Dopamine Release In Rats Research Articles

臼歯咬合支持喪失の程度がラット両側線条体ドパミン放出に及ぼす影響(大阪歯科大学大学院歯学研究科博士(歯学)学位論文内容要旨および論文審査結果要旨の公表)

臼歯咬合支持喪失の程度がラット両側線条体ドパミン放出に及ぼす影響(大阪歯科大学大学院歯学研究科博士(歯学)学位論文内容要旨および論文審査結果要旨の公表)

Individual differences in psychostimulant responses of female rats are associated with ovarian hormones and dopamine neuroanatomy

Ovarian hormones modulate the pharmacological effects of psychostimulants and may enhance vulnerability to drug addiction. Female rats have more midbrain dopamine neurons than males and greater dopamine uptake and release rates. Cocaine stimulates motor behavior and dopamine efflux more in female than male rats, but the mediating mechanisms are unknown. This study investigated individual differences in anatomic, neurochemical, and behavioral measures in female rats to understand how ovarian hormones affect the relatedness of these endpoints.Ovarian hormone effects were assessed by comparing individual responses in ovariectomized (OVX) and sham adult female rats. Locomotion was determined before and following 10mg/kg cocaine. Electrically-stimulated dopamine efflux was assessed using fast cyclic voltammetry in vivo. Dopamine neuron number and density in substantia nigra (SN) and ventral tegmental area (VTA) were determined in the same animals using tyrosine-hydroxylase immunohistochemistry and unbiased stereology. Locomotor behavior and dopamine efflux did not differ at baseline but were greater in sham than OVX following cocaine. Cocaine increased dopamine release rates in both groups but uptake inhibition (Km) was greater in sham than OVX. Dopamine neuron number and density in SN and VTA were greater in shams. Sham females with the largest uterine weights exhibited the highest density of dopamine neurons in the SN, and the most cocaine-stimulated behavior and dopamine efflux. Ovariectomy eliminated these relationships. We postulate that SN density could link ovarian hormones and high-psychostimulant responses in females. Similar mechanisms may be involved in individual differences in the addiction vulnerability of women.

Effect of pre-ischaemic conditioning on hypoxic depolarization of dopamine efflux in the rat caudate brain slice measured in real-time with fast cyclic voltammetry

Fast cyclic voltammetry can be used to measure dopamine release after oxygen and glucose deprivation (OGD) induced anoxic depolarization in vitro. Here we measure dopamine efflux with 1s time resolution, which is appropriate to measure OGD-evoked dopamine efflux accurately. In the present study, we examined whether OGD-evoked dopamine efflux could be used to show pre-ischaemic conditioning in the rat caudate brain slice. Caudate slices were exposed to 0, 2, or 10min OGD pre-ischaemic conditioning, then 60min later exposed to a second OGD event of 15min duration. We measured the OGD-evoked dopamine efflux using fast cyclic voltammetry and in some experiments caudate dopamine and DOPAC tissue levels were measured using HPLC and 20μm cryostat sections were Nissl stained to indicate neuronal loss. We found that 10 but not 2min OGD pre-ischaemic conditioning resulted in a longer time to onset of OGD-evoked dopamine efflux on the main OGD event (475±31 and 287±30s for 10 Vs 0min pre-ischaemic conditioning respectively). Further, 10min OGD pre-ischaemic conditioning resulted in less dopamine efflux on the second OGD event (4.23±1.12 and 8.14±0.82μM for 10 Vs 0min pre-ischaemic conditioning respectively), despite these slices having similar tissue dopamine content and DOPAC/DA ratio, and the rate of dopamine release was slower in the main OGD event (21±5 and 74±8nM/s for 10 Vs 0min pre-ischaemic conditioning respectively). These data suggest that 10min OGD pre-ischaemic conditioning can evoke tolerance to a second OGD event and that voltammetric recording of OGD-evoked dopamine efflux is a useful model of pre-ischaemic conditioning in neuronal tissue.

Imaging of alcohol‐induced dopamine release in rats:Preliminary findings with [11C]raclopride PET

Microdialysis studies report that systemic alcohol increases extracellular dopamine (DA) in the rat striatum. The present study examined whether changes in striatal DA could be detected in rats using small animal positron emission tomography (PET). PET images were acquired in 44 alcohol-naïve male Wistar and alcohol-preferring (P) rats. Subjects received up to three [(11) C]raclopride scans (rest, alcohol, and saline). Animals were anesthetized with isoflurane and secured on a stereotactic-like holder during all scans. Blood samples were collected from the tail or lateral saphenous vein of 12 animals 10 min after tracer injection for determination of blood alcohol concentration (BAC). Time activity curves were extracted from the striatum and the cerebellum and binding potential (BP(ND) ) was calculated as a measure of D(2) receptor availability. Wistars given 1.0 g kg(-1) alcohol (20%v/v) i.v. or 3.0 g kg(-1) alcohol (20%v/v) i.p. showed significant alcohol-induced decreases in BP(ND) . In P rats (given 1.5, 2.25, or 3.0 g kg(-1) alcohol), no individual group showed a statistical effect of alcohol on BP(ND) , but taken together, all P rats receiving i.p. alcohol had significantly lower BP(ND) than rest or saline scans. Large decreases in BP(ND) were primarily observed in rats with BAC above 200 mg%. Also, a significant difference was found between baseline BP(ND) of Wistars who had undergone jugular catheterization surgery for i.v. alcohol administration and those who had not. Preliminary results suggest that alcohol-induced DA release in the rat striatum is detectable using small animal PET given sufficiently large cohorts and adequate blood alcohol levels.

Effects of unilateral 6-OHDA lesions on [3H]-N-propylnorapomorphine binding in striatum ex vivo and vulnerability to amphetamine-evoked dopamine release in rat

It has been argued that agonist ligands for dopamine D2/3 receptors recognize a privileged subset of the receptors in living striatum, those which are functionally coupled to intracellular G-proteins. In support of this claim, the D2/3 agonist [3H]-N-propylnorapomorphine ([3H]NPA) proved to be more vulnerable to competition from endogenous dopamine than was the antagonist ligand [11C]raclopride, measured ex vivo in mouse striatum, and subsequently in multi-tracer PET studies of analogous design. Based on these results, we predicted that prolonged dopamine depletion would result in a preferential increase in agonist binding, and a lesser competition from residual dopamine to the agonist binding. To test this hypothesis we used autoradiography to measure [3H]NPA and [3H]raclopride binding sites in hemi-parkinsonian rats with unilateral 6-OHDA lesions, with and without amphetamine challenge. Unilateral lesions were associated with a more distinct increase in [3H]NPA binding ex vivo than was seen for [3H]raclopride binding in vitro. Furthermore, this preferential asymmetry in [3H]NPA binding was more pronounced in amphetamine treated rats. We consequently predict that agonist ligands should likewise be fitter than antagonists for detecting responses to denervation in positron emission tomography studies of idiopathic Parkinson's disease. Agonist binding increases in vivo are likely to reflect the composite of a sensitization-like phenomenon, and relatively less competition from endogenous dopamine, as seen in the lesioned side of 6-OHDA induced hemi-parkinsonism.

Music and methamphetamine: Conditioned cue-induced increases in locomotor activity and dopamine release in rats

Associations between drugs of abuse and cues facilitate the acquisition and maintenance of addictive behaviors. Although significant research has been done to elucidate the role that simple discriminative or discrete conditioned stimuli (e.g., a tone or a light) play in addiction, less is known about complex environmental cues. The purpose of the present study was to examine the role of a musical conditioned stimulus by assessing locomotor activity and in vivo microdialysis. Two groups of rats were given non-contingent injections of methamphetamine (1.0mg/kg) or vehicle and placed in standard conditioning chambers. During these conditioning sessions both groups were exposed to a continuous conditioned stimulus, in the form of a musical selection (“Four” by Miles Davis) played repeatedly for 90min. After seven consecutive conditioning days subjects were given one day of rest, and subsequently tested for locomotor activity or dopamine release in the absence of drugs while the musical conditioned stimulus was continually present. The brain regions examined included the basolateral amygdala, nucleus accumbens, and prefrontal cortex. The results show that music is an effective contextual conditioned stimulus, significantly increasing locomotor activity after repeated association with methamphetamine. Furthermore, this musical conditioned stimulus significantly increased extracellular dopamine levels in the basolateral amygdala and nucleus accumbens. These findings support other evidence showing the importance of these brain regions in conditioned learning paradigms, and demonstrate that music is an effective conditioned stimulus warranting further investigation.

Traumatic brain injury reduces striatal tyrosine hydroxylase activity and potassium-evoked dopamine release in rats

There is increasing evidence that traumatic brain injury (TBI) induces hypofunction of the striatal dopaminergic system, the mechanisms of which are unknown. In this study, we analyzed the activity of striatal tyrosine hydroxylase (TH) in rats at 1day, 1week, and 4weeks after TBI using the controlled cortical impact model. There were no changes in the level of TH phosphorylated at serine 40 site (pser40TH) at 1day or 4weeks. At 1week, injured animals showed decreased pser40TH to 73.9±7.3% (p≤0.05) of sham injured rats. The in vivo TH activity assay showed no significant difference between injured and sham rats at 1day. However, there was a decreased activity in injured rats to 62.1±8.2% (p≤0.05) and 68.8±6.2% (p≤0.05) of sham injured rats at 1 and 4weeks, respectively. Also, the activity of protein kinase A, which activates TH, decreased at 1week (injured: 87.8±2.8%, sham: 100.0±4.2%, p≤0.05). To study the release activity of dopamine after injury, potassium (80mM)-evoked dopamine release was measured by microdialysis in awake, freely moving rats. Dialysates were collected and analyzed by high-performance liquid chromatography. There were no significant differences in dopamine release at 1day and 4weeks between sham and injured groups. At 1week, there was a significant decrease (injured: 0.067±0.015μM, sham: 0.127±0.027μM, p≤0.05). These results suggest that TBI-induced dopamine neurotransmission deficits are, at least in part, attributable to deficits in TH activity.

Optogenetic control of striatal dopamine release in rats

Optogenetic control over neuronal firing has become an increasingly elegant method to dissect the microcircuitry of mammalian brains. To date, examination of these manipulations on neurotransmitter release has been minimal. Here we present the first in-depth analysis of optogenetic stimulation on dopamine neurotransmission in the dorsal striatum of urethane-anesthetized rats. By combining the tight spatial and temporal resolution of both optogenetics and fast-scan cyclic voltammetry we have determined the parameters necessary to control phasic dopamine release in the dorsal striatum of rats in vivo. The kinetics of optically induced dopamine release mirror established models of electrically evoked release, indicating that potential artifacts of electrical stimulation on ion channels and the dopamine transporter are negligible. Furthermore a lack of change in extracellular pH indicates that optical stimulation does not alter blood flow. Optical control over dopamine release is highly reproducible and flexible. We are able to repeatedly evoke concentrations of dopamine release as small as a single dopamine transient (50 nM). An inverted U-shaped frequency response curve exists with maximal stimulation inducing dopamine effluxes exceeding 500 nM. Taken together, these results have obvious implications for understanding the neurobiological basis of dopaminergic-based disorders and provide the framework to effectively manipulate dopamine patterns.

NMDA‐mediated modulation of dopamine release is modified in rat prefrontal cortex and nucleus accumbens after chronic nicotine treatment

In this study, we investigate the effects of chronic administration of (-)nicotine on the function of the NMDA-mediated modulation of [(3)H]dopamine (DA) release in rat prefrontal cortex (PFC) and nucleus accumbens (NAc). In the PFC synaptosomes NMDA in a concentration-dependent manner evoked [(3)H]DA release in rats chronically treated with vehicle (14 days) with an EC(50) of 13.1 +/- 2.0 microM. The NMDA-evoked overflow of the [(3)H]DA in PFC nerve endings of rats treated with (-)nicotine was significantly lower (-43%) than in vehicle treated rats. The EC(50) was 9.0 +/- 1.4 microM. Exposure of NAc synaptosomes of rats treated with vehicle to NMDA produced an increase in [(3)H]DA overflow with an EC(50) of 14.5 +/- 5.5 microM. This effect was significantly enhanced in chronically treated animals. The EC(50) was 10.5 +/- 0.5 microM. The K(+)-evoked release of [(3)H]DA was not modified by the (-)nicotine administration. Both the changes of the NMDA-evoked [(3)H]DA overflow in the NAc and PFC disappeared after 14 days withdrawal. The results show that chronic (-)nicotine differentially affects the NMDA-mediated [(3)H]DA release in the PFC and NAc of the rat.

A synaptic DEG/ENaC ion channel mediates learning in C. elegans by facilitating dopamine signalling

An important component of learned behaviour is the ability to forecast positive or negative outcomes based on specific sensory cues. Predictive capacity is typically manifested by appropriate behavioural patterning. However, the molecular mechanisms underlying behavioural plasticity are poorly understood. Caenorhabditis elegans displays experience-dependent behavioural responses by associating distinct environmental signals. We find that ASIC-1, a member of the degenerin/epithelial sodium channel family, which localizes at presynaptic terminals of dopaminergic neurons, is required for associative learning in C. elegans. ASIC-1 functions in these neurons to amplify normal dopaminergic signalling, necessary for associative learning. Our results reveal a novel role of DEG/ENaC ion channels in neuronal communication by enhancing the activity of dopaminergic synapses. Similar mechanisms may facilitate synaptic plasticity in vertebrates.

Cocaine increases stimulated dopamine release more in periadolescent than adult rats

The neural mechanisms responsible for the enhanced adolescent vulnerability for initiating drug abuse are unclear. We investigated whether age differences in dopamine neurotransmission could explain cocaine's enhanced psychomotor effects in the periadolescent rat. Electrical stimulation of the medial forebrain bundle of anesthetized post-natal age 28 days (PN28) and PN65 rats elicited dopamine release in caudate nucleus and nucleus accumbens core before and after 15 mg/kg cocaine i.p. Extracellular dopamine concentrations were greater in PN65 than PN28 caudate following 20 and 60 Hz stimulations and in the PN65 nucleus accumbens following 60 Hz stimulations. Cocaine increased dopamine concentrations elicited by 20 Hz stimulations 3-fold in the adult, but almost 9-fold in periadolescent caudate. Dopamine release rate was lower in the periadolescent caudate although total dopamine clearance was similar to that of adults. The periadolescent caudate achieved adult levels of clearance by compensating for a lower V max with higher uptake affinity. Tighter regulation of extracellular dopamine by the higher uptake/release ratio in periadolescents led to greater increases after cocaine. In nucleus accumbens, dopamine release and V max were lower in periadolescents than adults, but uptake affinity and cocaine effects were similar. Immaturity of dopamine neurotransmission in dorsal striatum may underlie enhanced acute responses to psychostimulants in adolescent rats and suggests a mechanism for the greater vulnerability of adolescent humans to drug addiction.

Initial Comparison of ntPET with Microdialysis Measurements of Methamphetamine-Induced Dopamine Release in Rats: Support for Estimation of Dopamine Curves from PET Data

A recently introduced mathematical method for extracting temporal characteristics of neurotransmitter release from dynamic positron emission tomography (PET) data was tested. The method was developed with the hope that by uncovering temporal information about neurotransmitter (nt) dynamics in PET data, researchers could shed new light on mechanisms of psychiatric diseases such as drug abuse and its treatment. In this study, we apply our model-based method, "ntPET", to (11)C-raclopride PET scans of rats in which the dopaminergic response to a microinfusion of methamphetamine in one striatum was assayed simultaneously by microdialysis and PET. Uptake of (11)C-raclopride into the untreated contralateral striatum was used as an input to the ntPET model. Direct comparisons of the model-based ntPET analysis and the microdialysis measurements confirmed that ntPET produced dopamine curves that were very similar in timing (takeoff and peak times) to the microdialysis curves. Variances in takeoff and peak times were comparable for the two methods. Neither method detected a false dopamine response to drug in a control animal. The high degree of correspondence between ntPET estimates and microdialysis measurements lends strong support to the idea that temporal information regarding dopamine release exists in dynamic (11)C-raclopride PET data and that it can be estimated reliably via ntPET. The method is entirely translatable to human PET imaging.

Dopaminergic modulation of tracer coupling in a ganglion-amacrine cell network

Many retinal ganglion cells are coupled via gap junctions with neighboring amacrine cells and ganglion cells. We investigated the extent and dynamics of coupling in one such network, the OFF alpha ganglion cell of rabbit retina and its associated amacrine cells. We also observed the relative spread of Neurobiotin injected into a ganglion cell in the presence of modulators of gap junctional permeability. We found that gap junctions between amacrine cells were closed via stimulation of a D(1) dopamine receptor, while the gap junctions between ganglion cells were closed via stimulation of a D(2) dopamine receptor. The pairs of hemichannels making up the heterologous gap junctions between the ganglion and amacrine cells were modulated independently, so that elevations of cAMP in the ganglion cell open the ganglion cell hemichannels, while elevations of cAMP in the amacrine cell close its hemichannels. We also measured endogenous dopamine release from an eyecup preparation and found a basal release from the dark-adapted retina of approximately 2 pmol/min during the day. Maximal stimulation with light increased the rate of dopamine release from rabbit retina by 66%. The results suggest that coupling between members of the OFF alpha ganglion cell/amacrine cell network is differentially modulated with changing levels of dopamine.

Decoding of dopaminergic mesolimbic activity and depressive behavior

Dopaminergic mesolimbic and mesocortical systems are involved in hedonia and motivation, two core symptoms of depression. However, their role in the pathophysiology of depression and their manipulation to treat depression has received little attention. Previously, we showed decreased limbic dopamine (DA) neurotransmission in an animal model of depression, Flinder sensitive line (FSL) rats. Here we describe a high correlation between phase-space algorithm of bursting-like activity of DA cells in the ventral tegmental area (VTA) and efficiency of DA release in the accumbens. This bursting-like activity of VTA DA cells of FSL rats is characterized by a low dimension complexity. Treatment with the antidepressant desipramine affected both the dimension complexity of cell firing in the VTA and rate of DA release in the accumbens, as well as alleviating depressive-like behavior. Our findings indicate the potential usefulness of monitoring limbic dopaminergic dynamics in combination with non-linear analysis. Decoding the functionality of the dopaminergic system may help in development of future antidepressant drugs.

Mapping the amphetamine-evoked changes in [11C]raclopride binding in living rat using small animal PET: Modulation by MAO-inhibition

The performance of small animal PET for neuroreceptor studies in a psychopharmacological challenge paradigm is not yet well-described. Therefore, we used microPET and [11C]raclopride to map the availability of dopamine D2/3 receptors in brain of anesthetized rats, first in a baseline condition, and again after challenge with saline or d-amphetamine. Parametric maps of the specific binding (binding potential, pB) were calculated using a reference tissue input from cerebellum, and spatially normalized to a digitized stereotaxic coordinate system for rat brain. In volumes of interest (VOIs), the mean baseline pB (n=6) was 2.05 in dorsal striatum (caudate-putamen), and 1.34 in ventral striatum (nucleus accumbens), and did not significantly differ upon retest 2 h later. The availability of [11C]raclopride binding sites at baseline was 8% higher in the right striatum. Challenge with amphetamine sulfate (1 mg/kg, i.v., n=4) decreased pB by 19% in both ventral and dorsal striatum. We have earlier predicted that blockade of monoamine oxidase (MAO) should potentiate the amphetamine-evoked dopamine release, thus enhancing the displacement of [11C]raclopride binding in vivo. However, pretreatment of rats with pargyline hydrochloride (4 mg/kg, n=4; 20 mg/kg, n=4) 1 day prior to PET did not potentiate the amphetamine-evoked reduction in dopamine receptor availability within the extended striatum. We conclude that small animal PET can be used to investigate stimulant-induced dopamine release, but that the spatial resolution is insufficient to detect differences between relative changes in dorsal vs. ventral divisions of the rat striatum. Furthermore, the present results do not reveal potentiation of the amphetamine-evoked release of dopamine in rats with MAO inhibition.

Prior Exposure to Chronic Stress and MDMA Potentiates Mesoaccumbens Dopamine Release Mediated by the 5-HT1B Receptor

(+) 3,4,-Methylenedioxymethamphetamine (MDMA) is an abused drug that acutely releases serotonin (5-HT) and dopamine (DA) but produces long-term damage to 5-HT terminals. MDMA-induced DA release has been shown to be dampened by 5-HT. Although stress also activates the mesolimbic DA pathway, it is unknown if chronic stress after exposure to neurotoxic doses of MDMA will augment MDMA-induced DA release in the nucleus accumbens shell (NAcc(sh)). Rats were pretreated with MDMA (10 mg/kg x 4, intraperitoneal (i.p.)). After 7 days, rats were subjected to 10 days of chronic unpredictable stress. DA release in the NAcc(sh) and 5-HT in the ventral tegmental area (VTA) were measured after a challenge injection of MDMA (5 mg/kg, i.p.). The combination of pretreatment with MDMA+stress decreased basal concentrations of 5-HT in the VTA and DA in the NAcc(sh) and enhanced MDMA-stimulated DA release in the NAcc(sh). Pretreatment with MDMA or stress alone blunted MDMA-induced 5-HT release in the VTA. The augmentation of MDMA-induced DA release in rats pretreated with MDMA+chronic stress was attenuated by perfusion of the 5-HT(1B) antagonist, GR127935 into the VTA before the MDMA challenge injection. These results suggest that prior exposure to both MDMA and stress can produce a long-term augmentation in mesolimbic DA transmission and enhanced drug abuse vulnerability that is mediated, in part, by the 5-HT(1B) receptor in the VTA.

Diurnal patterns of dopamine release in chicken retina

The retinal dopaminergic system appears to play a major role in the regulation of global retinal processes related to light adaptation. Although most reports agree that dopamine release is stimulated by light, some retinal functions that are mediated by dopamine exhibit circadian patterns of activity, suggesting that dopamine release may be controlled by a circadian oscillator as well as by light. Using the accumulation of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) in the vitreous as a measure of dopamine release rates, we have investigated the balance between circadian- and light control over dopamine release. In chickens held under diurnal light:dark conditions, vitreal levels of DOPAC showed daily oscillations with the steady-state levels increasing nine-fold during the light phase. Kinetic analysis of this data indicates that apparent dopamine release rates increased almost four-fold at the onset of light and then remained continuously elevated throughout the 12 h light phase. In constant darkness, vitreal levels of DOPAC displayed circadian oscillations, with an almost two-fold increase in dopamine release rates coinciding with subjective dawn/early morning. This circadian rise in vitreal DOPAC could be blocked by intravitreal administration of melatonin (10 nmol), as predicted by the model of the dark–light switch where a circadian fall in melatonin would relieve dopamine release of inhibition and thus be responsible for the slight circadian increase in dopamine release. The increase in vitreal DOPAC in response to light, however, was only partially suppressed by melatonin. The activity of the dopaminergic amacrine cell in the chicken retina thus appears to be dominated by light-activated input.

Dopamine release in PC12 cells is mediated by Ca2+‐dependent production of ceramide via sphingomyelin pathway

A presynaptic membrane disturbance is an essential process for the release of various neurotransmitters. Ceramide, which is a tumor suppressive lipid, has been shown to act as a channel-forming molecule and serve as a precursor of ceramide-1-phosphate, which can disturb the cellular membrane. This study found that while permeable ceramide increases the rate of dopamine release in the presence of a Ca(2+)-ionophore, A23187, permeable ceramide-1-phosphate provoked its release even without the ionophore. The treatment of PC12 cells with the ionophore at concentrations < 2 microM produced ceramide via the sphingomyelin (SM) pathway with a concomitant release of dopamine, and no cell damage was observed. The addition of a Ca(2+) chelator, EGTA, to the medium inhibited the increase in the release of both the ceramide and dopamine. This suggests that ceramide might be produced by Ca(2+) and is implicated in the membrane disturbance associated with the release of dopamine as a result of its conversion to ceramide-1-phosphate. Consistent with these results, this study detected a membrane-associated and neutral pH optimum sphingomyelinase (SMase) whose activity was increased by Ca(2+). Together, these results demonstrate that ceramide can be produced via the activation of a neutral form of SMase through Ca(2+), and is involved in the dopamine release in concert with Ca(2+).

Cortical glutamate–dopamine interaction and ketamine-induced psychotic symptoms in man

The noncompetitive glutamate N-methyl-D: -aspartate receptor antagonist ketamine induces transient psychotic symptoms in man. Involvement of dopaminergic mechanisms in these effects has been suggested. The purpose of this article is to study the effects of ketamine on extrastriatal dopamine receptor availability in healthy subjects and extracellular dopamine levels in rat cortex. The effect of computer-driven subanesthetic ketamine infusion on cortical dopamine release was studied in healthy male subjects using a controlled study design. Dopamine D2/D3 receptor availability was quantified using positron emission tomography (PET) and [11C]FLB 457. A conventional region of interest-based analysis and voxel-based analysis was applied to the PET data. The ketamine-induced cortical dopamine release in rats was studied using in vivo microdialysis. Ketamine infusion reduced significantly the [11C]FLB 457 binding potential (BP) in the posterior cingulate/retrosplenial cortices, suggestive of increased dopamine release. This brain imaging finding was further supported by a microdialysis experiment in rats showing that ketamine increased the extracellular dopamine concentration by up to 200% in the retrosplenial cortex. Ketamine-induced psychotic symptoms were associated with changes in the [11C]FLB 457 BP in the dorsolateral prefrontal and anterior cingulate cortices. Our results suggest that cortical dopaminergic mechanisms have a role in the emergence of ketamine-induced psychosis-like symptoms in man. The glutamate-dopamine interaction in the posterior cingulate during ketamine infusion is well in line with the recent functional and structural imaging studies suggesting involvement of this cortical area in the development of schizophrenic psychosis.

Effect of chronic lithium and withdrawal from chronic lithium on presynaptic dopamine function in the rat

Bipolar affective disorders can be successfully treated with long-term use of the mood stabilizer lithium. However, discontinuation of lithium treatment is followed by a high incidence of manic episodes. In the present study, we attempted to identify neurobiological changes that might mediate this rebound mania. In vivo microdialysis in the anaesthetized rat and in situ hybridization histochemistry were used to study the effect of chronic lithium treatment and withdrawal from chronic lithium treatment on presynaptic dopamine (DA) function. Rats were maintained for 28 days on a lithium diet or control diet. The lithium-withdrawn treatment group had their lithium diet substituted for control diet from day 25 of the treatment period. Microdialysis probes were implanted in the shell of the nucleus accumbens and both basal extracellular DA levels and DA levels in the presence of the DA uptake inhibitor bupropion (1 microM) were collected. Basal DA levels did not differ between any of the treatment groups. However, during local perfusion of bupropion, the increase in DA was significantly attenuated in the lithium-treated animals compared to controls or lithium-withdrawn animals. In situ hybridization of DA transporter mRNA in the ventral tegmental area revealed no difference in the abundance of this mRNA in any of the groups. These data suggest that there is impaired DA release in rats during chronic lithium treatment, but DA release returns to normal levels on withdrawal from lithium treatment, and is therefore unlikely to underlie the rebound mania associated with lithium withdrawal.