Extracellular dopamine in the rat ventral tegmental area and nucleus accumbens following ventral tegmental infusion of cocaine

Rats were implanted with dual dialysis probes, one in the ventral tegmental area, and another one ipsilateral in the nucleus accumbens. Infusion of cocaine (10, 100, 1000 mM) into the ventral tegmental area gradually increased extracellular dopamine to 164, 329 and 991% of baseline in the ventral tegmental area, but reduced dopamine to 76, 47 and 38% of baseline in the nucleus acumbens. These results are consistent with cocaine-induced feedback regulation of dopamine cell activity involving somatodendritec impulse-regulating dopamine D₂ autoreceptors.     

Increase of tyrosine hydroxylase-like immunoreactive neurons in the nucleus accumbens and the olfactory bulb in the rat with the lesion in the ventral tegmental area of the midbrain

A small number of neurons in the nucleus accumbens of the rat showed tyrosine hydroxylase-like immunoreactivity (TH-LI). These TH-LI neurons had medium-sized cell bodies with several spiny dendrites. When a lesion was produced in the ventral tegmental area of the midbrain by injecting 6-hydroxydopamine, TH-LI neurons in the nucleus accumbens, as well as those in the olfactory bulb, were increased in number on the side ipsilateral to the lesion. The results indicated that expression of TH might be enhanced in some neurons deprived of dopaminergic afferent fibers.     

An electrophysiological study of inputs to neurons of the ventral tegmental area from the nucleus accumbens and medial preoptic-anterior hypothalamic areas

Extracellular recordings were obtained from neurons in the ventral tegmental area (VTA) of urethane-anesthetized rats. Neurons were devided into two types based on the latencies of antidromic activation following electrical stimulation of the nucleus accumbens (NAcc), and on the durations of action potentials. Type A neurons had longer latencies for antidromic activation (mean 15.9 msec) and longer durations of action potentials (2.6msec), while type B neurons had shorter latencies (mean 4.5 msec) and shorter duration of action potentials (< 2.6msec).Electrical stimulation of the medial preoptic-anterior hypothalamic areas (mPOA-AHA) and NAcc produced the following effects on the two types of VTA neurons: (i) the majority of both type A and B neurons were suppressed by mPOA-AHA stimula stimulation with onset latencies of less than 10 msec; (ii) 42% of type B neurons were also suppressed by NAcc stimulation, with onset latencies of less than 10 msec; (iii) type A neurons were suppressed (33%) or activated (43%) by NAcc stimulation, the onset latencies usually being longer than 10 msec; (iv) 71% of type A neurons tested had convergent inputs from the mPOA-AHA and NAcc, usually suppressed-suppressed or suppressed-activated, while 45% of type B neurons had convergent inputs from these two areas, usually suppressed-suppressed.     

The nucleus accumbens and inhibition in the ventral tegmental area play a causal role in the Kamin blocking effect

The discovery of Kamin blocking led to the idea that associative learning occurs only when there is a mismatch between actual and predicted outcomes, or prediction error. The neural substrates involved in regulating this prediction error during behavioral learning are still not fully elucidated. We investigated in rats the role of the ventral tegmental area and the nucleus accumbens in Kamin blocking. Our blocking paradigm involved three phases: appetitive classical conditioning of a lever cue, conditioning of a compound of the lever cue plus an auditory cue, and testing response to the auditory cue in extinction. We found that disruption of inhibition in the ventral tegmental area by bicuculline, or designer receptor mediated inactivation of the nucleus accumbens, during compound cue conditioning, attenuated Kamin blocking. These results suggest that inhibition in the ventral tegmental area and inhibitory output from the nucleus accumbens are necessary for blocking and make behaviorally significant contributions to the computation of reward prediction error. In addition, we found that inactivating the neurons in the nucleus accumbens during classical conditioning of the lever cue also attenuated blocking, without affecting classical conditioning of the lever. This indicates that learning in the nucleus accumbens is necessary for blocking and reward estimation. Our results reveal a causal role for nucleus accumbens modulated inhibitory inputs to the ventral tegmental area in the blocking effect and suggest that they contribute to computation of reward prediction error during associative learning.     

Neurotensin neurons in the ventral tegmental area project to the medial nucleus accumbens

Opiate receptors measured in vitro or in vivo with [3H]lofentanil in the rat vagus nerve were found to accumulate on both sides of a ligature, thus indicating a bidirectional axoplasmic transport of these receptors. When rats were treated with capsaicin, the accumulation of opiate receptors was tremendously reduced in the vagus whereas muscarinic receptors in ligated sciatic nerves were unaffected. Since capsaicin is known to affect sensory neurones, mostly those containing substance P, the present results support the idea that the opiate receptors in the vagus are associated with substance P neurones.     

Stimulation of ventral tegmental area and nucleus accumbens reduce receptive fields for hypothalamic biting reflex in cats

Stimulation of the ventral tegmental area (VTA) and nucleus accumbens (NA) suppressed attack behavior elicited by hypothalamic stimulation. Because the nondirected somatic motor and autonomic components of attack were not affected by VTA or NA stimulation, and previous work had demonstrated the importance of sensory guidance in attack, the mechanism for suppression was postulated to be on the sensory component of the attack reaction. We investigated the effects of VTA and NA stimulation on the biting reflex, one of the sensory-controlled components of hypothalamically elicited attack behavior. The receptive field for biting was measured during hypothalamic stimulation with and without concurrent VTA and NA stimulation. At stimulation parameters that inhibited attack, the extent of the receptive field was reduced. Thus, VTA and NA may produce inhibition of attack by acting on the sensory component of the response mechanism. We suggest that reduction of receptive fields is a mechanism by which behavioral inhibition is mediated in the central nervous system.     

Suppression of attack behavior in cats by stimulation of ventral tegmental area and nucleus accumbens

Low frequency (6 pps) stimulation of ventral tegmental area (VTA) and nucleus accumbens (NA) produced EEG synchronization and suppressed attack behavior elicited by hypothalamic stimulation. Both quiet biting and affective attack with rage were suppressed. Autonomic and non-directed somatic motor components of the attack reaction were unaffected.High frequency (60 pps) stimulation of VTA failed to suppress any components of the attack reaction; high frequency stimulation of NA, however, did produce suppression of attack.Low frequency (6 pps) sensory stimulation, delivered by photic or lateral geniculate stimulation, produced EEG synchronization but failed to cause suppression of attack. These results indicate that low frequency stimulation per se does not cause suppression of ongoing behavior.This study demonstrates that VTA and NA, components of the mesolimbic dopamine system, are involved in the inhibition of emotional-type behaviors.     

Nicotine injections into the ventral tegmental area increase locomotion and Fos-like immunoreactivity in the nucleus accumbens of the rat

Systemic administration of nicotine has been shown to increase locomotor activity in rats, an effect which is enhanced by chronic pretreatment with the drug. Furthermore, administration of nicotine either systemically, or locally within the ventral tegmental area (VTA), increases extracellular levels of dopamine (DA) in the nucleus accumbens (NAc). In the present study, we examined the effect of local, bilateral injections into the VTA of nicotine (0.02, 0.2, 2.0 and 8.0 μg/0.5μl/side) on locomotor activity of rats in an open field. Nicotine (8.0 μg/side) significantly increased forward locomotion within 20 min after injection, whereas rearing was not affected. The stimulatory effect of locally applied nicotine was completely blocked by pretreatment with mecamylamine (1.0 mg/kg, s.c.). Repeated intra-tegmental injections of a subthreshold dose of nicotine (2.0 μg/side every 2 days), gradually increased locomotion, compared to the effect of acute intra-tegmental administration or control injections of saline, after the fifth and sixth injection. The effects of intra-tegmental injections of nicotine were further investigated on cells in several target areas for the VTA-DA neurons through determination of c-fos expression by means of Fos immunohistochemistry. Intra-tegmental injections of nicotine (8.0 μg/side) increased Fos-like immunoreactivity in the NAc, but did not affect the number of Fos-positive nuclei in the medial prefrontal cortex or in the dorsolateral striatum. The increase in accumbal Fos-like immunoreactivity was attenuated by pretreatment with mecamylamine (1.0 mg/kg, s.c.). Our data demonstrate that locomotor activating effects similar to those evoked by systemically administered nicotine, including behavioral sensitization, can be produced by intra-tegmental nicotine administration. Moreover, such local VTA administration of the drug was found to significantly affect neurons within DA target areas. Our findings support the notion that the effects of systemically administered nicotine in mesolimbic target areas are largely dependent on stimulation of nicotini receptors in the VTA.     

Sensitization occurs to the locomotor effects of morphine and the specific μ opioid receptor agonist, DAGO, administered repeatedly to the ventral tegmental area but not to the nucleus accumbens

Several recent reports have demonstrated that opiate action in both the ventral tegmental area (VTA) and the nucleus accumbens (N.Acc.) produces an increase in locomotor activity. In the present experiments, the effect of repeated bilateral injections into these sites of either morphine or the mu opioid receptor agonist Tyr-d-Ala-Gly-NMe-Phe-Gly-ol (DAGO) was investigated. As previously reported with morphine and other opioids, repeated injections of either morphine or DAGO into the VTA produced a progressive enhancement or sensitization of their locomotor activating effects. On the other hand, although both substances injected into the N.Acc. elicited increased locomotion, repeated injections did not lead to sensitization. It has been suggested that the increased locomotor activity produced by opiate injection into the VTA is dopamine-dependent while that produced by intra-N.Acc. injections is not¹⁵. The present findings provide neuroanatomical support for the view thatsensitization to the locomotor activating effects of opiates and opioids brought about by repeated drug exposure involves the mesolimbic dopamine system.     

Neurotensin self-injection in the ventral tegmental area

Earlier work with the conditioned place-preference paradigm suggested that neurotensin (NT) acts as a behavioral reinforcer when microinjected into the ventral tegmental area (VTA) of the midbrain. We report here that animals will perform an operant task to obtain microinfusions of NT into the VTA. Rats reliably pressed a lever to obtain NT infusions while neglecting an identical but inactive lever. Substitution of saline for NT initiated response extinction; following the reintroduction of NT, reliable responding resumed. These results extend earlier work suggesting that NT in the VTA can be a positive reinforcer.     

Increased food intake after opioid microinjections into nucleus accumbens and ventral tegmental area of rat

The nucleus accumbens (ACC) and ventral tegmental area (VTA), two areas believed to subserve reinforcement and increases in locomotor activity produced by opioid microinjections, were examined for their involvement in opioid-produced changes in ingestive behavior. Opioids were infused bilaterally, and food and water intakes were measured for 1 h thereafter. Different morphine doses were administered and, with placements in globus pallidus and lateral ventricles as controls for diffusion, it was found that only ACC and VTA microinjections (0.1-10 nmol) produced dose-related increases in food intake. In both the ACC and VTA low doses of morphine also produced increases in water intake while in ACC high doses produced a decrease. Administration of morphine and an enkephalin analogue (Tyr-D-Met-Gly-Phe(4-NO2)-Pro-NH2) at different depths in the ACC indicated that the increase in food intake occurred at a site separate from that of the decrease in water intake. Using levorphanol, dextrorphan and morphine mixed with naloxone, it was shown that the effects were due to activation of opioid receptors. Additional experiments demonstrated that food intake is increased by ACC morphine under different levels of deprivation, with different times of testing and with availabilities of various goal objects in addition to food. The effect also did not appear to undergo development of tolerance or sensitization. It was concluded that there are sites in the ACC and VTA where increased activity of endogenous opioid peptide systems reliably increase food intake and it was hypothesized that these sites may contribute to changes in ingestive behavior after systemic morphine administration. Also, together with other effects produced by opioid microinjections into the ACC and VTA, the present findings suggest that increased opioid activity in these areas produce a pattern of behaviors similar to that produced in normal animals by food conditioned stimuli.     

Neurotensin and cholecystokinin microinjected into the ventral tegmental area modulate microdialysate concentrations of dopamine and metabolites in the posterior nucleus accumbens

Neurotensin and cholecystokinin, neuropeptides which coexist with dopamine in many ventral tegmental neurons, were microinjected into the ventral tegmental area during in vivo microdialysis in the posterior nucleus accumbens. Neurotensin significantly elevated concentrations of dopamine and its metabolites at doses of 10 pmol, 1 nmol, and 10 nmol, while cholecystokinin significantly elevated dopamine metabolite concentrations only at a dose of 10 nmol. These data suggest that neurotensin potently mediates the release of dopamine from the mesolimbic pathway via direct actions on the cell body.     

Circling from intracranial morphine applied to the ventral tegmental area in rats

Crystalline morphine applied unilaterally to the ventral tegmental area in rats caused circling away from the side of application. This circling was reversed by naloxone (3 mg/kg) and blocked by pretreatment with pimozide (0.5 mg/kg). When tested in an open field the animals followed the perimeter of the enlcosure; thus the radius of the circles described was determined by environmental rather than central factors. Morphine induced forward locomotion in all four limbs; there were no major signs of postural asymmetry noted in the longitudinal axis of the animal's body. This study suggests that morphine activates a population of A-10 dopamine cells known to be involved in locomotion.     

Methylphenidate dose–response behavioral and neurophysiological study of the ventral tegmental area and nucleus accumbens in adolescent rats

The psychostimulant methylphenidate (MPD) is the most common medication used in treating ADHD in children. Studies have shown an increasing prevalence among adolescents without ADHD to take MPD as a cognitive booster and recreational drug, even though it is a Schedule II drug and has a high potential for abuse. The objective of this study is to explore if there is an association between the animals’ behavioral and neurophysiological responses to acute and/or chronic methylphenidate exposure within the ventral tegmental area and the nucleus accumbens, and to compare how these two brain structures fire in response to methylphenidate. Freely moving adolescent rats implanted with semimicroelectrodes within the VTA and NAc were divided into three MPD dosing groups: 0.6, 2.5, and 10 mg/kg i.p., as well as a saline control group. The animals were divided into two groups based on their behavioral responses to chronic MPD, behavioral sensitization and tolerance, and the neuronal responses of the two groups were compared for each MPD dosing. Significant differences in the proportion of neuronal units in the VTA and NAc responding to MPD were observed at the 0.6 and 10.0 mg/kg MPD dosing groups. Moreover, the same doses of 0.6, 2.5, and 10.0 mg/kg MPD elicited behavioral sensitization in some animals and behavioral tolerance in others. This specific study shows that the VTA and NAc neurons respond differently to the same doses of MPD. MPD has different neuronal and behavioral effects depending on the individual, the dosage of MPD, and the brain structure studied.     

Raphe neurons and barbiturate induced rhythmic activity in the subthalamic nucleus and ventral tegmental area

A continuous rhythmic discharge in the subthalamic nucleus (STN), lateral habenular nucleus, and ventral tegmental area (VTA) is associated with tremor in cats lightly anesthetized with barbiturate. The pontine raphe nuclei centralis superior and inferior also show barbiturate dependent slow wave and unitary activity. Stimulation of the raphe region produces evoked potentials and synchronization of the oscillatory activity in STN and VTA. The latency of the evoked response is shortest in STN. Extensive raphe lesions abolish the rhythmic activity in STN and VTA, but lesions which do not completely destroy nuclei centralis superior and inferior are not effective. In single cell recordings 81% of 142 cells in the pontine raphe region and medial reticular formation are inhibited following VTA stimulation. Fifty-four percent of 129 cells in the same region were inhibited when tested with STN stimulation. Forty-seven raphe paramedian reticular formation cells showed convergence of inhibitory input from STN, VTA, and contralateral sciatic nerve (Group II and III fibers). Depletion of serotonin with p-chlorophenylalanine did not affect the appearance of barbiturate rhythmic activity. It is concluded that the pontine raphe region is not essential for maintenance of the oscillatory activity in STN and VTA, and that the raphe region is on the output side of the system.     

Region-specific contribution of the ventral tegmental area to heroin-induced conditioned immunomodulation

Dopamine receptor stimulation is critical for heroin-conditioned immunomodulation; however, it is unclear whether the ventral tegmental area (VTA) contributes to this phenomenon. Hence, rats received repeated pairings of heroin with placement into a distinct environmental context. At test, they were re-exposed to the previously heroin-paired environment followed by systemic lipopolysaccharide treatment to induce an immune response. Bilateral GABA agonist-induced neural inactivation of the anterior, but not the posterior VTA, prior to context re-exposure inhibited the ability of the heroin-paired environment to suppress peripheral nitric oxide and tumor necrosis factor-α expression, suggesting a role for the anterior VTA in heroin-conditioned immunomodulation.     

Dopamine-dependent contralateral circling induced by neurotensin applied unilaterally to the ventral tegmental area in rats

Unilateral application of neurotensin (5, 10, and 15 micrograms) to the ventral tegmental area in rats caused contralateral circling. Pretreatment with pimozide (0.5 mg/kg) blocked the behavior. As is the case with circling elicited by unilateral ventral tegmental morphine, the diameter of the circles made by the animals was determined by environmental factors rather than by internal motor programming.     

Cis-flupentixol antagonism of the rat prefrontal cortex neuronal response to apomorphine and ventral tegmental area input

This study was designed to characterize the response of a select population of prefrontal cortex neurons to exogenous and endogenous dopaminergic influences. Of particular interest were neurons with efferent projections to the ventral tegmental area (VTA) which are part of a reciprocal innervation between the prefrontal cortex and the VTA. Extracellular single unit recording techniques were used to determine the response of cortical neurons to electrical stimulation of the VTA in chloral hydrate anesthetized rats. The neurons were selected on the basis of their electrophysiological characteristics (large amplitude with positive initial deflection) and were classified as to whether or not they were antidromically activated from the VTA. Apomorphine (25 micrograms/kg, IV) significantly reduced the spontaneous activity of both the antidromically identified and the unidentified prefrontal cortex neurons. The apomorphine (25 micrograms/kg, IV) response was antagonized by cis-flupentixol (1.0 mg/kg, IV) in both antidromically identified and unidentified cortical neurons. Stimulation of the VTA also induced a synaptically mediated inhibition of the cortical neuron spontaneous activity. The orthodromic VTA stimulus-evoked inhibition was antagonized by cis-flupentixol (1.0 mg/kg, IV) for both the antidromically identified and the unidentified neurons (63 and 71% of the neurons respectively). The results indicate that a select population of prefrontal cortex neurons respond specifically to exogenous and endogenous dopaminergic influences and that the response is independent of efferent projections to the VTA.     

CCK—8及损毁MFB对腹侧被盖区和伏核多巴胺,CCK—8含量的影响

应用荧光分光光度法和放射免疫法，在以６－羟基多巴胺（６－ＯＨＤＡ）单侧损毁内侧前脑束（ＭＦＢ）制备的偏侧帕金森病（ＰＤ）大鼠模型身上，测定了腹侧被盖区（ＶＴＡ）和伏核（Ａｃｂ）中多巴胺（ＤＡ）和八胺胆囊收缩素（ＣＣＫ－８）的含量，并测定了ＴＶＡ和Ａｃｂ区微量注射ＣＣＫ－８对正常大鼠ＤＡ含量的影响。结果如下：ＰＤ大鼠模型损毁侧ＶＴＡ和Ａｃｂ的ＤＡ和ＣＣＫ－８的含量与健康及对照组相比均减少（Ｐ〈０．０