Smaller effect of propofol than sevoflurane anesthesia on dopamine turnover induced by methamphetamine and nomifensine in the rat striatum: an in vivo microdialysis study.

Volatile anesthetics accelerate dopamine turnover in the brain, especially when used in conjunction with psychotropic agents such as methamphetamine and nomifensine. The effect of intravenous propofol anesthesia on the extracellular dopamine concentrations is unclear. The aim of this study was to compare the effect of two anesthetics on the extracellular concentrations of dopamine and metabolites using an in vivo microdialysis model. Male Sprague Dawley rats were implanted with a microdialysis probe into the right striatum. The probe was perfused with modified Ringer's solution, and the dialysate was directly injected into a high-performance liquid chromatography system every 20 min. The rats were intraperitoneally administered saline, methamphetamine at 2 mg/kg, or nomifensine at 10 mg/kg. After treatment, the rats were anesthetized with intravenous propofol (20 mg/kg followed by 25 or 50 mg/kg/h) or inhalational sevoflurane (2.5%) for 1 h. Propofol showed no effect on the extracellular concentration of dopamine during anesthesia; however, propofol decreased the dopamine concentration after anesthesia in the high-dose group. Sevoflurane anesthesia increased the concentration of metabolites. Systemic administration of methamphetamine and nomifensine increased the extracellular concentration of dopamine. Sevoflurane anesthesia significantly enhanced the increase in the dopamine concentration induced by both methamphetamine and nomifensine, whereas propofol anesthesia showed no effect on the methamphetamine- and nomifensine-induced dopamine increase during anesthesia. The enhancing effect of psychotropic agent-induced acceleration of dopamine turnover was smaller for propofol anesthesia than for sevoflurane anesthesia.

In Vivo Monitoring of Dopamine by Microdialysis with 1 min Temporal Resolution Using Online Capillary Liquid Chromatography with Electrochemical Detection.

Microdialysis is often applied to understanding brain function. Because neurotransmission involves rapid events, increasing the temporal resolution of in vivo measurements is desirable. Here, we demonstrate microdialysis with online capillary liquid chromatography for the analysis of 1 min rat brain dialysate samples at 1 min intervals. Mobile phase optimization involved adjusting the pH, buffer composition, and surfactant concentration to eliminate interferences with the dopamine peak. By analyzing electrically evoked dopamine transients carefully synchronized with the switching of the online LC sample valve, we demonstrate that our system has both 1 min sampling capabilities and bona fide 1 min temporal resolution. Evoked DA transients were confined to single, 1 min brain dialysate samples. After uptake inhibition with nomifensine (20 mg/kg i.p.), responses to electrical stimuli of 1 s duration were detected.

Long-lasting cognitive deficit induced by stress is alleviated by acute administration of antidepressants.

Deficits in executive control associated with frontal lobe dysfunction have been reported in affective disorder, which is often precipitated by stressful life events. Here we examined the impact of repeated restraint stress (1h daily for 7 days) on rats' performance in the attentional set-shifting task (ASST). To evaluate the persistence of cognitive deficits, the performance of separate groups of rats was assessed on the 4th, 7th, 14th and 21st day following stress cessation. Stressed rats exhibited unusually long-lasting extra-dimensional (ED) set-shifting impairments, since these deficits were demonstrated even 3 weeks following stress termination. An inhibitor of corticosterone synthesis, the drug metyrapone (50mg/kg, IP) protected rats from the cognitive impairment suggesting an involvement of endogenous adrenal steroids in the debilitating effects of stress. Acute intraperitoneal administration of four different antidepressants (desipramine, nomifensine, fluoxetine and escitalopram) at the minimum effective doses of 3, 0.3, 1 and 1mg/kg, respectively, reversed the deficits of ED set-shifting in stressed animals. Desipramine, nomifensine, fluoxetine and escitalopram at the minimum effective doses of 6, 1, 1 and 1mg/kg, IP, respectively, promoted also cognitive flexibility in unstressed groups. We conclude that stress-induced long-term set-shifting impairment may represent a useful model mimicking clinically relevant aspects of depression, i.e., the persistence of executive dysfunction. The potential utility of antidepressants in treating frontal-like cognitive impairments is suggested.

Forced swim test behavior in postpartum rats.

This study was undertaken to determine whether depression-like behavior can be observed in gonadally intact females that have experienced normal pregnancy. When tested on the forced swim test (FST) on postpartum days 1-7, previously pregnant rats spent slightly more time immobile, significantly less time swimming and diving, and defecated more than virgin controls. Subchronic treatment with nomifensine (DA reuptake inhibitor, 2.5mg/kg) but not sertraline (serotonin reuptake inhibitor, 10mg/kg) or desipramine (norepinephrine reuptake inhibitor, 10mg/kg) significantly decreased immobility on postpartum day 2. In rats pre-exposed to the FST in mid-pregnancy, neither subchronic nor chronic treatment with desipramine or sertraline decreased immobility on postpartum day 2; in contrast, chronic desipramine significantly decreased immobility in virgin controls. These results indicate that postpartum female rats, compared to virgin controls, show a reduction in some "active coping behaviors" but no significant increase in immobility when tested during the early postpartum period, unlike ovariectomized females that have undergone hormone-simulated pregnancy (HSP). Additionally, immobility that is increased by FST pre-exposure is not readily prevented by treatment with standard antidepressant medications in postpartum females. Depression-like behaviors previously observed in females that have undergone HSP may result from the more dramatic changes in estradiol, prolactin or corticosterone that occur during the early "postpartum" period, compared to the more subtle changes in these hormones that occur in actual postpartum females.

Effects of acute and sustained administration of the catecholamine reuptake inhibitor nomifensine on the firing activity of monoaminergic neurons.

Nomifensine potently inhibits the reuptake of norepinephrine and dopamine in vitro. It is one of few antidepressants with marked potency to block dopamine reuptake that has ever been used clinically. Acute and sustained administration of nomifensine was investigated on the firing of monoaminergic neurons to understand its mechanism of action. In vivo extracellular recordings of locus coeruleus, ventral tegmental area and dorsal raphe nucleus neurons were obtained from male Sprague-Dawley rats. The intravenous injection of nomifensine in the locus coeruleus and ventral tegmental area yielded ED(50) values of 40 +/- 1 and 450 +/- 41 microg/kg, respectively, suggesting that nomifensine directly acted upon dopamine and norepinephrine neurons, since these values are proportional to its affinities for norepinephrine and dopamine transporters. There was no effect on 5-HT neurons. Nomifensine (5 mg/kg/day, subcutaneous, using minipumps) potently and significantly inhibited dopamine neuronal firing in the ventral tegmental area after 2 days, with recovery to normal after the 14-day treatment due to D(2) autoreceptor desensitization. Norepinephrine neuronal firing in the locus coeruleus was significantly decreased after 2 and 14 days. A significant increase in dorsal raphe nucleus 5-HT neuronal firing was seen after a two-day regimen, and remained elevated after 14 days. Desensitization of the 5-HT(1A) receptor on 5-HT neurons of the dorsal raphe nucleus occurred after two days of nomifensine administration. Nomifensine likely treated depression by acting on dopamine, norepinephrine and 5-HT neurons, highlighting the importance of the functional connectivity between these three monoaminergic systems.

Continuous stimulation of dopaminergic receptors by rotigotine does not interfere with the sleep-wake cycle in the rat.

Rotigotine is a new, non-ergoline dopamine receptor agonist developed for the treatment of Parkinson's disease in a transdermal formulation (Neupro ) to provide sustained drug delivery for 24 h with a once daily dosing. The aim of the present study was to determine whether or not continuous dopaminergic stimulation can interfere with the sleep-wake cycle. To achieve this, rotigotine was administered as a slow release formulation to provide stable plasma and brain levels over a period of 6 days and the sleep-wake cycle was evaluated in the freely-moving male rat using electroencephalagraphic recording. For comparison, the mixed dopamine/noradrenaline reuptake inhibitor nomifensine (16 mg/kg p.o.) was administered once daily for 6 days. In contrast to nomifensine, rotigotine (0.5 and 5 mg/kg s.c.) had no clear effects on the sleep-wake cycle. Nomifensine delayed the onset of rapid eye movement (REM) sleep and, to a lesser extent, also that of slow wave sleep (SWS). In addition, it increased the duration of waking time and decreased the duration of SWS and REM sleep. These effects were observed on all days and repeated administration lead neither to potentiation nor attenuation of the effects. It is concluded that a continuous dopaminergic stimulation of dopamine receptors by rotigotine may not only be beneficial for the treatment of the motor symptoms of Parkinson's disease but also have additional benefits by not compromising either sleep architecture or circadian rhythm.

Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease.

Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs.

[Dopaminergic regulation of theta activity of septohippocampal neuron in the awake rabbit]. / Dofaminergicheskaia reguliatsiia teta-aktivnosti septo-gippokampal'nykh neironov u bodrstvuiushchikh krolikov.

The effects of dopamine reuptake blocker nomifensine and nonselective antagonist of dopamine receptors haloperidol on the theta rhythmicity of the medial septal neurons and hippocampal EEG were investigated in the rabbit. Bilateral intracerebroventricular infusion of nomifensine (9 micrograms in each ventriculus) produced an increase in both the rate of firing and the theta modulation of medial septal neurons; the theta power of the hippocampal EEG also augmented. The degree of neuronal theta stability (time constant of damping, tao theta) significantly increased. The frequency of rhythmic bursts in the neuronal firing also substantially elevated. The amplitude, regularity and frequency of theta waves in the hippocampal EEG also increased. The antagonist haloperidol (12.5 mg) caused the opposite effect. The theta activity of medial septal neurons and the theta power of the hippocampal EEG decreased after haloperidol injection. Theta rhythmicity of septal neurons significantly diminished, the rate of rhythmic bursts in the neuronal firing also decreased, although not substantially. The theta amplitude and regularity in the hippocampal EEG also decreased. Effects of both drugs built up rapidly and then gradually attenuated. Nomifensine infusion against the background of exposure to haloperidol provoked neither increasing neuronal firing rate, nor elevating theta activity. These finding suggest that dopaminergic system produces activation of the septohippocampal system in situations that require selective attention to functionally important information.

Enhanced attention in rhesus monkeys as a common factor for the cognitive effects of drugs with abuse potential.

RATIONALE: One of the common neurochemical features of many drugs of abuse is their ability to directly or indirectly enhance dopaminergic activity in the brain, particularly within the ventral tegmental-nucleus accumbens pathway. Dopaminergic pathways in the frontal and limbic cortex also may be targets for these agents, where pharmacological effects could result in heightened attention and/or support self-administration behavior. OBJECTIVES: The purpose of this study was to determine whether drugs from differing pharmacological classes that exhibit abuse potential would share the ability to counter distractability in the delayed matching task. METHODS: Well trained mature macaques performed a computer-assisted delayed matching-to-sample task which included trials associated with three delay intervals and randomly interspersed task-relevant distractors. Drug regimens included four to five doses and subjects were tested no more than twice per week. RESULTS: All but one of the six compounds (tomoxetine), on average, increased task accuracy for either non-distractor or distractor trials. It was evident that for several compounds, doses required to improve accuracy for non-distractor trials were routinely greater than the doses required to improve accuracy for distractor trials. Data for the individualized Best dose (based upon the subject's optimal level of accuracy during distractor trials) revealed statistically significant distractor-related improvements in task accuracy for the same five compounds. The relative efficacy for reversing distractor-induced decrements in task accuracy was estimated by the level of improvement with respect to baseline: nomifensine (31%)>nicotine (22%) approximately morphine (19%) approximately caffeine (19%) approximately methylphenidate (22%) >tomoxetine (9%). Tomoxetine (noradrenergic preferring) was the only compound that did not produce a significant improvement in accuracy. CONCLUSIONS: These results provide pharmacological support for the concept that attentional mechanisms may play an important role in the "environmental" associative aspects of drug seeking behavior, and as such they may provide the basis for treatment strategies aimed at preventing relapse in detoxified addicts.

Preferential increases in nucleus accumbens dopamine after systemic cocaine administration are caused by unique characteristics of dopamine neurotransmission.

In vivo voltammetry was used to investigate the preferential increase of extracellular dopamine in the nucleus accumbens relative to the caudate-putamen after systemic cocaine administration. In the first part of this study, cocaine (40 mg/kg, i.p.) was compared with two other blockers of dopamine uptake, nomifensine (10 mg/kg, i.p.) and 3beta-(p-chlorophenyl)tropan-2beta-carboxylic acid p-isothiocyanatophenylmethyl ester hydrochloride (RTI-76; 100 nmol, i.c.v.), to assess whether the inhibitory mechanism of cocaine differed in the two regions. All three drugs robustly increased electrically evoked levels of dopamine, and cocaine elevated dopamine signals to a greater extent in the nucleus accumbens. However, kinetic analysis of the evoked dopamine signals indicated that cocaine and nomifensine increased the K(m) for dopamine uptake whereas the dominant effect of RTI-76 was a decrease in V(max). Under the present in vivo conditions, therefore, cocaine is a competitive inhibitor of dopamine uptake in both the nucleus accumbens and caudate-putamen. Whether the preferential effect of cocaine was mediated by regional differences in the presynaptic control of extracellular DA that are described by rates for DA uptake and release was examined next by a correlation analysis. The lower rates for dopamine release and uptake measured in the nucleus accumbens were found to underlie the preferential increase in extracellular dopamine after cocaine. This relationship explains the paradox that cocaine more effectively increases accumbal dopamine despite identical effects on the dopamine transporter in the two regions. The mechanism proposed for the preferential actions of cocaine may also mediate the differential effects of psychostimulant in extrastriatal regions and other uptake inhibitors in the striatum.

Changes in seizure susceptibility to local anesthetics by repeated administration of cocaine and nomifensine but not GBR12935: possible involvement of noradrenergic system.

We examined cross-sensitization of cocaine and synthetic local anesthetics to their seizure susceptibility after repeated administration. Seizure susceptibility of procaine and lidocaine increased after the end of two days of treatment with a subconvulsive dose of cocaine. Acute treatment with nomifensine but not GBR12935, a specific inhibitor of the dopamine transporter, facilitated lidocaine-induced convulsion. Furthermore, daily treatment with nomifensine for two days enhanced lidocaine-induced convulsion. These results suggest the possible involvement of the brain noradrenergic system in the changes in seizure susceptibility after repeated administration of some local anesthetics.

A comparison of the patterns of striatal Fos-like immunoreactivity induced by various dopamine agonists in rats.

In contrast to the highly patchy patterns of Fos-like immunoreactivity seen in the rostral striatum after administration of a number of dopamine agonists, the monoamine uptake blocker cocaine has been reported to produce a relatively homogeneous pattern of gene expression. In the current study we extended these observations by using a quantitative technique to demonstrate that while amphetamine and apomorphine produce patchy striatal Fos expression, the selective dopamine uptake inhibitors amfonelic acid, nomifensine and GBR-12909 all, like cocaine, produce near random patterns of gene expression. These findings suggest that the production of relatively 'non-patchy' patterns of immediate early gene expression may be a general property of dopamine transport inhibitors unrelated to any unique pharmacological properties of cocaine.

Ethanol effects on self-administration of alfentanil, cocaine, and nomifensine in rhesus monkeys.

A common form of polydrug use is that of cocaine and ethanol. The identification of an ethanol-cocaine combination product, cocaethylene, with properties in common with cocaine, has led to speculation that this metabolite may contribute to the co-abuse of cocaine and ethanol. In order to determine whether ethanol pretreatments selectively altered cocaine's reinforcing potency, ethanol pretreatments were given to monkeys trained to press levers and receive IV infusions of several doses of cocaine or alfentanil. In addition, nomifensine, a drug which has a mechanism of action similar to cocaine's, was evaluated in the presence and absence of ethanol in monkeys with the cocaine baseline history. Ethanol, in doses ranging from 100 to 1780 mg/kg, given 10 min before the 130-min session, had no effect on responding maintained by alfentanil. These doses also had no significant effect on cocaine-maintained responding, although the potency of cocaine as a reinforcer was increased following administration of 1000 mg/kg ethanol in two of the four subjects. The potency of nomifensine as a reinforcer was significantly increased by 1000 mg/kg ethanol, but again, this enhancement was limited to the same two subjects. These data indicate that, in this paradigm, cocaethylene did not selectively modify cocaine's reinforcing potency, but there appear to be individual differences with respect to ethanol's ability to stimulate rates of drug-maintained responding.

Habit-forming actions of nomifensine in nucleus accumbens.

Rats learned to lever-press when reinforced with response-contingent microinfusions of the dopamine uptake inhibitor nomifensine (1.7 nmol per injection) into the ventro-medial (shell) region of nucleus accumbens septi (NAS). The drug was not effective when similar injections were given either in random relation to lever-pressing, into the more dorso-lateral (core) region of NAS, or into the frontal cortex. Cocaine was also effective in NAS, but considerably less so. These data suggest that response-contingent dopamine uptake blockade within the NAS is sufficient to establish and maintain instrumental response habits.

Effect of local infusion of glutamate analogues into the nucleus accumbens of rats: an electrochemical and behavioural study.

In vivo voltammetry at electrochemically pretreated carbon fibre electrodes was used to investigate the effect of local infusion of glutamate analogues on dopamine (DA) release in rat nucleus accumbens. Infusion of a low dose of NMDA or AMPA (1 mM/0.2 microliter), but not L-glutamate or kainate, was followed a few minutes later by a large but short-lived increase in the extracellular concentration of DA. The involvement of spreading depression was indicated since this response could be repeated only after a short refractory period, and the response magnitude did not seem to be dependent on the dose infused. Furthermore, the increase in DA release was accompanied by a marked negative shift in brain field potential and a similar increase in release could be induced by local infusion of K+. The infusion of NMDA, AMPA or kainate was followed by behavioural activation of the animals but not convulsions. The behavioural response induced by NMDA was dose-dependently reduced by haloperidol, which suggests the involvement of a DA-dependent mechanism in this effect. Co-infusion of the DA transport inhibitors, nomifensine or GBR 12909, failed to alter the DA response to NMDA, while this response was completely blocked by co-infusion of tetrodotoxin or pretreatment with reserpine. It is evident from this study that local infusion of NMDA or AMPA may induce spreading depression in rat nucleus accumbens and that this condition is associated with a vast release of DA and behavioural activation.

Clearance of exogenous dopamine in rat dorsal striatum and nucleus accumbens: role of metabolism and effects of locally applied uptake inhibitors.

In vivo electrochemistry was used to investigate the mechanisms contributing to the clearance of locally applied dopamine in the dorsal striatum and nucleus accumbens of urethane-anesthetized rats. Chronoamperometric recordings were continuously made at 5 Hz using Nafion-coated carbon fiber electrodes. When a finite amount of dopamine was pressure-ejected at 5-min intervals from a micropipette adjacent to the electrode, transient and reproducible dopamine signals were detected. Substitution of L-alpha-methyldopamine, a substrate for the dopamine transporter but not for monoamine oxidase, for dopamine in the micropipette did not substantially alter the time course of the resulting signals. This indicates that metabolism of locally applied dopamine to 3,4-dihydroxy-phenylacetic acid is not responsible for the decline in the dopamine signal. Similarly, changing the applied oxidation potential from +0.45 to +0.80 V, which allows for detection of 3-methoxytyramine formed from dopamine via catechol-O-methyltransferase, had little effect on signal amplitude or time course. In contrast, lesioning the dopamine terminals with 6-hydroxydopamine, or locally applying the dopamine uptake inhibitors cocaine or nomifensine before pressure ejection of dopamine, significantly increased the amplitude and time course of the dopamine signals in both regions. The effects of cocaine and nomifensine were greater in the nucleus accumbens than in the dorsal striatum. Local application of lidocaine and procaine had no effect on the dopamine signals. Initial attempts at modeling resulted in curves that were in qualitative agreement with our experimental findings. Taken together, these data indicate that (1) uptake of dopamine by the neuronal dopamine transporter, rather than metabolism or diffusion, is the major mechanism for clearing locally applied dopamine from the extracellular milieu of the dorsal striatum and nucleus accumbens, and (2) the nucleus accumbens is more sensitive to the effects of inhibitors of dopamine uptake than is the dorsal striatum.

Acute therapy of depression.

The acute therapy (the initial 8 weeks of treatment) of depression (including the whole spectrum of "less than major," "major," and "more than major") has been reviewed comparing the old tricyclics with the new generations (especially mianserin, moclobemide, and the serotonin selective reuptake inhibitors (SSRIs), i.e., citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline). The Hamilton Rating Scale for Depression has been used to measure clinical efficacy. Statistically, the method of meta-analysis has been applied. The results showed that the SSRIs and moclobemide are equal to the tricyclics. Mianserin is inferior to tricyclics as well as to SSRIs. The antidepressive profile of the SSRIs is nonsedation but still with anxiolytic effects. The safety profile of the SSRIs is much more benign than that of the tricyclics.

DuP 753, a nonpeptide angiotensin II-1 receptor antagonist, alters dopaminergic function in rat striatum.

The purpose of this study was to determine if the nonpeptide angiotensin II-1 receptor antagonist DuP 753 after, acute or chronic administration in vivo or after in vitro exposure, altered indices of dopaminergic function in rat striatum. In vivo studies examined the effect of acute and chronic 21-day administration of DuP 753 (10 mg/kg, s.c.) on levels of dopamine (DA) and its metabolite, dihydroxyphenylacetic acid (DOPAC). To determine if chronic treatment with DuP 753 was able to inhibit the pressor response to angiotensin II, a single i.v. dose of angiotensin II (0.1 microgram/kg) was administered 18 hours after the last dose of DuP 753. Acute DuP 753 resulted in significantly decreased (14%) levels of DA. Chronic DuP 753 resulted in increased (1.64 fold) levels of DOPAC, although DA levels were not altered. The single i.v. administration of angiotensin II resulted in increased (88%) DOPAC levels regardless of chronic DuP 753. The in vitro effect of DuP 753 (0.1 nM-1.0 microM) on basal and field stimulation-evoked release of DA and DOPAC was determined in superfused striatal slices from drug naive rats. DA was not detected in these experiments. DuP 753 did not alter basal outflow of DOPAC. At low concentrations (1.0-10 nM), DuP 753 decreased (53%) stimulation-evoked DOPAC overflow; however, at concentrations greater than 10 nM, the inhibitory effect was diminished. Nomifensine (10 microM; a DA uptake inhibitor) was included in the superfusion buffer in order to measure the effect of DuP 753 on the concentration of DA in superfusate. DuP 753 had no effect on basal DA and DOPAC outflow.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of amphetamine and nomifensine on intracranial self-stimulation discrimination behavior in rats.

Rats implanted with electrodes in the medial forebrain bundle-lateral hypothalamus were trained in a discrete trial procedure to make a differential response (right or left lever press) in the presence or absence of brain stimulation [intracranial self-stimulation (ICSS)]. When animals reached a high level of accuracy (95% correct) in the discrimination task, testing was begun. In the first experiment, we compared the effects of saline and 0.3 mg/kg d-amphetamine when the intertrial interval (ITI) was 1, 5, 10, and 15 s. In the second experiment, animals were tested either with saline, 0.3 mg/kg d-amphetamine, or 1, 3, or 10 mg/kg nomifensine and the ITI was held constant at 5 s. Increasing the ITI from 1-15 s did not produce a drug-induced change in the discriminative stimulus properties of ICSS, although it did produce changes in total numbers of lever presses and numbers of intertrial lever presses. In the second experiment, neither d-amphetamine nor nomifensine altered the discriminative stimulus properties of ICSS, but a dose-response increase occurred in the time to complete the test session and in total number of lever presses and in presses on the initiating lever. Under conditions known to increase extracellular dopamine (DA) levels in brain, both amphetamine and nomifensine produced large increases in locomotor activity, but neither drug produced changes in the detection threshold for ICSS. Results indicated that the internal cues produced by ICSS are different from those produced by these psychomotor stimulant drugs.

Characterization and pharmacological responsiveness of dopamine release recorded by microdialysis in the substantia nigra of conscious rats.

The extracellular concentration of dopamine (DA) and 3,4-dihydroxyphenylacetic acid in the substantia nigra (SN) and striatum was estimated by microdialysis. The dialysate content of DA from the SN was recorded during infusion of a DA uptake blocker (nomifensine; 5 mumol/L) dissolved in the perfusion fluid. Perfusion of tetrodotoxin (1 mumol/L) produced a virtually complete disappearance of nigral and striatal DA release. Dendritic as well as terminal release of DA was inhibited for several hours when the nerve impulse flow in dopaminergic neurons was blocked by systemic administration of gamma-butyrolactone (750 mg/kg, i.p.). The systemic administration (0.3 mg/kg, i.p.) as well as infusion (1 mumol/L) of the D2 agonist (-)-N-0437 [2-(n-propyl-N-2-thienylethylamino)-5-hydroxytetralin] produced a significant decrease in the release of DA in both the striatum and the SN. DA levels were recorded in the striatum both with and without addition of nomifensine to the perfusion fluid. The decrease in the striatum after (-)-N-0437 was suppressed in the presence of nomifensine. Infusion (1 mumol/L) as well as systemic administration (40 mg/kg) of sulpiride caused a similar increase in the release of striatal DA; this increase was, in both experiments, potentiated by nomifensine coinfusion. Sulpiride administration induced a small increase in the release of nigral DA. Infusion of (-)-N-0437 or (-)-sulpiride into the nigra caused a moderate decrease and increase, respectively, of striatal DA level.(ABSTRACT TRUNCATED AT 250 WORDS)