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...

Ventral tegmental area (VTA) neuron firing precedes behaviors elicited by reward-predictive sensory cues and scales with the magnitude and unpredictability of received rewards. These patterns are consistent with roles in the performance of learned appetitive behaviors and in positive reinforcement, respectively. The VTA includes subpopulations of neurons with different afferent connections, neurotransmitter content, and projection targets. Because the VTA and substantia nigra pars compacta are the sole sources of striatal and limbic forebrain dopamine, measurements of dopamine release and manipulations of dopamine function have provided critical evidence supporting a VTA contribution to these functions. However, the VTA also sends GABAergic and glutamatergic projections to the nucleus accumbens and prefrontal cortex. Furthermore, VTA-mediated but dopamine-independent positive reinforcement has been demonstrated. Consequently, identifying the neurotransmitter content and projection target of VTA neurons recorded in vivo will be critical for determining their contribution to learned appetitive behaviors.

Dopaminergic afferents arising from the ventral tegmental area (VTA) are crucial elements in the neural circuits that mediate arousal, motivation, and reinforcement. Two major targets of these afferents are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Whereas dopamine (DA) in the mPFC has been implicated in working memory and attentional processes, DA in the NAc is required for responding to reward predictive cues. These distinct functions suggest a role for independent firing patterns of dopaminergic neurons projecting to these brain regions. In fact, DA release in mPFC and NAc can be differentially modulated. However, to date, electrophysiological studies have largely overlooked heterogeneity among VTA neurons. Here, we provide direct evidence for differential neurotransmitter control of DA neural activity and corresponding DA release based on projection target. opioid receptor agonists inhibit VTA DA neurons that project to the mPFC but not those that project to the NAc. Moreover, DA levels in the mPFC, but not the NAc, are reduced after local infusion of opioid receptor agonists into the VTA. These findings demonstrate that DA release in specific brain regions can be independently regulated by opioid targeting of a subpopulation of VTA DA neurons. Selective control of VTA DA neurons projecting to the mPFC has important implications for understanding addiction, attention disorders, and schizophrenia, all of which are associated with DA dysfunction in the mPFC.GABA ͉ reward ͉ motivation ͉ nucleus accumbens ͉ ventral tegmental area T he dopaminergic neurons of the ventral tegmental area (VTA) play a critical role in motivation and reinforcement (1-3). Two major projection targets of VTA dopamine (DA) neurons are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). DA plays different roles in these two projection targets, contributing to working memory processes in the mPFC (4, 5) and motivated responding in the NAc (6). Despite evidence that DA levels in the mPFC and NAc are differentially modulated during various behavioral conditions (7,8), electrophysiological studies have focused on the functional similarities among the VTA neurons.The VTA is an important site for opioid control of goaldirected behaviors (9). We previously showed that opioid receptor (KOP-R) agonists directly inhibit a subset of DA neurons in the VTA through activation of a G-protein-coupled, inwardly rectifying potassium channel (10). This finding, in conjunction with previous reports that limbic and cortical projections arise from largely separate populations of VTA neurons (11, 12), led us to hypothesize that postsynaptic KOP-R agonist effects on VTA neurons segregate on the basis of projection target. To address this question, we made whole-cell, patchclamp recordings in VTA neurons that were retrogradely labeled from the NAc or the mPFC and tested their postsynaptic sensitivity to KOP-R agonists. Neurons were filled with biocytin, and, after recording, brain slices were fixed and immunohistochemi...

Ca2+-sensitive kinases are thought to play a role in long-term potentiation (LTP

The ventral tegmental area (VTA) has a central role in the neural processes that underlie motivation and behavioral reinforcement. Although thought to contain only dopamine and GABA neurons, the VTA also includes a recently discovered population of glutamate neurons identified through the expression of vesicular glutamate transporter VGLUT2. A subset of VGLUT2+ VTA neurons corelease dopamine with glutamate at terminals in the NAc, but others do not express dopaminergic markers and remain poorly characterized. Using transgenic mice that express fluorescent proteins in distinct cell populations, we now find that both dopamine and glutamate neurons in the medial VTA exhibit a smaller hyperpolarization-activated current (Ih) than more lateral dopamine neurons and less consistent inhibition by dopamine D2 receptor agonists. In addition, VGLUT2+ VTA neurons project to the nucleus accumbens (NAc), lateral habenula (LHb), ventral pallidum (VP) and amygdala. Optical stimulation of VGLUT2+ projections expressing channelrhodopsin-2 further reveals functional excitatory synapses in the VP as well as the NAc. Thus, glutamate neurons form a physiologically and anatomically distinct sub-population of VTA projection neurons.

Dopaminergic neurons of the ventral tegmental area (VTA) play a critical role in motivation and reinforcement of goal-directed behaviors. Furthermore, excitation of these neurons has been implicated in the addictive process initiated by drugs such as morphine that act at the micro-opioid receptor (MOR). In contrast, kappa-opioid receptor (KOR) activation in the VTA produces behavioral actions opposite to those elicited by MOR activation. The mechanism underlying this functional opposition, however, is poorly understood. VTA neurons have been categorized previously as principal, secondary, or tertiary on the basis of electrophysiological and pharmacological characteristics. In the present study using whole-cell patch-clamp recordings, we demonstrate that a selective KOR agonist (U69593, 1 microm) directly inhibits a subset of principal and tertiary but not secondary neurons in the VTA. This KOR-mediated inhibition occurs via the activation of a G-protein-coupled inwardly rectifying potassium channel and is blocked by the selective KOR antagonist nor-Binaltorphimine (100 nm). Significantly, regardless of cell class, KOR-mediated inhibition was found only in tyrosine hydroxylase-immunoreactive and thus dopaminergic neurons. In addition, we found a subset of principal neurons that exhibited both disinhibition by a selective MOR agonist ([d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin) (3 microm) and direct inhibition by KOR agonists. These results provide a cellular mechanism for the opposing behavioral effects of KOR and MOR agonists and shed light on how KORs might regulate the motivational effects of both natural rewards and addictive drugs.

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The midbrain ventral tegmental area (VTA) projection to the nucleus accumbens (NAc) is implicated in motivation and reinforcement. A significant number of NAc medium spiny neurons (MSNs) project back to the VTA, although the nature of this projection is essentially unknown. For example, do NAc MSNs directly target accumbens-projecting dopamine neurons and do they act via the GABA A or GABA B receptor? To address these issues, we expressed the light-sensitive channel rhodopsin-2 in the rat NAc and made electrophysiological recordings from VTA neurons ex vivo. We found that the NAc directly targets non-dopaminergic VTA neurons, including some that project back to the NAc. These MSN GABAergic terminals are opioid sensitive and act via GABA A receptors.