Dopamine Levels In Ventral Tegmental Area Research Articles

Differential modulation of methamphetamine-mediated behavioral sensitization by overexpression of Mu opioid receptors in nucleus accumbens and ventral tegmental area.

Repeated administration of methamphetamine (Meth) induces behavioral sensitization which is characterized by a progressive increase in locomotor response after each injection. Previous studies have shown that Mu opioid receptors (MORs) can regulate Meth-mediated behavioral sensitization. However, the reported interactions are controversial; systemic activation of MORs either enhanced or suppressed Meth sensitization. It is possible that alteration of Meth sensitization after systemic administration of MOR ligands reflects the sum of distinct MOR reactions in multiple brain regions. The purpose of the present study was to examine the actions of MORs on Meth sensitization after regionally selective overexpression of human MOR through an AAV6-based gene delivery system. We demonstrated that adeno-associated virus (AAV)-MOR increased MOR immunoreactivity and binding in vitro. AAV-MOR or AAV-green fluorescent protein (GFP) was injected into the nucleus accumbens (NAc) or ventral tegmental area (VTA) of adult mice. Two weeks after viral infection, animals received Meth or saline for five consecutive days. Locomotor behavior and striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) level were determined. Repeated administration of Meth progressively increased locomotor activity; this sensitization reaction was attenuated by intra-NAc AAV-MOR microinjections. Infusion of AAV-MOR to VTA enhanced Meth sensitization. AAV-MOR significantly enhanced DA levels in VTA after VTA infection but reduced DOPAC/DA turnover in the NAc after NAc injection. Our data suggest a differential modulation of Meth sensitization by overexpression of MOR in NAc and VTA. Regional manipulation of MOR expression through AAV may be a novel approach to control Meth abuse and psychomimetic activity.

Heroin Self-Administration Experience Establishes Control of Ventral Tegmental Glutamate Release by Stress and Environmental Stimuli

Heroin and cocaine have very different unconditioned receptor-mediated actions; however, in the brain circuitry of drug-reward and motivation, the two drugs establish common conditioned consequences. A single experience with either drug can change the sensitivity of ventral tegmental area (VTA) dopamine neurons to glutamatergic input. In the case of cocaine, repeated intravenous self-administration establishes de novo VTA glutamate release and dopaminergic activation in response to conditioned stimuli and mild footshock stress. Here we determined whether repeated self-administration of heroin would establish similar glutamate release and dopaminergic activation. Although self-administration of heroin itself did not cause VTA glutamate release, conditioned glutamate release was seen when rats expecting rewarding heroin were given nonrewarding saline in its place. Mild footshock stress also caused glutamate release in heroin-trained animals. In each case, the VTA glutamate release was accompanied by elevations in VTA dopamine levels, indicative of dopaminergic activation. In each case, infusion of the ionotropic glutamate antagonist kynurenic acid blocked the VTA dopamine release associated with VTA glutamate elevation. Although glutamate levels in the extinction and reinstatement tests were similar to those reported in cocaine studies, the effects of heroin self-administration itself were quite different from what has been seen during cocaine self-administration.

Dopamine and glutamate release in the nucleus accumbens and ventral tegmental area of rat following lateral hypothalamic self-stimulation

Rewarding hypothalamic brain stimulation is thought to depend on trans-synaptic activation of high-threshold (and thus rarely directly depolarized by rewarding stimulation) dopaminergic fibers of the medial forebrain bundle. We used in vivo microdialysis and high-performance liquid chromatography coupled with electrochemical or fluorometric detection to investigate the concurrent release of dopamine and glutamate in the nucleus accumbens septi and in the ventral tegmental area, as a function of lateral hypothalamic self-stimulation. Self-stimulation at a variety of stimulation frequencies and pulse widths increased levels of dopamine and its primary metabolites, dihydroxyphenylacetic acid and homovanillic acid in the nucleus accumbens. Lateral hypothalamic self-stimulation also induced significant increases in ventral tegmental area dopamine and metabolite levels, and the percentage increase of dopamine was higher in this region than in the nucleus accumbens. Local perfusion with the dopamine uptake inhibitor nomifensine (10 μM) increased dopamine levels in the nucleus accumbens about three-fold and potentiated the increase of dopamine levels induced by self-stimulation. Nomifensine perfusion also induced a delayed decrease in nucleus accumbens glutamate levels, and self-stimulation did not modify this effect of the drug. Local perfusion with the D2-type dopamine receptor antagonist raclopride significantly increased both basal and self-stimulation induced dopamine release in the nucleus accumbens. Neither nomifensine nor raclopride perfusion significantly affected the maximal rates of self-stimulation. Perfusion with tetrodotoxin (2 μM) into nucleus accumbens significantly decreased basal and prevented stimulation-induced increases in accumbens dopamine levels but only slightly decreased the rate of self-stimulation. In contrast, perfusion of tetrodotoxin (0.5 μM) into the ventral tegmental area decreased basal and blocked stimulation-induced increases in both nucleus accumbens and ventral tegmental area dopamine levels; this treatment also blocked or strongly inhibited self-stimulation. While it had no effect on glutamate levels in the nucleus accumbens, lateral hypothalamic self-stimulation induced a significant and tetrodotoxin-sensitive increase in glutamate levels in the ventral tegmental area. Taken together, the present results indicate that, across a broad range of stimulation parameters, rewarding lateral hypothalamus stimulation causes major and persistent activation of the mesolimbic dopamine system, and suggest descending glutamatergic fibers in the medial forebrain bundle as a candidate for the directly activated descending pathway in lateral hypothalamus brain stimulation reward.

Amphetamine-Induced Plasticity of AMPA Receptors in the Ventral Tegmental Area: Effects on Extracellular Levels of Dopamine and Glutamate in Freely Moving Rats

Previous electrophysiological studies suggested that the initiation of behavioral sensitization to cocaine and amphetamine involves a transient increase in AMPA receptor responsiveness in the ventral tegmental area (VTA). To test this, we used in vivo microdialysis to examine the effects of intra-VTA administration of AMPA (10 microm) and NMDA (100 microm) on dopamine (DA) and glutamate efflux in the VTA and the nucleus accumbens (NAC), an important target of VTA DA neurons. We compared rats treated for 5 d with saline or 5 mg/kg amphetamine and withdrawn for 3 or 10-14 d. After 3 d of withdrawal, intra-VTA AMPA increased both NAC and VTA DA levels to a greater extent in the amphetamine group, whereas NMDA produced similar effects in the saline and amphetamine groups. This enhanced responsiveness to AMPA was no longer evident in rats tested 10-14 d after the last injection. In addition, intra-VTA AMPA but not NMDA increased both VTA and NAC glutamate levels in rats tested 3 d after the last injection of amphetamine but not in saline controls. After 10-14 d, the responsiveness of glutamate levels to AMPA was no longer evident in the NAC but persisted in the VTA. Additional studies indicated that the glutamate effect in the NAC may involve increased responsiveness of DA receptors within the NAC. These findings establish an in vivo animal model with which to explore the consequences of repeated drug administration for AMPA receptor plasticity in the VTA. They also indicate that repeated amphetamine leads to potentiated interactions between DA and glutamate transmission.

NMDA receptors in nucleus accumbens modulate stress-induced dopamine release in nucleus accumbens and ventral tegmental area.

Converging evidence suggests that dopamine (DA) transmission in nucleus accumbens (NAcc) is modulated locally by an excitatory amino acid (EAA)-containing input possibly originating in medial prefrontal cortex (PFC). In the present study, we examined the effects of intra-NAcc administration of EAA receptor antagonists on stress-induced increases of NAcc DA levels and of dendritically released DA in the ventral tegmental area (VTA). Local injection of the NMDA receptor antagonist-AP-5 (0.05, 0.5, and 5.0 nmoles)-dose-dependently potentiated increases in NAcc DA levels elicited by 15 min of restraint stress. In contrast, local application of equivalent doses of the kainate/AMPA receptor antagonist-DNQX-failed to alter the NAcc DA stress response reliably. In a separate experiment, we found that intra-NAcc injection of AP-5 also potentiated stress-induced increases in VTA DA levels. These results indicate that EAAs acting at NMDA receptors in NAcc can modulate stress-induced DA release in this region. Our data indicate, however, that this action exerts an inhibitory influence on the NAcc DA stress response, suggesting that the relevant population of NMDA receptors are not located on NAcc DA terminals. The fact that intra-NAcc AP-5 injections also potentiated the DA stress response in VTA suggests instead an action mediated by NMDA receptors located on NAcc neurons that feedback, directly or indirectly, to cell bodies of the mesocorticolimbic DA system.

Effects of neonatal dopamine depletion on sensory inhibition in the rat

Central dopamine systems appear to play an important role in sensory information processing. In particular, the filtering (or gating) of repetitive auditory stimuli is modulated by pharmacological manipulations that affect dopaminergic neurotransmission. The present study further addressed the role of dopamine in auditory gating. Three-day-old male Sprague-Dawley rats, pretreated with desipramine, received intracisternal injections of 6-hydroxydopamine (6-OHDA; 75 μg in 10 μl) or the vehicle. At 4 months of age the rats were implanted for evoked potential recording and auditory gating was assessed using a paired click paradigm. Neonatally administered 6-OHDA did not alter gating in the adult rats. However, unlike for the control group, systemic amphetamine (1.83 mg/kg, IP) failed to disrupt gating in the treated rats. Apomorphine (1.0 mg/kg, SC) disrupted gating in both groups. Neonatal 6-OHDA treatment caused significant reductions in dopamine levels in the striatum, nucleus accumbens, and substantia nigra/ventral tegmental regions. There was an inverse relationship between substantia nigra/ ventral tegmental area dopamine levels and auditory gating. Overall, the results suggest that amphetamine-induced auditory gating loss requires presynaptic dopamine release, but that the deficiency occurs through postsynaptic dopamine receptor activation.

Ventral tegmental microinjection of Δ 9-tetrahydrocannabinol enhances ventral tegmental somatodendritic dopamine levels but not forebrain dopamine levels: evidence for local neural action by marijuana's psychoactive ingredient

Basal extracellular levels of dopamine (DA) and its metabolites in both ventral tegmental area (VTA) and nucleus accumbens (Acb) were simultaneously monitored by in vivo brain microdialysis in laboratory rats. Microinjection of 12 μg or 24 μg Δ 9-tetrahydrocannabinol (Δ 9-THC), the psychoactive ingredient in marijuana and hashish, into the VTA produced a dose-dependent increase in somatodendritic DA levels in VTA but failed to produce any simulatenous change in extracellular DA in Acb. Direct Δ 9-THC perfusion (5×10 −5 and 2×10 −4 M) into Acb via the microdialysis probes caused a significant increase in extracellular DA levels in Acb. These findings suggest that (1) Δ 9-THC has a facilitating effect on somatodendritic DA efflux, and (2) the elevation of Acb DA levels seen in our previous studies with systemic administration of Δ 9-THC may result from local actions of Δ 9-THC at or near the DA terminal projections in Acb.