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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Cocaine benzoylmethylecgonine , a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. Unfortunately, the relationships between its behavioral and electrophysiological effects are not clear. We investigated the effects of cocaine on the firing of midbrain dopaminergic DA neurons, both in anesthetized and awake rats, using pre-implanted multielectrode arrays and a recently developed telemetric recording system. In awake rats, however, injection of cocaine led to a very different pattern of changes in firing. Drug concentration measurements indicated that the observed differences between the two conditions did not have a pharmacokinetic origin. Taken together, our results demonstrate that cocaine injection differentially affects the electrical activity of DA neurons in awake and anesthetized states. The observed increases in neuronal activity may in part reflect the cocaine-induced synaptic potentiation found ex vivo in these neurons. Our observations also show that electrophysiological recordings in awake animals can uncover drug effects, which are masked by general anesthesia. Cocaine benzoylmethylecgonine is a naturally occurring alkaloid extracted from plants belonging to the Erythroxylum species. It is known to produce a number of pharmacological effects, including psychomotor stimulation, hypertension, tachycardia, anorexia, and pupillary dilation. Central effects of cocaine are attributed to its ability to inhibit reuptake of dopamine, serotonin, and norepinephrine Reith et al, , b ; Richelson and Pfenning, ; Ritz et al, ; Ross and Renyi, It is believed that blockade of the uptake, by increasing the synaptic concentrations of these neurotransmitters Bradberry and Roth, ; Li et al, ; Reith et al, a , leads to an increase in vigilance and sensory awareness, activation of defense mechanisms, cognitive distortion, euphoria, and a reduced need for sleep Clark et al, b ; Freye and Levy, Owing to its potent rewarding effect, cocaine has a high abuse liability. Its consumption in modern society has become increasingly common, as shown by population statistics Clark et al, b ; Freye and Levy, Consequences of chronic use include a massive addiction, an increased risk of psychiatric illnesses, and deleterious consequences on general health eg, an increased risk of myocardial infarction Lange and Hillis, The addictive properties of cocaine are thought to be mediated mainly by the dopaminergic DA mesocorticolimbic system—the pathways projecting from the ventral tegmental area VTA to the medial prefrontal cortex, nucleus accumbens NAc , amygdala, and hippocampus Chiodo et al, ; McCutcheon et al, ; Peoples et al, ; Wise and Bozarth, Using in vivo voltammetry, it was shown that systemic cocaine injection in awake and behaving rats produces a significant increase of DA concentration in NAc synapses, correlating to the cocaine-induced psychostimulant behaviors Broderick et al, On the other hand, application of cocaine in electrophysiological experiments leads to a decrease in the firing of DA neurons in vivo Einhorn et al, ; Hinerth et al, ; Mercuri et al, and a hyperpolarization of DA neurons in vitro Brodie and Dunwiddie, ; Einhorn et al, ; Lacey et al, ; Mercuri et al, , These effects are explained by the fact that dopamine, released from the axons and dendrites, enhances the activity of an NAc-VTA GABAergic negative feedback and activates somatodendritic autoreceptors on the DA neurons Einhorn et al, ; Kalivas, ; Wang, ; White and Wang, a , b , However, in vivo electrophysiological experiments mentioned above were conducted under general anesthesia, which is known to change the responses of central neurons to various compounds Kelland et al, , ; Nicoll and Madison, ; Windels and Kiyatkin, In particular, it was shown that anesthesia affects cocaine metabolism Benuck et al, ; Pan et al, , alters the reactivity of DA neurons to glutamate, GABA, DA agonists, and DA antagonists Bunney et al, a ; Clark et al, a , b ; Gessa et al, ; Kelland et al, , ; Melis et al, ; Mereu et al, , ; Windels and Kiyatkin, , and interferes with DA turnover Westerink et al, For example, nicotine and ethanol have a stimulating effect on the VTA neurons in awake rats, but fail to activate them in anesthetized animals Gessa et al, ; Mereu et al, A number of combined electrophysiological and behavioral studies on cocaine have been performed in awake rats, but have mostly focused on NAc neurons Carelli, ; Carelli and Deadwyler, ; Peoples et al, ; Peoples and West, ; Stuber et al, On the other hand, in vitro investigations of the cocaine effect on VTA neurons were performed in slices, where some important regulatory pathways are severed. These caveats make it difficult to compare cocaine-induced electrophysiological effects in the midbrain and its behavioral actions. Thus, the question of how cocaine administration changes the activity of DA neurons in awake, behaving animals remains open. To address this issue, we measured the effects of this drug on the firing rate and pattern of midbrain DA neurons in both awake and freely moving and anesthetized rats, taking advantage of the recent development of telemetric techniques. In addition, we measured plasma and brain concentrations of cocaine and its main metabolite, benzoylecgonine BZE Freye and Levy, , in order to evaluate the possibility of differential pharmacokinetics of cocaine in the two conditions and to measure the actual brain concentrations after the injection of a behaviorally relevant dose of the drug. Water and food were available ad lib. All animal care and handling was conducted in accordance with the guidelines stated in the Handbook for the Use of Animals in Neuroscience Research Society for Neuroscience, Soft tissues of the skull were anesthetized using a subcutaneous injection of 0. Four to five small holes were made in the skull around the area of entry using a 1. The area of entry was defined according to stereotaxic coordinates Ford and Williams, A small part of the skull between the lambda and the bregma was removed above the implantation point using a 0. An MEA 8 recording and one reference electrode; Supplementary Figure S1 was mounted on the micromanipulator and the tips of the electrodes were lowered into the VTA through the opening 5. Paul, MN. In all experiments reported here, this examination confirmed that the recording electrodes were positioned within the dorsocaudal section of the VTA Supplementary Figure S2A and B. This area is also known to be more important for the rewarding and addictive effects of drugs of abuse than the rostral VTA Ikemoto, ; Krebs et al, The transmitter was placed on the animal's back using a special jacket and was connected to the pre-implanted MEA via an Omnetics connector. The receiver was connected to the computer via a USB cable. Albans, VT. Experiments were run 4—6 days after surgery. Session 2: At the beginning of the session, animals received an injection of saline 0. Electrophysiological and pharmacological parameters were used in order to identify DA neurons. They have a slow firing rate range: 0. We did not use the spike shape as a criterion because the exact electrode position could not be controlled in our experimental conditions. Several studies have demonstrated that the extracellular spike waveform varies with the electrode position relatively to the site of action potential generation in the recorded cell Berretta et al, ; Cohen and Miles, ; Gold et al, The fast transients corresponding to spontaneous action potentials were captured online using the Alpha Omega TeleSpike software, and were subsequently transferred to the Spike2 6. We also calculated the percentage of spikes generated in a burst firing pattern with regard to the total number of spikes. Bursts were identified using previously established criteria for discriminating burst from non-burst events in A10 and A9 DA neurons Clark and Chiodo, ; Grace and Bunney, For the pharmacokinetic study, experimental conditions were set as close as possible to those of the electrophysiological recordings. Each of them then received an i. Sampling procedures were adapted from Bowman et al Animals were killed by decapitation. Brain tissue and blood collected from trunk vessels were used to measure cocaine and BZE levels see Supplementary materials for details. Cocaine hydrochloride for i. Quinpirole was obtained from Tocris Bristol, UK. The neurons were nested within the rats, which were in turn nested within the treatment groups anesthetized vs non-anesthetized subjects. The treatment groups were treated as a between-subject factor, while time points before and after cocaine administration were treated as a within-subject factor. Cocaine and BZE plasma and brain concentrations were evaluated by a two-tailed Student's t -test. Analysis of locomotor behavior during the baseline period did not reveal significant differences between the LCR and HCR groups. Recordings were made from a total of units in 28 awake rats and a total of 94 units in 19 anesthetized rats. Using the criteria described in the Materials and methods, we classified units in 24 awake animals and 80 units in 19 anesthetized animals as presumably DA. Their average firing frequency during the baseline period was 1. These values were not statistically different from each other. The main panel represents the mean activity of 24 neurons from anesthetized rats. The inset shows the activity from 27 neurons in the anesthetized group. In three of them, an increase in firing rate occurred shortly before the cocaine injection see text for further details. Error bars represent the standard error of mean SEM. PowerPoint slide. Cocaine, however, induced various patterns of changes in individual DA neurons. This allowed us to separate several subgroups of neurons in each group of rats. This biphasic effect of cocaine on some DA neurons in anesthetized animals was already described previously Einhorn et al, The basal activity in these two subgroups of neurons did not differ significantly and was 1. During the 10 last minutes of the observation period, the firing rate had decreased to 0. The panels show aggregate data from different subgroups see text. Examples of the effect of a systemic cocaine injection on the firing rate and bursting in two different rats during chloral hydrate anesthesia. Each vertical bar at the bottom of the panels represents an individual burst event see Materials and methods. These neurons had low basal firing rate 0. In two DA neurons, the injection of cocaine was followed by an increase in firing rate from 1. No bursting activity was detected in these neurons. Patterns of changes induced by cocaine in DA neurons from awake rats were much more variable than in anesthetized animals. In Subgroup 1 15 units, from 7 animals , injection of cocaine led to a gradual increase in firing rate. Firing rates increased up to 0. The degree of correlation between firing rate and locomotor activity Pearson's coefficient is indicated for each cell. The activity in Subgroup 3 27 units, from 8 animals fluctuated. This was the only subgroup of neurons in which the firing rate was positively correlated to the locomotor activity see Figure 5 for examples. Separate averaging of the activity recorded from HCR and LCR rats showed no significant difference in the basal firing rate of these neurons. It was significantly higher in Subgroup 2 2. Other recorded neurons did not show significant changes in activity after the cocaine injection within the period of observation. Other DA neurons did not undergo significant changes in either firing rate or bursting. Overall, this dose of i. The firing rate of three out of these seven neurons was completely inhibited and recovered only by the end of the anesthesia period see examples in Figure 6. There were no significant differences in cocaine concentrations between the awake and anesthetized rats in either plasma or brain tissue. BZE concentrations in the plasma were significantly lower in anesthetized animals than in awake rats. This suggests that breakdown of cocaine was inhibited under chloral hydrate anesthesia, which is in accordance with the finding by other groups that chloral hydrate inhibits cocaine esterase Benuck et al, ; Pan et al, , the enzyme forming BZE from cocaine Mets et al, The results of this study demonstrate that an acute injection of cocaine differentially affects midbrain DA neurons in awake and anesthetized rats. In anesthetized rats, the i. This is an anticipated effect, consistent with the knowledge about autoregulatory mechanisms within the mesolimbic pathways Kalivas, ; Wang, ; White and Wang, a , b , and congruent with the action of cocaine on the dopamine transporter Kuhar et al, It is consistent with previous electrophysiological experiments conducted in vivo under general anesthesia Einhorn et al, ; Hinerth et al, ; Mercuri et al, By contrast, in non-anesthetized rats, injection of the same dose of cocaine increased the firing rate and bursting of a majority of DA neurons. As discussed below, a number of mechanisms may account for the excitatory effects of cocaine in awake animals. We will discuss separately the two patterns of excitatory effects. To our knowledge, this effect has never been described before, and it was not observed in anesthetized animals in our hands. One attractive explanation for this result is the induction of a long-term potentiation of glutamatergic synapses on DA neurons. Such a phenomenon has been observed after a single exposure to cocaine in brain slices Ungless et al, Enhancement of NMDA-mediated transmission can be already measured within a few minutes Argilli et al, ; Schilstrom et al, , thus having a time course that is compatible with the one of our experiments Figure 4a , suggesting that these events might have a similar origin. It should also be remembered that several VTA-projecting areas release neurotransmitters that are able to excite DA neurons Geisler et al, ; Mathon et al, ; White, Geisler et al demonstrated that at least some of these afferents are activated in awake animals by repeated cocaine administration, which can in turn lead to the activation of VTA DA cells. General anesthesia can abolish this effect of cocaine, as it markedly decreases the activity of many central neurons. This can explain the difference between awake and anesthetized rats in our experiments. However, the local anesthetic effect of cocaine may require higher concentrations of the drug in the brain tissue than those achieved in our experiments Strichartz, Another possibility is that, by blocking the serotonin transporter Reith et al, ; Ritz et al, , cocaine may increase the concentration of serotonin in the VTA Reith et al, a , leading to the activation of inhibitory presynaptic 5HT 1D receptors on GABA terminals Cameron and Williams, ; Johnson et al, , and therefore disinhibition of DA neurons. A final explanation is provided by the block of the noradrenaline transporter by the drug. The concentration of noradrenaline is known to increase after the injection of cocaine Reith et al, a. We do not know whether fluctuations in the activity of these neurons were secondary to the cocaine-induced locomotor effects, or whether changes in their firing underlied locomotor activation. The fact that VTA neurons play an important role in motivation makes the latter interpretation very attractive, but this issue needs further investigation. Behavioral effects of cocaine that were observed in this study are in a good agreement with previous observations in Sprague—Dawley rats Gulley et al, ; Mandt and Zahniser, ; Sabeti et al, We would also like to emphasize the difference observed in the basal firing rate of the Subgroup 1 neurons recorded from LCR and HCR rats. Similar differences in the basal firing rate were reported for VTA DA neurons between rats expressing a low and high reaction to novelty McCutcheon et al, Interestingly, animals exhibiting a higher response to novelty also have an enhanced susceptibility to addiction Belin et al, ; Cain et al, ; Grimm and See, ; Marinelli and White, ; Piazza et al, , , ; Pierre and Vezina, ; Stoffel and Cunningham, Moreover, the reactivity of their VTA DA neurons is suggested to be critical for the development of addictive behavior Marinelli et al, , ; Marinelli and White, ; McCutcheon et al, ; Vezina, ; White and Kalivas, a. Although the relationship between the levels of locomotor response to novelty and of cocaine-induced locomotion remains controversial Allen et al, ; Chefer et al, ; Gulley et al, ; Hooks et al, ; Mercuri et al, ; Sabeti et al, , our findings suggest a possible common substratum of these two types of behavior. Physiological mechanisms underlying lower and higher behavioral reactivity to cocaine are not completely clear. The diversity of locomotor reactivity might be due to a recently demonstrated difference in the levels of DAT activity in the NAc and striatum Sabeti et al, , leading to different extracellular DA levels Nelson et al, DA cells from the lateral portion of VTA mostly project to the ventral pallidum Klitenick et al, Further studies are needed to evaluate possible relationship between the difference in the basal firing rate of these neurons observed in LCR and HCR rats and vulnerability of animals to the reinforcing effect of the drug. At the same time, mesopallidal DA projections play a role in the maintenance of locomotor activity, and microinjections of DA into the ventral pallidum were shown to stimulate locomotion Klitenick et al, It is possible that neurons from Subgroup 3 Figure 4c in our study belonged to this population. Differences between drug effects in awake and anesthetized animals have been reported in other brain areas. For example, cocaine increases the activity of striatal and accumbal neurons in freely moving animals Kiyatkin, ; Kiyatkin and Rebec, ; Pederson et al, ; White et al, b , but decreases their firing in anesthetized ones Kreuter et al, Chloral hydrate anesthesia has often been used in electrophysiological experiments on DA neurons Einhorn et al, ; Freeman et al, ; Grace and Bunney, ; Shepard and German, The reason is that the pattern of activity of DA neurons recorded from chloral hydrate-anesthetized animals is relatively similar to the pattern of activity of DA neurons recorded from animals in the awake state Freeman and Bunney, ; Hyland et al, This led to the assumption that chloral hydrate has a mild effect on the afferent synaptic inputs to the midbrain DA neurons. However, the tone of afferent inputs in anesthetized animals is probably different from the one in behaving animals, as anesthesia changes the activity and sensitivity of different components of central circuitry, including those sending afferent projections to the midbrain DA system Hamilton et al, ; Heym et al, ; Kreuter et al, ; Trulson and Trulson, a , b ; Warenycia and McKenzie, Moreover, chloral hydrate does affect midbrain DA neurons themselves, altering their responsiveness to various centrally acting drugs Bunney et al, a ; Gessa et al, ; Kelland et al, , ; Melis et al, ; Mereu et al, , particularly enhancing the ability of DA agonists to inhibit activity of DA neurons Kelland et al, A clear effect of chloral hydrate on DA neurons was observed in our study. Indeed, a majority of the DA neurons recorded in awake rats were partly or fully suppressed by chloral hydrate injection Figure 6. At the same time, we did not find significant differences in the baseline firing rate of DA neurons between awake and anesthetized animals Figure 1. Collectively, these observations suggest that populations of DA neurons recorded in the awake and anesthetized animals were different—a large fraction of the DA neurons, contributing to the firing rate under general anesthesia, were silent in the awake state, and vice versa. This would explain the difference in the cocaine effects, especially in view of the recent observation that the properties of glutamatergic synapses onto the various subpopulations of VTA DA neurons are heterogeneous Lammel et al, Anesthesia also excludes stress, which is known to affect the DA system. In the awake animals, a mild stress could potentiate DA neuron firing, as has been shown for mesoprefrontal neurons Thierry et al, However, we tried to minimize stress by careful habituation of the rats before the experimental sessions. We therefore do not favor this explanation as a reason for the observed differences. The previously demonstrated ability of general anesthesia to alter cocaine metabolism Benuck et al, ; Pan et al, suggested that differences in the cocaine effects between awake and anesthetized rats might have a pharmacokinetic origin. We found the expected difference in plasma BZE concentrations, which is explained by the inhibition of cocaine esterase by chloral hydrate Benuck et al, ; Pan et al, However, cocaine concentrations in the brain were not significantly different in the awake and anesthetized animal, and were much higher than the concentration of BZE. These results allow us to suggest that the differences observed in our electrophysiological experiments have a pharmacodynamic rather than a pharmacokinetic origin. This study demonstrates strikingly different effects of i. Such a difference is also likely to exist for other drugs of abuse. 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Supplementary Information accompanies the paper on the Neuropsychopharmacology website. Reprints and permissions. Koulchitsky, S. Neuropsychopharmacol 37 , — Download citation. Received : 03 November Accepted : 22 December Published : 01 February Issue Date : June Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content Thank you for visiting nature. Download PDF. Subjects Neurophysiology Pharmacodynamics. Abstract Cocaine benzoylmethylecgonine , a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. In vivo patch-clamp recordings reveal distinct subthreshold signatures and threshold dynamics of midbrain dopamine neurons Article Open access 08 December Identification of DA Neurons Electrophysiological and pharmacological parameters were used in order to identify DA neurons. Data Analysis The fast transients corresponding to spontaneous action potentials were captured online using the Alpha Omega TeleSpike software, and were subsequently transferred to the Spike2 6. Pharmacokinetic Study For the pharmacokinetic study, experimental conditions were set as close as possible to those of the electrophysiological recordings. Drugs and Chemicals Cocaine hydrochloride for i. Characteristics of Recorded Neurons Recordings were made from a total of units in 28 awake rats and a total of 94 units in 19 anesthetized rats. Figure 1. Full size image. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Effect of General Anesthesia Differences between drug effects in awake and anesthetized animals have been reported in other brain areas. Lack of Effect of Anesthesia on Brain Cocaine Concentrations The previously demonstrated ability of general anesthesia to alter cocaine metabolism Benuck et al, ; Pan et al, suggested that differences in the cocaine effects between awake and anesthetized rats might have a pharmacokinetic origin. Acknowledgements This work was supported by Grant No. View author publications. Ethics declarations Competing interests The authors declare no conflict of interest. Additional information Supplementary Information accompanies the paper on the Neuropsychopharmacology website. Supplementary information. Supplementary Information DOC 29 kb. Supplementary Figure 1 JPG kb. Supplementary Figure 2 JPG kb. Supplementary Figure 3 JPG kb. Supplementary Figure 4 JPG kb. Supplementary Figure 5 JPG kb. Supplementary Figure 6 JPG kb. PowerPoint slides PowerPoint slide for Fig. PowerPoint slide for Fig. Rights and permissions Reprints and permissions. About this article Cite this article Koulchitsky, S. 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drugs of abuse such as cocaine. A brain slice preparation of the VTA was used to assess the direct effects of cocaine on the spontaneous activity of.
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Behavioral studies have implicated central dopaminergic systems, especially the ventral tegmental area of Tsai VTA , in the mediation of the reinforcing effects of drugs of abuse such as cocaine. A brain slice preparation of the VTA was used to assess the direct effects of cocaine on the spontaneous activity of dopamine-type neurons. While there was a considerable variability in the response to a given concentration of cocaine among the individual units, every cell inhibited by dopamine was also inhibited by cocaine. The local anesthetic lidocaine had variable effects on firing rate, but never potentiated the inhibitory effects of dopamine. Inhibitory responses to either dopamine or cocaine were blocked by the specific D2 dopamine receptor antagonist sulpiride. Small concentrations of cocaine 0. Furthermore, the inhibitory action of apomorphine on spontaneous activity in the VTA was not potentiated by cocaine. These observations suggest that in low concentrations, cocaine can act as a dopamine reuptake inhibitor in the VTA, and that the resultant increase in extracellular dopamine acts upon dopamine autoreceptors to inhibit cellular activity. This is a preview of subscription content, log in via an institution to check access. Rent this article via DeepDyve. Institutional subscriptions. Albanese A, Minciacchi D Organization of the ascending projections from the ventral tegmental area: a multiple fluorescent retrograde tracer study in the rat. J Comp Neurol — Brain Res — Soc Neurosci Abstr Google Scholar. Brodie MS, Dunwiddie TV The effects of cocaine on ventral tegmental area spontaneous activity in vitro: Interactions with dopamine, sulpiride and cholecystokinin. Brodie MS, Dunwiddie TV Cholecystokinin potentiates dopamine inhibition of mesencephalic dopamine neurons in vitro. Carter DA, Fibiger HC Ascending projections of presumed dopamine-containing neurons in the ventral tegmentum of the rat as demonstrated by horseradish peroxidase. Neuroscience — Dahlstrom A, Fuxe K Evidence for the existence of monoamine-containing neurons in the central nervous system. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand 62 Suppl :1— J Neurophysiol — Einhorn LC, White FJ Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: Studies in the ventral tegmental area. Einhom LC, White FJ Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: Studies in the ventral tegmental area. J Neurosci — Science — Action potential generating mechanisms and morphological correlates. CAS Google Scholar. Biochem Pharmacol — Iversen LL Uptake mechanisms for neurotransmitter amines. J Physiol Lond — Br J Pharmacol — Llinas R, Greenfield SA, Jahnsen H Electrophysiology of pars compacta cells in the in vitro substantia nigra — a possible mechanism for dendritic release. Maeda H, Mogenson GJ An electrophysiological study of inputs to neurons of the ventral tegmental area from the nucleus accumbens and medial preoptic-anterior hypothalamic areas. Matthews RT, German DC Electrophysiological evidence for excitation of rat ventral tegmental area dopamine neurons by morphine. Psychopharmacology — Phillipson OT Afferent projections to the ventral tegmental area of Tsai and interfascicular nucleus: a horseradish peroxidase study in the rat. Pinnock RD Hyperpolarizing action of baclofen on neurons in the rat substantia nigra slice. Pitts DK, Marwah J a Effects of cocaine on single spontaneously firing central monoaminergic neurons. Pitts DK, Marwah J b Effects of cocaine on the electrical activity of single noradrenergic neurons from locus coeruleus. Life Sci — Pharmacol Biochem Behav — Roberts DCS, Koob GF Disruption of cocaine self-administration following 6-hydroxydopamine lesions of the ventral tegmental area in rats. Eur J Pharmacol — J Pharmacol Exp Ther — Strichartz G Molecular mechanisms of nerve block by local anesthetics. Anesthesiology — Suppes T, Pinnock RD Sensitivity of neuronal dopamine response in the substantia nigra and ventral tegmentum to clozapine, metoclopramide and SCH Neuropharmacology — Wang RY a Dopaminergic neurons in the rat ventral tegmental area. Identification and characterization. Brain Res Rev — Wang RY b Dopaminergic neurons in the rat ventral tegmental area. Evidence for autoregulation. Wang RY c Dopaminergic neurons in the rat ventral tegmental area. Effects of D- and l. White FJ Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: Studies in the nucleus accumbens. White FJ, Wang RY A10 dopamine neurons: role of autoreceptors in determining firing rate and sensitivity to dopamine agonists. Wise RA Catecholamine theories of reward: A critical review. Neurosci Lett — Download references. You can also search for this author in PubMed Google Scholar. Reprints and permissions. Brodie, M. Cocaine effects in the ventral tegmental area: Evidence for an indirect dopaminergic mechanism of action. Naunyn-Schmiedeberg's Arch Pharmacol , — Download citation. Received : 20 April Accepted : 31 July Issue Date : December Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Home Naunyn-Schmiedeberg's Archives of Pharmacology Article Cocaine effects in the ventral tegmental area: Evidence for an indirect dopaminergic mechanism of action Published: December Volume , pages —, Cite this article. Summary Behavioral studies have implicated central dopaminergic systems, especially the ventral tegmental area of Tsai VTA , in the mediation of the reinforcing effects of drugs of abuse such as cocaine. Access this article Log in via an institution. Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior Article 23 January Effects of abstinence from chronic cocaine self-administration on nonhuman primate dorsal and ventral noradrenergic bundle terminal field structures Article 27 May References Albanese A, Minciacchi D Organization of the ascending projections from the ventral tegmental area: a multiple fluorescent retrograde tracer study in the rat. Author information Author notes Mark S. Dunwiddie Authors Mark S. Brodie View author publications. View author publications. Additional information Send offprint requests to T. Rights and permissions Reprints and permissions. About this article Cite this article Brodie, M. Copy to clipboard. 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