scholarly journals Dopamine neurons in the ventral tegmental area fire faster in adolescent rats than in adults

2012 ◽  
Vol 108 (6) ◽  
pp. 1620-1630 ◽  
Author(s):  
James E. McCutcheon ◽  
Kelly L. Conrad ◽  
Steven B. Carr ◽  
Kerstin A. Ford ◽  
Daniel S. McGehee ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Drug Addiction ◽  
Brain Slices ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Membrane Properties ◽  
Neuron Firing ◽  
Postsynaptic Currents ◽  
Adolescent Rats ◽  
Ventral Tegmental

Adolescence may be a period of vulnerability to drug addiction. In rats, elevated firing activity of ventral tegmental area (VTA) dopamine neurons predicts enhanced addiction liability. Our aim was to determine if dopamine neurons are more active in adolescents than in adults and to examine mechanisms underlying any age-related difference. VTA dopamine neurons fired faster in adolescents than in adults as measured with in vivo extracellular recordings. Dopamine neuron firing can be divided into nonbursting (single spikes) and bursting activity (clusters of high-frequency spikes). Nonbursting activity was higher in adolescents compared with adults. Frequency of burst events did not differ between ages, but bursts were longer in adolescents than in adults. Elevated dopamine neuron firing in adolescent rats was also observed in cell-attached recordings in ex vivo brain slices. Using whole cell recordings, we found that passive and active membrane properties were similar across ages. Hyperpolarization-activated cation currents and small-conductance calcium-activated potassium channel currents were also comparable across ages. We found no difference in dopamine D2-class autoreceptor function across ages, although the high baseline firing in adolescents resulted in autoreceptor activation being less effective at silencing neurons. Finally, AMPA receptor-mediated spontaneous excitatory postsynaptic currents occurred at lower frequency in adolescents; GABAA receptor-mediated spontaneous inhibitory postsynaptic currents occurred at both lower frequency and smaller amplitude in adolescents. In conclusion, VTA dopamine neurons fire faster in adolescence, potentially because GABA tone increases as rats reach adulthood. This elevation of firing rate during adolescence is consistent with it representing a vulnerable period for developing drug addiction.

scholarly journals Neurotensin inhibits both dopamine- and GABA-mediated inhibition of ventral tegmental area dopamine neurons

2015 ◽  
Vol 114 (3) ◽  
pp. 1734-1745 ◽  
Author(s):  
Katherine Stuhrman ◽  
Aaron G. Roseberry
Keyword(s):  
Ventral Tegmental Area ◽  
Calcium Release ◽  
Transient Receptor Potential ◽  
Brain Slices ◽  
Receptor Activation ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Inward Current ◽  
Ventral Tegmental

Dopamine is an essential neurotransmitter that plays an important role in a number of different physiological processes and disorders. There is substantial evidence that the neuropeptide neurotensin interacts with the mesolimbic dopamine system and can regulate dopamine neuron activity. In these studies we have used whole cell patch-clamp electrophysiology in brain slices from mice to examine how neurotensin regulates dopamine neuron activity by examining the effect of neurotensin on the inhibitory postsynaptic current generated by somatodendritic dopamine release (D2R IPSC) in ventral tegmental area (VTA) dopamine neurons. Neurotensin inhibited the D2R IPSC and activated an inward current in VTA dopamine neurons that appeared to be at least partially mediated by activation of a transient receptor potential C-type channel. Neither the inward current nor the inhibition of the D2R IPSC was affected by blocking PKC or calcium release from intracellular stores, and the inhibition of the D2R IPSC was greater with neurotensin compared with activation of other Gq-coupled receptors. Interestingly, the effects of neurotensin were not specific to D2R signaling as neurotensin also inhibited GABAB inhibitory postsynaptic currents in VTA dopamine neurons. Finally, the effects of neurotensin were significantly larger when intracellular Ca2+ was strongly buffered, suggesting that reduced intracellular calcium facilitates these effects. Overall these results suggest that neurotensin may inhibit the D2R and GABAB IPSCs downstream of receptor activation, potentially through regulation of G protein-coupled inwardly rectifying potassium channels. These studies provide an important advance in our understanding of dopamine neuron activity and how it is controlled by neurotensin.

scholarly journals HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Peng Zhong ◽  
Casey R Vickstrom ◽  
Xiaojie Liu ◽  
Ying Hu ◽  
Laikang Yu ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Chronic Stress ◽  
Ex Vivo ◽  
Critical Role ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Hcn Channels ◽  
Neuron Firing ◽  
Ventral Tegmental

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors.

scholarly journals Estradiol enhances ethanol stimulation of ventral tegmental area dopamine neuron firing without limiting ethanol inhibition onto those neurons

2020 ◽  
Author(s):  
Philip Stanhope Lambeth ◽  
Amy W. Lasek ◽  
Regina A. Mangieri
Keyword(s):  
Firing Rate ◽  
Ventral Tegmental Area ◽  
Brain Slices ◽  
Brain Regions ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Synaptic Inhibition ◽  
Ventral Tegmental ◽  
Additional Support ◽  
Stimulation Of

Females can progress to alcohol and other substance use disorders more quickly than males. The ovarian hormone 17β-estradiol (E2) contributes to sex differences observed in drug use and abuse and may be a principal driver of these differences. However, it is not entirely clear how E2 acts to affect processing of ethanol reward, and several brain regions and mechanisms are implicated. We sought to clarify the role of E2 in modulating the response of ventral tegmental area dopamine neurons to ethanol. To this end, we recorded spontaneous action potentials and inhibitory post synaptic currents from dopaminergic neurons in acute horizontal brain slices from ovariectomized (OVX) dopamine neuron reporter mice (Pitx3-eGFP) treated with either vehicle (VEH) or E2. On the basis of prior work, we hypothesized that E2 administration would cause dopamine cells from OVX+E2 animals to show a more substantial ethanol-induced increase in firing rate compared to control animals. Our data confirmed that ethanol stimulation of the firing rate of dopamine neurons from OVX+E2 mice was greater than that of OVX+VEH animals. Further, we hypothesized that the firing rate increase would be accompanied by a concomitant decrease in ethanol stimulated inhibition onto those same neurons. We found that although ethanol caused the expected increase in GABAA receptor-mediated synaptic inhibition in both groups, there was no difference in this response between OVX+E2 and OVX+VEH animals. Our findings lend additional support for the ability of E2 to enhance ventral tegmental area dopamine neuron responses to ethanol and suggest that this effect is not mediated by an E2-elicited suppression of synaptic inhibition.

Serotonin Reduces the Hyperpolarization-Activated Current (Ih) in Ventral Tegmental Area Dopamine Neurons: Involvement of 5-HT2 Receptors and Protein Kinase C

2003 ◽  
Vol 90 (5) ◽  
pp. 3201-3212 ◽  
Author(s):  
Zhaoping Liu ◽  
E. Bradshaw Bunney ◽  
Sarah B. Appel ◽  
Mark S. Brodie
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ventral Tegmental Area ◽  
Kinase Inhibitor ◽  
Brain Slices ◽  
Dopamine Neurons ◽  
Dependent Manner ◽  
Cationic Current ◽  
Kinase C ◽  
Ventral Tegmental

Dopaminergic neurons of the ventral tegmental area (VTA) have been implicated in the rewarding properties of drugs of abuse and in the etiology of schizophrenia; serotonin modulation of these neurons may play a role in these phenomena. Whole cell patch-in-the-slice recording in rat brain slices was used to investigate modulation of the hyperpolarization-activated cationic current Ih by serotonin in these neurons. Serotonin (50-500 μM) reduced the amplitude of Ih in a concentration-dependent manner; this effect was reversible after prolonged washout of serotonin. This effect was mimicked by the 5-HT2 agonist α-methylserotonin (25 μM) and reversed by the 5-HT2 antagonist ketanserin (25 μM). Serotonin reduced the maximal Ih current and conductance (measured at -130 mV) and caused a negative shift in the voltage dependence of Ih activation. The serotonin-induced reduction in Ih amplitude was antagonized by intracellular administration of the nonspecific protein kinase inhibitor H-7 (75 μM) and the selective protein kinase C inhibitor chelerythrine (25 μM). The protein kinase C activator phorbol 12, 13 diacetate (PDA, 2 μM) reduced Ih amplitude; when PDA and serotonin were applied together, the effect on Ih was less than additive. These data support the conclusion that serotonin reduces Ih in dopaminergic VTA neurons by acting at serotonin 5-HT2 receptors, which activate protein kinase C. This reduction of Ih may be physiologically important, as the selective inhibitor of Ih, ZD7288, significantly increased dopamine inhibition of firing rate of dopaminergic VTA neurons, an effect that we previously demonstrated with serotonin.

Long-lasting synaptic regulation of dopamine neurons by astrocytes in the Ventral Tegmental Area

2021 ◽  
Author(s):  
Linda Requie ◽  
Marta Gómez-Gonzalo ◽  
Francesca Managò ◽  
Mauro Congiu ◽  
Marcello Melone ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Activation ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Activity ◽  
Astrocytic Process ◽  
Metabotropic Glutamate ◽  
Ventral Tegmental

Abstract The plasticity of glutamatergic transmission in the Ventral Tegmental Area (VTA) represents a fundamental mechanism in the modulation of dopamine neuron burst firing and the phasic dopamine release at VTA target regions. These processes encode basic behavioral responses, including locomotor activity, learning and motivated-behaviors. Here we describe a hitherto unidentified mechanism of long-lasting potentiation of glutamatergic synapses on DA neurons. We found that VTA astrocytes respond to dopamine neuron bursts with Ca2+ elevations that require activation of endocannabinoid CB1 and dopamine D2 receptors colocalized at the same astrocytic process. Astrocytes, in turn, release glutamate that, through presynaptic metabotropic glutamate receptor activation coupled with neuronal nitric oxide production, induces long-lasting potentiation of excitatory synapses on adjacent dopamine neurons. Consistent with this finding, selective activation of VTA astrocytes increases dopamine neuron bursts in vivo and induces locomotor hyperactivity. Astrocytes play, therefore, a key role in the modulation of VTA dopamine neuron activity.

scholarly journals Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters

2019 ◽  
Author(s):  
Rebecca D. Howell ◽  
Sergio Dominguez-Lopez ◽  
Sarah Ocañas ◽  
Willard M. Freeman ◽  
Michael J. Beckstead
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Disease Risk ◽  
Brain Slices ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Central Feature ◽  
Neuron Firing

SUMMARYThe degeneration of substantia nigra (SN) dopamine neurons is a central feature in the pathology associated with Parkinson’s disease, which is characterized by progressive loss of motor and cognitive functions. The largest risk factors for Parkinson’s disease are age and sex; most cases occur after age 60 and males have nearly twice the incidence as females. While much research in Parkinson’s has focused on the mechanisms underlying dopamine neuron degeneration, very little work has considered the influence of these two risk factors to disease risk and presentation. In this work, we performed whole cell patch clamp recordings in brain slices to study the alterations in intrinsic firing properties of single dopamine neurons in C57BL/6 mice across ages and between sexes. We observed a progressive decline in dopamine neuron firing activity in males by 18 months of age, while dopamine neurons from females remained largely unaffected. A semiquantitative analysis of midbrain dopamine neuron populations revealed a slight decrease only in substantia nigra dopamine neurons in males, while females did not change. This was also accompanied by increases in the expression of genes that have been linked to Parkinson’s including PTEN-induced kinase 1 (PINK1) in both males and females, and the ubiquitin ligase parkin, primarily in the substantia nigra of males. These impairments in dopamine neuron function in males may represent a vulnerability to further insults that could predispose these cells to neurodegenerative diseases such as in Parkinson’s.

Physiological Properties of Zebra Finch Ventral Tegmental Area and Substantia Nigra Pars Compacta Neurons

2006 ◽  
Vol 96 (5) ◽  
pp. 2295-2306 ◽  
Author(s):  
Samuel D. Gale ◽  
David J. Perkel
Keyword(s):  
Substantia Nigra ◽  
Ventral Tegmental Area ◽  
Zebra Finch ◽  
Dopaminergic Neurons ◽  
Brain Slices ◽  
Membrane Properties ◽  
Substantia Nigra Pars Compacta ◽  
D2 Dopamine Receptors ◽  
Physiological Properties ◽  
Ventral Tegmental

The neurotransmitter dopamine plays important roles in motor control, learning, and motivation in mammals and probably other animals as well. The strong dopaminergic projection to striatal regions and more moderate dopaminergic projections to other regions of the telencephalon predominantly arise from midbrain dopaminergic neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Homologous dopaminergic cell groups in songbirds project anatomically in a manner that may allow dopamine to influence song learning or song production. The electrophysiological properties of SNc and VTA neurons have not previously been studied in birds. Here we used whole cell recordings in brain slices in combination with tyrosine-hydroxylase immunolabeling as a marker of dopaminergic neurons to determine electrophysiological and pharmacological properties of dopaminergic and nondopaminergic neurons in the zebra finch SNc and VTA. Our results show that zebra finch dopaminergic neurons possess physiological properties very similar to those of mammalian dopaminergic neurons, including broad action potentials, calcium- and apamin-sensitive membrane-potential oscillations underlying pacemaker firing, powerful spike-frequency adaptation, and autoinhibition via D2 dopamine receptors. Moreover, the zebra finch SNc and VTA also contain nondopaminergic neurons with similarities (fast-firing, inhibition by the μ-opioid receptor agonist [d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO)) and differences (strong h-current that contributes to spontaneous firing) compared with GABAergic neurons in the mammalian SNc and VTA. Our results provide insight into the intrinsic membrane properties that regulate the activity of dopaminergic neurons in songbirds and add to strong evidence for anatomical, physiological, and functional similarities between the dopaminergic systems of mammals and birds.

Medial forebrain bundle stimulation evokes endocannabinoid-mediated modulation of ventral tegmental area dopamine neuron firing in vivo

2007 ◽  
Vol 191 (3) ◽  
pp. 843-853 ◽  
Author(s):  
Giuliano Pillolla ◽  
Miriam Melis ◽  
Simona Perra ◽  
Anna Lisa Muntoni ◽  
Gian Luigi Gessa ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Medial Forebrain Bundle ◽  
Dopamine Neuron ◽  
Neuron Firing ◽  
Ventral Tegmental
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