation of auto-inhibition of the spontaneous firing rate of VTA DA neurons [60] . In addition, activation of D 2 -like receptors in DA neurons would dramatically reduce Ih , which is secondary to the activation of potassium conductance [50,62,64] . For instance, the modulation of Ih by norepinephrine in VTA DA neurons has been attributed to its non-specific stimulation of D 2 -like receptors.…”