Tegmental Area Of Rats Research Articles

Amphetamine Injection into the Nucleus Accumbens and Electrical Stimulation of the Ventral Tegmental Area in Rats After Novelty Test-Behavioral and Neurochemical Correlates.

Amphetamine abuse is a global health epidemic that is difficult to treat due to individual differences in response to environmental factors, including stress reactivity and anxiety levels, as well as individual neuronal differences, which may result in increased/decreased vulnerability to addiction. In the present study, we investigated whether the Wistar rats behavioral traits of high (HR) and low (LR) locomotor activity to novelty influence motivational behavior (induced feeding model; iFR by electrical stimulation of the ventral tegmental area; Es-VTA) supported by amphetamine injection into the nucleus accumbens shell (AcbSh) (HRAmph, n = 5; LRAmph, n = 5). A correlation was found between the novelty test's locomotor activity score and the frequency threshold percentage change (p < 0.001, Rs = -0.867). In HRAmph, there was a shortening (-24.16%), while in LRAmph, there was a lengthening (+51.84%) of iFR latency. Immunofluorescence studies showed differential neuronal density (activity of tyrosine hydroxylase, choline acetyltransferase, and cFos protein) in the selected brain structures in HRAmph and LRAmph animals as well as in comparison to a control group (HRACSF, n = 5; LRACSF, n = 5). These results contribute to expanding the state of knowledge of the behavioral and neuronal propensity to take drug abuse.

Aging accentuates decrease in tyrosine hydroxylase immunoreactivity associated with the increase in the motor impairment in a model of reserpine-induced parkinsonism

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by progressive dopaminergic neuron loss. Animal models have been used to develop a better understanding of the pathophysiologic mechanisms of PD. However, these models are usually conducted with young animals diverging of the age of PD patients, suggesting a bias in translational science. Thus, the aim of the study was to evaluate the effect of the age on rats in a progressive parkinsonism model induced by reserpine (RES). Adult (6 – 8 month-old) or elderly (18 – 24 month-old) male rats were assigned to six groups: control-elderly (CTL-ELDERLY), reserpine-elderly (RES-ELDERLY), reserpine-elderly withdrawal (RES-ELDERLY WITHDRAWAL), control-adult (CTL-ADULT), reserpine-adult (RES-ADULT), and reserpine-adult withdrawal (RES-ADULT WITHDRAWAL). Animals received 15 injections every other day of RES (0.1 mg / kg) or vehicle during 30 days. Throughout treatment, animals were evaluated in the catalepsy test (every 48 h) and open field test (24 h after the second injection), and weight assessment (every 4 days) was also made. Upon completion of behavioral tests, rat brains were collected for tyrosine hydroxylase (TH) immunohistochemical analysis. Main results demonstrated that RES-treated animals spent more time in the catalepsy bar compared with control groups, moreover the RES-elderly group showed a longer catalepsy time compared with the RES-ADULT group. A shorter time from RES treatment to the development of symptoms was observed in the RES-ADULT group, compared with the RES-ELDERLY group. In addition, RES-induced weight loss in both RES-ELDERLY and RES-ADULT when compared with their corresponding controls. Cessation of RES treatment was followed by weight gain only in the RES-ADULT group. A significant decrease in TH-immunoreactive cells was observed in the substantia nigra pars compacta (SNpc) and dorsal striatum (STR) in the rats in both the RES-ADULT and RES-ELDERLY groups and in the ventral tegmental area in rats in the RES-ADULT group. Furthermore, TH immunoreactivity decrease was not reversible in SNpc and STR in the RES-ELDERLY. These results show that RES has an age-dependent effect in rats, suggesting a greater sensitivity of the dopaminergic pathway to RES with advancing age. These suggest that the RES rat model of parkinsonism can be useful in improving our knowledge on the effect of aging on neurodegeneration.

The effect of acute mental stress on the exchange of monoamines in the mesocortical and nigrostriatal systems of the rat brain

Background. Мesocortical and nigrostriatal dopaminergic systems are highly sensitive to stressful events. One of the most adequate models of acute psychogenic stress in animals is the death of a partner upon presentation of a predator.&#x0D; Aim. To study the content of dopamine (DA), serotonin and their metabolites: dioxyphenylacetic (DOPAC), homovanillic and 5-hydroxyindoleacetic (5-HIAA) acids in the prefrontal cortex, striatum, and ventral tegmental area in rats on days 3, 7, and 14 after the acute psychogenic stress of the death of a partner upon presentation of a predator.&#x0D; Materials and methods. 28 male Wistar rats were studied. Acute single psychotraumatic situation was used. A group of rats was placed in a tiger python terrarium. One animal died as a result of its nutritional needs, the rest of the rats experienced the death of a partner. The content of monoamines in the brain structures was carried out by high performance liquid chromatography with electrochemical detection.&#x0D; Results. Changes in the content of monoamines in the prefrontal cortex, striatum, and ventral tegmental area were found on the 7 and 14 days after the presentation of the predator. In the ventral tegmental area on the 7 day, there was an increase in the DOPAC/DA ratio and an increase in the serotonin metabolite 5-HIAA, which reflects an increase in the activity of dopamine and serotonin. In the prefrontal cortex on the 14 day, the DOPAС content and the DOPAС/DA index decreased. The 5-HIAA content in the prefrontal cortex and the 5-HIAA/5-HT value also significantly decreased.&#x0D; Conclusions. Changes in the metabolism of monoamines after presentation of a predator develop gradually: increase of the dopamine and serotonin activity in the ventral tegmental area was noted on the 7 day after presentation of the predator, decrease in their activity in the striatum and prefrontal cortex only on the 14 day, reflecting the development of depressive states and post-traumatic stress disorder.

Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats.

Early life adversities leave long-lasting structural and functional consequences on the brain, which may persist later in life. Dopamine is a neurotransmitter that is extremely important in mood and motor control. The aim of this study was to investigate the effect of maternal deprivation during the ninth postnatal day on the volume of dopaminergic nuclei and the number of dopaminergic neurons in adolescence and adulthood. Maternally deprived and control Wistar rats were sacrificed on postnatal day 35 or 60, and the dopaminergic neurons were stained in coronal histological sections of ventral midbrain with the tyrosine hydroxylase antibody. The volume of dopaminergic nuclei and the number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA) were analyzed in three representative coordinates. Maternal deprivation caused weight loss on postnatal day 21 (weaning) and corticosterone blood level elevation on postnatal days 35 and 60 in stressed compared to control rats. In maternally deprived animals, the volumes of SN and VTA were increased compared to the controls. This increase was accompanied by an elevation in the number of dopaminergic neurons in both nuclei. Altogether, based on somatic and corticosterone level measurements, maternal deprivation represents a substantial adversity, and the phenotype it causes in adulthood includes increased volume of the dopaminergic nuclei and number of dopaminergic neurons.

Effects of Cocaine Self-Administration and Its Extinction on the Rat Brain Cannabinoid CB1 and CB2 Receptors

The aim of this study was to evaluate changes in the expression of cannabinoid type 1 (CB1) and 2 (CB2) receptor proteins in several brain regions in rats undergoing cocaine self-administration and extinction training. We used a triad-yoked procedure to distinguish between the motivational and pharmacological effects of cocaine. Using immunohistochemistry, we observed a significant decrease in CB1 receptor expression in the prefrontal cortex, dorsal striatum, and the basolateral and basomedial amygdala following cocaine (0.5 mg/kg/infusion) self-administration. Increased CB1 receptor expression in the ventral tegmental area in rats with previous cocaine exposure was also found. Following cocaine abstinence after 10 days of extinction training, we detected increases in the expression of CB1 receptors in the substantia nigra in both cocaine groups and in the subregions of the amygdala for only the yoked cocaine controls, while any method of cocaine exposure resulted in a decrease in CB2 receptor expression in the prefrontal cortex (p < 0.01), nucleus accumbens (p < 0.01), and medial globus pallidus (p < 0.01). Our findings further support the idea that the eCB system and CB1 receptors are involved in cocaine-reinforced behaviors. Moreover, we detected a cocaine-evoked adaptation in CB2 receptors in the amygdala, prefrontal cortex, and globus pallidus.

GABA modulates baroreflex in the ventral tegmental area in rat.

There are some reports demonstrating the cardiovascular functions of the ventral tegmental area (VTA). About 20-30% of the VTA neurons are GABAergic, which might play a role in baroreflex modulation. This study was performed to find the effects of GABA(A), GABA(B) receptors and reversible synaptic blockade of the VTA on baroreflex. Drugs were microinjected into the VTA of urethane anesthetized rats, and the maximum change of blood pressure and the gain of the reflex bradycardia in response to intravenous phenylephrine (Phe) injection were compared with the preinjection and the control values. Microinjection of bicuculline methiodide (BMI, 100 pmol/100 nl), a GABA(A) antagonist, into the VTA strongly decreased the Phe-induced hypertension, indicating that GABA itself attenuated the baroreflex. Muscimol, a GABA(A) agonist (30 mM, 100 nl), produced no significant changes. Baclofen, a GABA(B) receptor agonist (1000 pmole/100 nl), moderately attenuated the baroreflex, however phaclofen, a GABA(B) receptor antagonist (1000 pmole/100 nl), had no significant effect. In conclusion, for the first time, we demonstrated that GABA(A) receptors of the VTA strongly attenuate and GABA(B) receptors of the VTA moderately attenuate baroreflex in rat.

The Alcohol Deprivation Effect: Marked Inhibition by Anticatalase Gene Administration into the Ventral Tegmental Area in Rats

Animals that have chronically consumed alcohol and are subsequently deprived of it markedly increase their intake above basal levels when access to alcohol is reinstated. Such an effect, termed the alcohol deprivation effect (ADE), has been proposed to reflect (i) an obsessive-compulsive behavior, (ii) craving, or (iii) an increased reinforcing value of ethanol (EtOH). It has been reported that acetaldehyde, a highly reinforcing metabolite of EtOH, is generated in the brain by the action of catalase. Recent studies show that the administration of an anticatalase (shRNA)-encoding lentiviral vector into the brain ventral tegmental area (VTA) of naïve rats virtually abolishes (85 to 95%) their EtOH intake. It is hypothesized that the antireinforcing effect of the anticatalase vector will also inhibit the ADE. Two-month-old Wistar-derived UChB alcohol drinker rats were offered free access to water and 10 and 20% EtOH for 67 days. Thereafter, the animals were deprived of EtOH for 15 days and were subsequently offered access to the EtOH solutions. At the start of the deprivation period, animals were microinjected a single dose of an anticatalase (or control) vector into the VTA. EtOH intake was measured on the first hour of EtOH re-exposure as well as on a 24-hour basis for 7 days. A marked ADE was observed when EtOH intake was measured on the first hour or 24 hours following EtOH re-exposure, compared to the corresponding controls. The administration of the anticatalase vector reduced ADE by 60 to 80% (p < 0.001) on the first hour and by 63 to 80% (p < 0.001) on the initial 24 hours of EtOH re-exposure (first and second ADE, respectively) without changing the total fluid intake, indicating a specific effect on EtOH drinking. Ethanol intake associated with ADE--a binge-like drinking behavior--is markedly inhibited by the administration of an anticatalase vector into the VTA, which blocks the conversion of EtOH into acetaldehyde, strongly suggesting that the marked increased EtOH intake that follows an alcohol deprivation period is mediated by acetaldehyde and its reinforcing metabolite.

Intracerebroventricular transplanted bone marrow stem cells survive and migrate into the brain of rats with Parkinson's disease.

In this study, 6-hydroxydopamine was stereotaxically injected into the right substantia nigra compact and ventral tegmental area of rats to establish Parkinson's disease models. The rats then received a transplantation of bone marrow stromal cells that were previously isolated, cultured and labeled with 5-bromo-2’-deoxyuridine in vitro. Transplantation of the bone marrow stromal cells significantly decreased apomorphine-induced rotation time and the escape latency in the Morris water maze test as compared with rats with untreated Parkinson's disease. Immunohistochemical staining showed that, 5-bromo-2’-deoxyuridine-immunoreactive cells were present in the lateral ventricular wall and the choroid plexus 1 day after transplantation. These immunoreactive cells migrated to the surrounding areas of the lateral cerebral ventricle along the corpus callosum. The results indicated that bone marrow stromal cells could migrate to tissues surround the cerebral ventricle via the cerebrospinal fluid circulation and fuse with cells in the brain, thus altering the phenotype of cells or forming neuron-like cells or astrocytes capable of expressing neuron-specific proteins. Taken together, the present findings indicate that bone marrow stromal cells transplanted intracerebroventricularly could survive, migrate and significantly improve the rotational behavior and cognitive function of rats with experimentally induced Parkinson's disease.

Low doses of dextromethorphan attenuate morphine-induced rewarding via the sigma-1 receptor at ventral tegmental area in rats

Chronic use of morphine causes rewarding and behavioral sensitization, which may lead to the development of psychological craving. In our previous study, we found that a widely used antitussive dextromethorphan (known as a low affinity NMDA receptor antagonist), at doses of 10–20 mg/kg (i.p.), effectively decreased morphine rewarding in rats. In this study, we further investigated the effects and mechanisms of low doses of DM (μg/kg range) on morphine rewarding and behavioral sensitization. A conditioned place preference test was used to determine the rewarding and a locomotor activity test was used to determine the behavioral sensitization induced by the drug(s) in rats. When a low dose of DM (3 or 10 μg/kg, i.p.) was co-administered with morphine (5 mg/kg, s.c.), the rewarding effect, but not behavioral sensitization, induced by morphine was inhibited. The inhibiting effect of DM could be blocked by systemically administering a sigma-1 receptor antagonist, BD1047 (3 mg/kg, i.p.). When BD1047 (5 nmole/site) was locally given at the VTA, it also blocked the effects of a low dose of DM in inhibiting morphine rewarding. Our findings suggest that the activation of the sigma-1 receptor at the VTA may be involved in the mechanism of low doses of DM in inhibiting the morphine rewarding effect and the possibility of using extremely low doses of DM in treatment of opioid addiction in clinics.

Region-specific diet-induced and leptin-induced cellular leptin resistance includes the ventral tegmental area in rats

Diet-induced obesity (DIO) results in region-specific cellular leptin resistance in the arcuate nucleus (ARC) of the hypothalamus in one strain of mice and in several medial basal hypothalamic regions in another. We hypothesized that the ventral tegmental area (VTA) is also likely susceptible to diet-induced and leptin-induced leptin resistance in parallel to that in hypothalamic areas. We examined two forms of leptin resistance in F344xBN rats, that induced by 6-months of high fat (HF) feeding and that induced by 15-months of central leptin overexpression by use of recombinant adeno-associated viral (rAAV)-mediated gene delivery of rat leptin. Cellular leptin resistance was assessed by leptin-stimulated phosphorylation of signal transducers and activators of transcription 3 (STAT3) in medial basal hypothalamic areas and the VTA. The regional pattern and degree of leptin resistance with HF was distinctly different than that with leptin overexpression. Chronic HF feeding induced a cellular leptin resistance that was identified in the ARC and VTA, but absent in the lateral hypothalamus (LH), ventromedial hypothalamus (VMH), and dorsomedial hypothalamus (DMH). In contrast, chronic central leptin overexpression induced cellular leptin resistance in all areas examined. The identification of leptin resistance in the VTA, in addition to the leptin resistance in the hypothalamus, provides one potential mechanism, underlying the increased susceptibility of leptin resistant rats to HF-induced obesity.

Cutaneous tactile stimulation increases dopamine release in the nucleus accumbens via excitation of the ventral tegmental area in rats

Cutaneous tactile stimulation increases dopamine release in the nucleus accumbens via excitation of the ventral tegmental area in rats

Dynamic changes in dopamine tone during self-stimulation of the ventral tegmental area in rats

In a prior study, phasic release of dopamine (DA) in the nucleus accumbens (NAc) was only transiently and rarely detected by means of fast-scan cyclic voltammetry (FCSV) in rats already trained to work for electrical stimulation of the ventral tegmental area (VTA) on a continuous reinforcement schedule. However, in rats receiving rewarding electrical stimulation via lateral hypothalamic (LH) electrodes, elevated DA tone in the NAc terminal field was detected via microdialysis for up to 2 h, even when short (1.5 s) inter-train intervals were employed. To better characterize the similarities and differences between the FSCV and microdialysis measurements, we trained rats to self-administer VTA stimulation under conditions similar to those employed in the initial FSCV study. The results resemble those obtained by means of microdialysis in rats receiving LH stimulation but differed from the prior FSCV data. Although the concentration of DA in dialysate obtained from NAc probes did fall after having peaked at the 30 min mark, this decline set in much later than in the FSCV studies, and elevated DA tone could still be detected after 110 min of self-stimulation. The stimulation-induced peak in DA tone could be restored by a 30 min rest period, a manipulation that was ineffective previously in restoring the FSCV measure of phasic release. These findings are discussed in terms of the differential sensitivity of the FSCV and microdialysis methods to phasic and tonic signaling by DA neurons and to different transitions between their activity states.

Affective Analgesia Following Muscarinic Activation of the Ventral Tegmental Area in Rats

Cholinergic stimulation of dopamine neurons in the ventral tegmental area (VTA) underlies activation of the brain reward circuitry. Activation of this circuit is proposed to preferentially suppress the affective reaction to noxious stimulation. Vocalization afterdischarges (VADs) are a validated model of the affective response of rats to noxious tail shock. The antinociceptive action of the acetylcholine agonist carbachol microinjected into the VTA on VAD threshold was compared with its effect on the thresholds of other tail shock-elicited responses (VDS, vocalizations during shock; SMR, spinal motor reflexes). Whereas VADs are organized within the forebrain, VDSs and SMRs are organized at medullary and spinal levels of the neuraxis, respectively. Carbachol (1 microg, 2 microg, and 4 microg) injected into VTA produced dose-dependent increases in VAD and VDS thresholds, although increases in VAD threshold were significantly greater than increases in VDS threshold. Administration of carbachol into VTA failed to elevate SMR threshold. Elevations in vocalization thresholds produced by intra-VTA carbachol were reversed in a dose-dependent manner by local administration of the muscarinic receptor antagonist atropine sulfate (30 microg and 60 microg). These results provide the first demonstration of the involvement of the VTA in muscarinic-induced suppression of pain affect. Cholinergic activation of the brain reward circuit produced a preferential suppression of rats' affective reaction to noxious stimulation. The neurobiology that relates reinforcement to suppression of pain affect may provide insights into new treatments for pain and its associated affective disorders.

PRECLINICAL STUDY: Chronic morphine‐induced neuronal morphological changes in the ventral tegmental area in rats are reversed by electroacupuncture treatment

The aim of this study was to observe the effect of electroacupuncture (EA) on chronic morphine-induced neuronal morphological changes in the ventral tegmental area (VTA) in rats at electron-microscopic level. Fourteen days of administering escalating doses of morphine induced pathological morphological changes of neurons in the VTA: the rough endoplasmic reticulum swelled, membrane configuration of the nucleus and mitochondria blurred, and structure of myelin sheath changed. Both 2 and 100 Hz EA treatment reversed the morphological alterations induced by chronic morphine administration. The findings provide new evidence that EA may serve as a potential therapy in treating opiate addiction.

Dopamine neurons encode the better option in rats deciding between differently delayed or sized rewards

The dopamine system is thought to be involved in making decisions about reward. Here we recorded from the ventral tegmental area in rats learning to choose between differently delayed and sized rewards. As expected, the activity of many putative dopamine neurons reflected reward prediction errors, changing when the value of the reward increased or decreased unexpectedly. During learning, neural responses to reward in these neurons waned and responses to cues that predicted reward emerged. Notably, this cue-evoked activity varied with size and delay. Moreover, when rats were given a choice between two differently valued outcomes, the activity of the neurons initially reflected the more valuable option, even when it was not subsequently selected.

Food reward: Orexin-signaling in ventral tegmental area contributes to high-fat intake induced by accumbens opioid stimulation.

The nucleus accumbens in the ventral striatum is considered a pivotal structure in food reward and addictive behavior. Injection of the mu-opioid agonist DAMGO into this structure powerfully stimulates intake of preferred palatable foods such as high fat, but the downstream neural mechanisms are not well understood. We have previously shown that accumbens-hypothalamic projections and orexin-signaling are important since ICV administration of the selective orexin receptor antagonist SB334768 blocks about 70% of the feeding response to accumbens DAMGO. Here we examined the effects of focal injections of the orexin-blocker into brain sites receiving dense orexin-innervation in order to identify the site of action of orexin-signaling. SB334768 injected bilaterally into the ventral tegmental area of rats, significantly attenuated accumbens DAMGO-induced high-fat intake by about 50%. Focal injections into other areas receiving heavy orexin projections, including the arcuate nucleus, paraventricular nucleus of the hypothalamus, and paraventricular nucleus of the thalamus did not significantly change DAMGO-induced high-fat intake. We conclude that orexin-signaling in the ventral tegmental area is crucial for the expression of palatable food consumption elicited by opioid-stimulation of the nucleus accumbens. This pathway is likely to activate the mesolimbic dopamine system eliciting the “wanting” aspect of food reward. Involvement of additional sites of orexin-signaling such as the lateral hypothalamus, locus coeruleus, and or nucleus of the solitary tract in this model for reward-driven appetite remains to be tested. Supported by NIDDK 47348.

Toxicological and cytotoxic evaluation of standardized extracts of Galphimia glauca

Galphimia glauca Cav (Malpighiaceae) has been widely used in Mexican traditional medicine as a remedy for the treatment of mental disorders, principally as a sedative and tranquilizer. The sedative activity of extracts obtained from this plant has been demonstrated with different neuropharmacological models. Different triterpenes, known as galphimines, have been identified from the active extract. Galphimine-B (G-B) possesses anxiolytic activity and is able to selectively inhibit discharges of dopaminergic neurons in the ventral tegmental area in rats. Nevertheless, there have been no toxicological investigations carried out with products obtained from this plant. In this work three different extracts (aqueous, ethanolic, and methanolic) of Galphimia glauca, standardized in the content of three galphimines, were evaluated for their behavioral and pharmaco-toxicological effects. After administering the extracts to mice for 28 days (2.5 g/kg, p.o.), no deaths were found and the histopathological analysis of different organs did not show alterations; only the behavioral parameters analyzed showed a diminution of spontaneous activity. The administration of these extracts for 56 days (same doses and route) in mice did not cause any changes in the biochemical parameters that evaluate liver function. On the other hand, no cytotoxic effects were found on KB, UISO, and OVCAR-5 transformed cell lines, but all extracts specifically inhibited colon cancer cell line growth with an ED 50 lower than 2 μg/ml. The extracts were also evaluated in genotoxicity tests in vitro (250, 100 and 50 μg/ml), which demonstrate that none of the three extracts from Galphimia glauca showed a genotoxic effect.

Differential conditioned place preference responses to endomorphin-1 and endomorphin-2 microinjected into the posterior nucleus accumbens shell and ventral tegmental area in the rat.

An unbiased conditioned place preference (CPP) paradigm was used to evaluate the reward effects of endogenous mu-opioid receptor ligands endomorphin-1 (EM-1) and endomorphin-2 (EM-2) from the mesolimbic posterior nucleus accumbens (Acb) shell and the ventral tegmental area (VTA) in CD rats. EM-1 (1.6-8.1 nmol) microinjected into posterior Acb shell produced CPP, whereas EM-2 (8.7-17.5 nmol) given into the same Acb shell produced conditioned place aversion (CPA). EM-1 (1.6-16.3 nmol) microinjected into the VTA produced CPP, whereas EM-2 (8.7 and 17.5 nmol) given into the same VTA site did not produce any effect, but at a high dose (35 nmol) produced CPP. EM-1 (3.3 nmol) or EM-2 (17.5 nmol) microinjected into the nigrostriatal substantia nigra was not significantly different from vehicle-injected groups. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) at 94.13 pmol or 3-methoxynaltrexone at 0.64 pmol microinjected into the posterior Acb shell blocked EM-1-induced CPP and EM-2-induced CPA. At a higher dose, CTOP (941.3 pmol) and 3-methoxynaltrexone (6.4 pmol) produced CPA and CPP, respectively. Coadministration with antiserum against dynorphin A(1-17) (Dyn) (10 microg) microinjected into the posterior Acb shell blocked EM-2-induced CPA. However, it did not affect EM-1-induced CPP. It is concluded that EM-1 and EM-2 produce site-dependent CPP and CPA, respectively, by stimulation of different subtypes of mu-opioid-receptors; stimulation of one subtype of mu-opioid-receptor at the posterior Acb shell and VTA by EM-1 induces CPP, whereas stimulation of another subtype of mu-opioid receptor at the posterior Acb shell, but not the VTA, by EM-2 induces the release of Dyn to produce CPA.

Unconditional hyperactivity and transient reinforcing effects of NMDA administration into the ventral tegmental area in rats

The dopaminergic projection from the ventral tegmental area (VTA) to the nucleus accumbens plays an important role in positive reinforcement and locomotion. Intra-VTA administration of many drugs capable of activating these neurons has been shown to be reinforcing and induce locomotion. Administration of the excitatory amino acid NMDA (N-methyl-D-aspartate) into the VTA may likewise be positively reinforcing, because it stimulates the meso-accumbens dopamine system and locomotion. Locomotor-rearing experiments were conducted to pinpoint the range of NMDA concentrations that induce significant locomotion and rearing, and to determine whether co-administration of the glycine binding site agonist d-serine would enhance the effects of NMDA administration into the VTA. Reinforcing effects of NMDA were assessed by intracranial self-administration procedures: a lever-press delivered a 75-nl infusion containing NMDA (0.1, 0.3 or 1.0 mM) plus serine into the VTA or an adjacent region, the supramammillary nucleus. Co-administration of serine slightly enhanced rearing induced by NMDA administration. Administration of NMDA at concentrations of 0.3 or 1.0 mM (500 nl) induced vigorous locomotion and rearing. NMDA (0.3 mM) was self-administered into the VTA slightly more than vehicle in the first or second sessions, yet this small reinforcing effect became irregular in subsequent sessions. The rats did not learn to self-administer NMDA into the supramammillary nucleus. Ventral tegmental NMDA injections, in the concentration range that induced marked unconditional hyperactivity, supported only marginal and transient self-administration.

Ethanol suppresses fast potentiation of glycine currents by glutamate.

Excitatory (glutamate) and inhibitory (GABA(A) and glycine) receptor/channels coexist in many neurons. To assess effects of ethanol on the interaction of glutamate and glycine receptors, glycine-induced current (I(Gly)) was recorded by a whole-cell patch-clamp technique from neurons freshly dissociated from the ventral tegmental area of rats. A conditioning prepulse of glutamate (1-3 s, 1 mM) significantly and reversibly potentiated responses to a pulse of glycine. This potentiation was increased when extracellular calcium was raised to 12 mM and reduced by including 10 mM 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid in the internal recording medium. It was not affected by 5 microM 1-N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62), a selective inhibitor of calcium/calmodulin-dependent protein kinase II. In a concentration-response analysis, a conditioning pulse of glutamate significantly lowered the EC(50) for glycine and increased the maximal I(Gly). Kinetic analysis of the currents indicated that glutamate slowed deactivation of glycine-gated chloride channels; therefore, glutamate may increase the affinity of glycine receptors for glycine. When coapplied with glycine, ethanol (10 mM) potentiated I(Gly) in 35% of neurons from the ventral tegmental area. In contrast, when coapplied with glutamate and glycine, ethanol suppressed the glutamate-induced potentiation of I(Gly) in these neurons. This suppression was also observed when ethanol and glycine were coapplied after a glutamate prepulse. A similar effect was observed when ethanol alone did not potentiate I(Gly). These findings suggest that glutamate-induced calcium influx modulates glycine receptors by a mechanism that can be blocked by ethanol.