The ventral tegmental area revisited: is there an electrophysiological marker for dopaminergic neurons?

Abstract

The ventral tegmental area (VTA) and in particular VTA dopamine (DA) neurons are postulated to play a central role in reward, motivation and drug addiction. However, most evidence implicating VTA DA neurons in these functions is based on indirect electrophysiological characterization, rather than cytochemical identification. These physiological criteria were first established in the substantia nigra pars compacta (SNc), but their validity in the VTA is uncertain. In the current study we found that while 88 ± 2% of SNc neurons labelled by the neuronal marker NeuN were co-labelled for the catecholamine enzyme tyrosine hydroxylase (TH), a much smaller percentage (55 ± 2%) of VTA neurons co-expressed TH. In addition, using in vitro whole-cell recordings we found that widely accepted physiological criteria for VTA DA neurons, including the hyperpolarization-activated inwardly rectifying non-specific cation current (I h ), spike duration, and inhibition by DA D2 receptor agonists, do not reliably predict the DA content of VTA neurons. We could not distinguish DA neurons from other VTA neurons by size, shape, input resistance, I h size, or spontaneous firing rate. Although the absence of an I h reliably predicted that a VTA neuron was non-dopaminergic, and I h (−) neurons differ from I h (+) neurons in firing rate, interspike interval (ISI) standard deviation, and ISI skew, no physiological property examined here is both sensitive and selective for DA neurons in the VTA. We conclude that reliable physiological criteria for VTA DA neuron identification have yet to be determined, and that the criteria currently being used are unreliable. Ventral tegmental area (VTA) neurons are the source of dopamine (DA) projections to the limbic forebrain and have been implicated in attention, memory, reward and motivation (Chudasama & Robbins, 2004;Wise, 2004;Nicola et al. 2005). In vivo single unit electrophysiological recordings have demonstrated that VTA neurons respond to novel stimuli, unexpected rewards, and reward predictive sensory cues, and that they fire in a pattern consistent with the encoding of reward expectancy error (Schultz, 1998;Hyland et al. 2002;Dommett et al. 2005). The conclusion that neurons with these patterns of response are dopaminergic is critical to hypotheses about the role of dopamine signalling in motivation, reward and drug addiction.Unfortunately, current criteria for VTA DA neuron identification are based largely on indirect and in some cases conflicting evidence. Furthermore, when these criteria are used, subsets of putative DA neurons have different patterns of response (e.g. Kiyatkin & Rebec, 2001;Hyland et al. 2002;Tobler et al. 2003). For example, in vivo studies in which DA neurons were identified during extracellular recordings by action potential waveform and firing pattern properties found both excitations and inhibitions induced by noxious stimuli (Mantz et al. 1989;Romo & Schultz, 1989). However, Ungless et al. (2004), using in vivo intracellular recordings, showed that only inhibitions occ...

Increased desensitization of dopamine D2 receptor-mediated response in the ventral tegmental area in the absence of adenosine A2A receptors

“…Dopamine did not inhibit the firing of these classically defined non-dopaminergic or GABAergic neurons (Grace & Onn, 1989;Johnson & North, 1992). A recent study confirmed that almost all electrophysiologically-classified dopaminergic neurons are tyrosine hydroxylasepositive (Brown et al, 2009), despite discrepancies found in some other studies (Margolis et al, 2006;Margolis et al, 2010). "Dopamine neurones" referred to in this study are therefore those that conform to electrophysiological and pharmacological criteria, but not necessarily to the content of dopamine.…”

High-Frequency Afferent Stimulation Induces Long-Term Potentiation of Field Potentials in the Ventral Tegmental Area

“…If the I h current during a step from À50 to À100 mV was present, the neuron was considered a dopamine neuron; if not, the cell was classified as a GABA neuron. While the absence of I h reliably predicts that a VTA neuron is non-dopaminergic, I h is also present in a group of VTA neurons, which are not dopaminergic (Margolis et al, 2006).…”

Local Application of Drugs to Study Nicotinic Acetylcholine Receptor Function in Mouse Brain Slices

“…For example, the expression of I h current, resting membrane potential, spontaneous firing rate, and cell size are typical measures used to characterize DA neurons 2,7,8,16,17 . Using our method, it is also possible to characterize neurons based on their response to locally-applied nicotine or ACh 18,19 .…”