Preferential stimulation of ventral tegmental area dopaminergic neurons by nicotine

The effect of intravenous (i.v.) nicotine on the single unit activity of midbrain dopamine (DA) neurons was studied in rats under either local or general anesthesia. Nicotine (50-500 micrograms/kg) produced a dose-related increase in the firing rate of nigral pars compacta DA cells (A9), up to 25% above baseline, irrespective of the preparation. The same range of doses was more than three times as effective on ventral tegmental area DA cells (A10) in rats paralyzed and given a local anesthetic. By contrast, the majority of these cells were temporarily depressed in deeply anesthetized animals. All of the above effects were reversed and prevented by i.v. mecamylamine suggesting the involvement of nicotine cholinergic receptors. Moreover, after nicotine-induced stimulation, low doses of i.v. apomorphine inhibited the firing rate similar to controls indicating that dopamine receptors are not directly involved in the nicotinic action. The results suggest that acute nicotine shares with other drugs of abuse the characteristic of being more effective in stimulating A10 than A9 neurons.     

Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms

The major brain noradrenergic nucleus locus coeruleus (LC) has long been thought to be involved in states of alertness and cognitive processes. These functional characteristics make this nucleus interesting with regard to the signs of schizophrenia, especially the negative symptoms of the disease. In the present in-vivo electrophysiological study we analyse a putative interaction between endogenous kynurenic acid (KYNA) and the antipsychotic drugs clozapine and haloperidol on noradrenergic LC neurons. Previous studies have shown that systemically administered antipsychotic drugs increase the neuronal activity of LC noradrenaline (NA) neurons. In line with these findings, our results show that clozapine (1.25-10 mg/kg i.v.) and haloperidol (0.05-0.08 mg/kg i.v.) increased the firing rate of LC NA neurons in anaesthetized rats. Pretreatment with PNU 156561A (40 mg/kg i.v., 3 h), a potent inhibitor of kynurenine 3-hydroxylase, produced a 2-fold increase in rat brain KYNA levels. This treatment prevented the increase in firing rate of LC NA neurons induced by haloperidol (0.05-0.08 mg/kg i.v.) and clozapine in high doses (2.5-10 mg/kg i.v.). However, the excitatory action of the lowest dose of clozapine (1.25 mg/kg i.v.) was not abolished by elevated levels of brain KYNA. Furthermore, pretreatment with L-701,324 (4 mg/kg i.v.) a selective antagonist at the glycine site of the NMDA receptor prevented the excitatory effects of both clozapine and haloperidol. The present results suggest that the excitation of LC NA neurons by haloperidol and clozapine involves a glutamatergic component.     

Inhibitory action of clozapine on rat ventral tegmental area dopamine neurons following increased levels of endogenous kynurenic acid.

The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still unknown. In the present in vivo electrophysiological study, we investigate the effects of haloperidol (a typical antipsychotic drug) and clozapine on ventral tegmental area (VTA) dopamine (DA) neurons in a situation of hyperdopaminergic activity in order to mimic tentatively a condition similar to that seen in schizophrenia. Increased DA transmission was induced by elevating endogenous levels of the N-methyl-D-aspartate receptor and alpha7(*) nicotinic receptor antagonist kynurenic acid (KYNA; by means of PNU 156561A, 40 mg /kg, i.v.). In control rats, i.v. administered haloperidol (0.05-0.8 mg/kg) or clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, in rats displaying hyperdopaminergia (induced by elevated levels of KYNA), the effects of clozapine on VTA DA neurons were converted into pure inhibitory responses, including decrease in burst firing activity. In contrast, haloperidol still produced an excitatory action on VTA DA neurons in rats with elevated levels of endogenous brain KYNA. The results of the present study suggest that clozapine facilitates or inhibits VTA DA neurotransmission, depending on brain concentration of KYNA. Such an effect of clozapine may be related to its unique effect in also ameliorating negative symptoms of schizophrenia.     

Systemically administered glucosamine-kynurenic acid, but not pure kynurenic acid, is effective in decreasing the evoked activity in area CA1 of the rat hippocampus

The metabolism of tryptophan along the kynurenine pathway yields several neuroactive intermediates, including kynurenic acid, which is one of the few known endogenous N-methyl-d-aspartate receptor inhibitors; in parallel with this, it is an alpha7 nicotinic acetylcholinergic receptor antagonist. On the basis of these properties, kynurenic acid might therefore come into consideration as a therapeutic agent in certain neurobiological disorders. However, the use of kynurenic acid as a neuroprotective agent is practically excluded because kynurenic acid hardly crosses the blood-brain barrier. We recently synthetized a new compound, glucosamine-kynurenic acid, which is presumed to cross the blood-brain barrier more easily. In this study, the effects of systemically administered kynurenic acid and glucosamine-kynurenic acid on CA3 stimulation-evoked population spike activity in region CA1 of the rat hippocampus were compared. The effect of kynurenic acid or glucosamine-kynurenic acid was augmented by probenecid (200 mg/kg), which inhibits kynurenic acid excretion from the cerebrospinal fluid. The results showed that, while kynurenic acid administered i.p. or i.v. in doses of 17, 34, 68 or 136 micromol/kg did not cause any observable change in the animals, 136 micromol/kg glucosamine-kynurenic acid (either i.p. or i.v.) resulted in the sudden death of all the animals. The dose of 68 micromol/kg i.v., but not i.p., resulted in a sudden stoppage of breath, but the animals could be reanimated. As small a dose of glucosamine-kynurenic acid as 17 micromol/kg i.p. resulted in a reduction in population spike amplitudes; this effect was further augmented by probenecid, whereas neither 17 micromol/kg nor higher doses of pure kynurenic acid had a similar effect. The results presented here suggest that glucosamine-kynurenic acid passes the blood-brain barrier much more readily than does kynurenic acid.     

Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: implications for schizophrenia

Kynurenic acid (KYNA) is an endogenous compound implicated in the pathophysiology of schizophrenia. This tryptophan metabolite antagonizes both the N-methyl-D-aspartate (NMDA) receptors and the nicotinic alpha7* receptors at micromolar concentrations. In the present study the effects of amphetamine on dopamine (DA) release in the nucleus accumbens and on firing of DA neurons in the ventral tegmental area (VTA) were investigated in rats treated with kynurenine, the precursor of KYNA, in order to elevate brain KYNA levels. In rats subchronically treated with kynurenine (90 mg/kg x d for 6 d via osmotic minipumps, resulting in a 2-fold increase in whole-brain KYNA), the amphetamine-induced (2 mg/kg i.p.) increase in accumbal DA release was clearly enhanced compared to controls. Furthermore, subchronic treatment with kynurenine reduced the inhibitory action of amphetamine (0.2-25.6 mg/kg i.v.) on firing rate and burst firing activity of VTA DA neurons. A single dose of kynurenine (5 mg/kg s.c., 60 min, resulting in a 3-fold increase in whole-brain KYNA) did not alter the amphetamine-induced effects on DA neurotransmission compared to control rats. Present data are in agreement with the increased striatal DA release by amphetamine as observed by brain-imaging studies in patients with schizophrenia. Thus, subchronic elevation of rat brain KYNA, may rationally serve as an animal model similar to a pathophysiological condition of schizophrenia. It is proposed that the reduced responsivity of VTA DA neurons to the inhibitory action of amphetamine observed in rats with subchronically elevated KYNA levels may partly account for the increase in terminal DA release.     

GBR 13098, a selective dopamine uptake inhibitor; behavioural,biochemical and electrophysiological studies

Summary Previous in vitro studies have suggested that GBR 13098 (1-(2-(bis(4-fluophenyl methoxy) ethyl)-4-(3-(4-fluorophenyl)-propyl)piperazine) dimethane sulfonate) acts as a selective dopamine uptake inhibitor. In the present study, behavioural, biochemical and electrophysiological effects of GBR 13098 in rats were analyzed.GBR 13098 (10–40 mg/kg, i.p.) increased locomotor activity of habituated rats. The effect was almost totally prevented by pretreatment with the monoamine-depleting drug reserpine (5 mg/kg, 6 h) or the dopamine receptor antagonist haloperidol (0.3 mg/kg, 30 min).GBR 13098 (20 mg/kg, i.p.) reduced DOPA formation in the striatum and in the limbic region, whereas the dopamine poor hemispheres were unaffected in this regard.GBR 13098 (0.1–20 mg/kg, i.v.; or 20 mg/kg, i.p.) did not alter the spontaneous firing rate of dopamine neurons in the substantia nigra zona compacta. However, pretreatment with the drug (20 mg/kg, i.p., 10–30 min) enhanced the inhibitory response of microiontophoretically applied dopamine onto the dopamine neurons of substantia nigra.Taken together, the present series of experiments show that GBR 13098 acts as a specific and potent inhibitor of dopamine uptake in brain. Present electrophysiological data are in line with the existence of a somatic or dendritic uptake system of dopamine within the substantia nigra but do not support the notion that the impulse activity of nigral dopamine neurons is regulated via a striatonigral feedback pathway.     

γ-Hydroxybutyric acid (GHBA) induces pacemaker activity and inhibition of substantia nigra dopamine neurons by activating GABAB-receptors

Summary In the present study the actions of -hydroxybutyric acid (GHBA) on dopaminergic neurons in the rat substantia nigra (SN) were pharmacologically analysed utilising extracellular single unit recording techniques. Intravenous administration of GHBA was associated with several effects on the neuronal activity of nigral dopamine (DA) neurons. Low doses (<200 mg/kg) of GHBA produced a slight excitation of the neurons, concomitant with a regularised firing rhythm and lack of burst activity. In higher doses GHBA produced an even higher degree of regularisation but, in contrast to low doses, an inhibition of firing rate. Administration of the GABA_B-receptor agonist baclofen, in all essential respects, mimicked the effect of GHBA on the firing of nigral DA neurons. Both the regularisation of the firing pattern and inhibition of firing rate produced by systemic administration of GHBA were antagonised by the GABA_B-receptor antagonist CGP 35348 (200 mg/kg, i.v.).Our observations show that GHBA affects the firing pattern of nigral DA neurons in doses considerably lower than those required to inhibit the firing rate of the neurons. This action, as well as the decreased firing rate observed after high doses of GHBA, are mediated via activation of GABA_B-receptors. Correspondence to: G. Engberg at the above address     

The effect of γ-acetylenic GABA, an enzyme-activated irreversible inhibitor of GABA-transaminase, on dopamine pathways of the extrapyramidal and limbic systems

γ-Acetylenic GABA (100 mg/kg i.p.) inhibited GABA-transaminase activity and caused a several-fold increase in the concentration of GABA in rat brain. This increased GABA concentration was associated with a decreased rate of dopamine depletion following -methyl-p-tyrosine treatment and a decrease in homovanillic acid in extrapyramidal and limbic structures suggesting a decrease in dopamine turnover in both pathways. In addition, γ-acetylenic GABA injected into the ventral mesencephalic tegmentum decreased dopamine turnover in the mesolimbic forebrain. These results are consistent with a modulatory function of GABAergic neurons on extrapyramidal and limbic dopamine pathways. Inhibitory effects on dopaminergic functions of the extrapyramidal and limbic systems were also indicated by the amphetamine and apormorphine-induced ipsilateral turning after unilateral substantia nigral injections of γ-acetylenic GABA and by the attenuation of dopamine-induced hypermotility after bilateral injections of γ-acetylenic GABA into the nucleus accumbens.     

Nicotine potentiation of brain stimulation reward reversed by DHβE and SCH 23390, but not by eticlopride, LY 314582 or MPEP in rats

RATIONALE: Systemic nicotine administration increases dopamine and glutamate levels in reward-related brain areas. Nicotine-induced increases of dopamine in the nucleus accumbens are in part mediated by glutamatergic projections to the ventral tegmental area dopamine neurons. OBJECTIVES: To assess the effects of actions at acetylcholine, dopamine, presynaptic (mGluR(2/3)) and postsynaptic (mGluR(5)) metabotropic glutamate receptors (mGluRs) on the potentiation of brain stimulation reward induced by systemically administered nicotine (0.125-0.5 mg/kg; free base) in rats. METHODS: A discrete-trial current-threshold s stimulation reward procedure (electrodes placed in the posterior lateral hypothalamus) was used to assess the effects of DH beta E (0.5-5 mg/kg), an acetylcholine nicotinic receptor antagonist, SCH 23390 (1.25-5 microg/kg), a dopamine D(1) receptor antagonist, eticlopride (2.5-20 microg/kg), a dopamine D(2) receptor antagonist, LY 314582 (1-20 mg/kg), an mGluR(2/3) agonist, and MPEP (1-9 mg/kg), an mGluR(5) antagonist, on the reward potentiating effects of nicotine (0.25 mg/kg). RESULTS: DH beta E had no effect on reward thresholds when administered alone, but dose-dependently reversed the nicotine-induced potentiation of brain stimulation reward. SCH 23390 (5 microg/kg) elevated thresholds when administered alone, and reversed the nicotine-induced potentiation of brain stimulation reward even at a dose (2.5 microg/kg) that had no effect on reward thresholds. Eticlopride (10-20 microg/kg), LY 314582 (10-20 mg/kg) and MPEP (9 mg/kg) elevated thresholds when administered alone but had no effect on the nicotine-induced potentiation of brain stimulation reward. CONCLUSIONS: These results indicate that nicotinic and dopamine D(1) receptors are involved in the nicotine-induced potentiation of brain stimulation reward, while actions at dopamine D(2), mGlu(2/3) and mGlu(5) receptors did not modulate this effect of nicotine.     

Effects of a potential antipsychotic, BMY 14802, on firing of central serotonergic and noradrenergic neurons in rats

BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1- piperazinebutanol HCl) is a novel potential antipsychotic drug which does not bind to dopamine receptors, does bind to 5-HT1A receptors, and also binds stereoselectively to sigma sites. The effects of acute systemic administration of this compound on spontaneously firing serotonergic dorsal raphe neurons and noradrenergic locus coeruleus neurons were assessed by means of extracellular single unit recordings in chloral hydrate anesthetized male Sprague-Dawley rats. (+/-)-BMY 14802 produced inhibition of firing of serotonergic dorsal raphe neurons when given intravenously (ED50 = 0.19 mg/kg) and intragastrically (effective dose = 20 mg/kg). Racemic and enantiomeric BMY 14802 mainly produced mild increases in firing (approximately 60% or less) of noradrenergic locus coeruleus neurons, with (-)-BMY 14802 slightly more potent (ED25 = 0.31 mg/kg i.v.) than (+)-BMY 14802 (ED25 = 0.55 mg/kg i.v.), and the racemate being intermediate (ED25 = 0.36 mg/kg i.v.). These electrophysiological studies demonstrate that in this rat preparation acute systemic administration of BMY 14802 produces changes in serotonergic and noradrenergic brain function.     

Subchronic intermittent nicotine treatment enhances ethanol-induced locomotor stimulation and dopamine turnover in mice

Most drugs of abuse enhance mesolimbic dopaminergic transmission and locomotor activity in laboratory animals and, when given repeatedly, further increase these measures, a phenomenon termed sensitization. Sensitization-related neuroadaptations have been proposed to be important in the development and maintenance of addiction. It has been suggested that both ethanol and nicotine interfere with central nicotinic acetylcholine receptors located on brain dopamine neurons, a mechanism of action that may provide a basis for the often observed co-administration of these drugs of abuse. In this study we investigated the effects of a challenge with ethanol (2.5g/kg, i.p.) or nicotine (0.2mg/kg, s.c.) on locomotor activity and monoamine turnover in mice subchronically pretreated with nicotine. Nicotine pretreatment significantly enhanced the ethanol-induced locomotor stimulation and elevation of dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) quotient in the brain. These results suggest that neuronal mechanisms related to the locomotor stimulatory effects of ethanol may be sensitized by preexposure to nicotine.     

Role of type A and B monoamine oxidase on the formation of 3,4-dihydroxyphenylacetic acid (DOPAC) in tissues from the brain of the rat

The role of monamine oxidase (MAO), type A and B, on the deamination of dopamine in the striatum, nucleus accumbens and frontal cortex of the rat was studied. Levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) tissue were quantified by means of high pressure liquid chromatography with electrochemical detection. Rats were given pargyline (75 mg/kg), selegyline (5 mg/kg) or clorgyline (2 mg/kg) by the intraperitoneal route, 60 min before sacrifice; in another set of experiments, clorgyline (2 mg/kg, i.p.) was given 15 or 30 min before sacrifice. Only clorgyline and pargyline were found to reduce significantly the formation of DOPAC and HVA in all the three areas of brain under study (83-97% reduction). The inhibition of deamination of dopamine by clorgyline and pargyline was accompanied by an increase in levels of dopamine in tissue. The increase of the levels of amine in tissue, as a result of inhibition of MAOA was more marked in the frontal cortex (52% increase) and the accumbens (39% increase), than in the striatum (25% increase). The results suggest that a substantial amount of DOPAC in brain derives from the deamination of dopamine by MAOA.     

Differential effects of nicotine against stress-induced changes in dopaminergic system in rat striatum and hippocampus

A number of studies have shown an increase in nicotine self-administration among smokers when exposed to stress. Since it is well known that nicotine or stress alter the dopaminergic system, we examined the effect of chronic nicotine administration on the dopamine level and its metabolism in the striatum and the hippocampus during stressful conditions in rats. Nicotine (0.4 mg/kg, i.p. for 14 days) increased the dopamine level in the striatum (P<0. 05) and decreased it in the hippocampus (P<0.05) in comparison with the effect of saline. Three hours of water-immersion restraint stress sharply elevated the dopamine level (P<0.05) and reduced the 3-methoxytyramine level (P ranged from 0.05 to 0.001 depending on the area and time point) in both brain regions studied, while dihydroxyphenylacetic acid and homovanilic acid levels were not altered. Nicotine pretreatment attenuated some of these changes in a region- and time-dependent manner. However, stress induced a decrease in dopamine turnover in the hippocampus (P<0.05) but not in the striatum, and nicotine failed to prevent this effect. Stress-induced alterations gradually returned toward normal during the 48-h observation period, and in some cases this was facilitated by nicotine. Thus, we demonstrated differential, region- and time-dependent protective effects of chronic nicotine administration against stress-induced changes in dopamine levels and release in brain regions critically affected by stress.     

The effects of nicotine on locomotor activity and dopamine overflow in the alcohol-preferring AA and alcohol-avoiding ANA rats

The aim of the study was to investigate the importance of the interaction between central dopaminergic and cholinergic mechanisms for ethanol reinforcement. This was done by comparing the effects of nicotine on locomotor activity and release of dopamine in the nucleus accumbens of the alcohol-preferring Alko Alcohol (AA) and alcohol-avoiding alko non-alcohol (ANA) rats. Nicotine was administered acutely (0.25, 0.50 or 0.75 mg/kg, s.c.) or repeatedly once daily (0.5 mg/kg, s.c.) for 8 days. An acute dose of nicotine increased locomotor activity and the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) measured with in vivo microdialysis suggesting stimulation of dopamine release by nicotine. No difference in the stimulation of locomotor activity or in the increase in the extracellular concentrations of dopamine or its metabolites by nicotine was found between the rat lines. The concentrations of nicotine in the plasma were also identical. The rats treated repeatedly with nicotine showed a progressive increase in locomotion. On the challenge day, 1 week after termination of nicotine or saline injections, rats previously treated with nicotine were activated more by nicotine than saline-treated rats. This behavioral sensitization was not accompanied by an increase in the amplitude of the neurochemical response to nicotine, but the duration of the increase in the levels of DOPAC was longer in the nicotine than saline-treated animals. The increases in locomotor activity and metabolite levels were, however, similar in both rat lines. These data suggest that differences in the interaction of central dopaminergic and cholinergic mechanisms probably do not contribute to the difference in ethanol self-administration between the AA and ANA rat lines.     

The effect of niaprazine on the turnover of 5-hydroxytryptamine in the rat brain

Niaprazine (60 mg/kg i.p.) increased rat brain 5-hydroxyindole acetic acid (5-HIAA) concentrations 30 min after treatment, and reduced them at 3-8 hr after treatment. Rat brain 5-hydroxytryptamine (5-HT) levels were unchanged. Niaprazine also produced a short-lasting depletion of rat brain noradrenaline (NA) and dopamine (DA). Pretreatment with alpha-phenyl-alpha-propyl-benzeneacetic acid, 2-(diethylamino) ethyl ester hydrochloride (SKF 525A) (75 mg/kg i.p.) potentiated the increase in 5-HIAA and depletion of catecholamines produced 1 hr after niaprazine, but abolished the reduction in 5-HIAA produced 8 hr after the drug. This suggested that a metabolite might be responsible for the delayed reduction in 5-HIAA levels. A potential metabolite, p-fluoro-phenylpiperazine (FPP) (5-40 mg/kg i.p.) reduced rat brain 5-HIAA and 3,4-dihydroxyphenyl acetic acid (DOPAC), and inhibited 5-HT and NA uptake in vitro. Unlike niaprazine, FPP produced no behavioural sedation, but in large doses produced a behavioural syndrome indicative of serotonergic stimulation. Studies of the metabolism of 14C-niaprazine in rats indicated the presence of a urinary metabolite with the same chromatographic characteristics as FPP. These results suggest that niaprazine itself depletes brain catecholamines and increases 5-HT turnover, while a metabolite, FPP, subsequently reduces the turnover of 5-HT and DA.     

Effects of nicotine on head-shakes and tryptophan metabolites

RATIONALE: Nicotine appears to ameliorate the tics of Tourette syndrome. There is evidence that plasma concentrations of the tryptophan metabolite kynurenine may be elevated in this condition. Rodent head-shakes have been proposed as a putative model of Tourette syndrome and are potentiated by kynurenine. OBJECTIVES: To determine the effects of acute and chronic nicotine on mouse head-shakes, and to study whether nicotine influences brain and plasma levels of kynurenine and certain of its further metabolites in this species. METHODS: Behavioural and biochemical studies. RESULTS: Acute (-10 min) administration of (-)-nicotine, or the nicotinic agonist (+)-epibatidine, dose dependently attenuated head-shakes induced by the 5-HT2A/2C receptor agonist +/-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). This attenuation was inhibited by the nicotinic receptor antagonist mecamylamine. Acute nicotine did not affect either spontaneous head-shakes or plasma and brain kynurenine. Fifteen hours after the last of twice daily injections of nicotine (1.6 mg/kg for 7 days), the frequency of spontaneous and DOI-induced head-shakes was significantly potentiated and there was a significant elevation of both plasma and brain kynurenine, although no differences were detected in plasma concentrations of tryptophan, kynurenic acid, 3-hydroxykynurenine or 3-hydroxyanthranilic acid. Brain levels of 5-hydroxytryptamine and 5-hydroxyindole acetic acid were also unaffected. In contrast, all these measures were unchanged 15 h after a single nicotine dose (1.6 mg/kg). CONCLUSIONS: The acute studies indicate that head-shakes induced by DOI are indeed inhibited by nicotinic receptor agonists and suggest that this is not a consequence of an increase in kynurenine. While a role for kynurenine or its metabolites in increasing the head-shake rate after chronic nicotine cannot be excluded, alternative explanations included alterations in the expression or functional status of nicotinic receptor components and further work will be required to characterise this effect.     

B-HT 958--an antagonist at alpha 2-adrenoceptors and an agonist at dopamine autoreceptors in the brain

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]az epine), a compound chemically related to clonidine-like drugs of the azepine type, was described previously as a mixed agonist-antagonist at peripheral alpha 2-adrenoceptor sites. In the present experiments the actions of B-HT 958 on brain noradrenergic and dopaminergic mechanisms were examined using behavioural, pharmacological and biochemical methods. (i) In the dog, intracisternally injected B-HT 958 (300 micrograms/kg) abolished the reflex bradycardia facilitated by the alpha 2-agonist B-HT 920 (10 micrograms/kg i.ci.). (ii) In the whole mouse brain as well as in the rat hypothalamus and neocortex, but not in the hippocampus, amygdala and nucleus accumbens B-HT 958 (5-20 mg/kg s.c.) accelerated the alpha-methyltyrosine (alpha-MT)-induced disappearance of noradrenaline. (iii) B-HT 958 decreased in a dose-dependent manner the exploratory activity of mice (ED50: 6.3 mg/kg s.c.) and slightly enhanced the motor activity of reserpine-treated mice only in high doses. (iv) B-HT 958 (20 mg/kg s.c.) lowered the level of homovanillic acid in the striatum and nucleus accumbens and dose dependently (1-20 mg/kg) slowed the alpha-MT-induced disappearance of dopamine in these 2 brain regions of the rat as well as in the whole mouse brain. (v) The gamma-butyrolactone-induced increase in DOPA levels was effectively antagonized by B-HT 958 (1 and 5 mg/kg s.c.) in the rat striatum and nucleus accumbens. These behavioural, pharmacological and biochemical observations indicate that B-HT 958 possesses central alpha-adrenoceptor blocking activity and exerts a strong agonistic effect on brain dopamine autoreceptors.     

Dopamine release and metabolism after chronic delivery of selective or nonselective dopamine autoreceptor agonists

The metabolism and release of dopamine by rat mesostriatal and mesolimbic dopamine neurons were determined after 2 or 14 days of subcutaneous administration via Alzet minipumps of a selective (CGS 15855A) or nonselective (apomorphine) dopamine autoreceptor agonist. Bioassays and high performance liquid chromatography assays showed that each drug was accurately delivered for the 2- and 14-day periods. CGS 15855A levels in the plasma and brain increased with increases in the daily dose given, although plasma levels of CGS 15855A at 14 days were less than those at 2 days for each dose. Striatal dopamine metabolism and release, assessed with dihydroxyphenylacetic acid and 3-methoxytyramine concentrations, respectively, were suppressed by 2-day treatments of 50-200 micrograms/day CGS 15855A or 250 micrograms/day apomorphine. These suppressions were potentiated by acute challenge with 1 mg/kg intraperitoneally of CGS 15855A or 2 mg/kg subcutaneously of apomorphine. In contrast, dopamine metabolism and release were unchanged after 14 days of administration of 40-400 micrograms/day of CGS 15855A or 250 micrograms/day of apomorphine, even when plasma levels of drug were as high as at 2 days. Dopamine release was decreased in only one of six groups 30 min after an additional acute injection of the agonist given for 14 days, whereas dopamine metabolism was decreased in five of six groups. Striatal dopamine levels were increased 20-57% after 14 but not 2 days of cgs 15855A followed by acute challenge with the vehicle or CGS 15855A injections. Thus, the responsiveness of dopamine neurons to the release-suppressing properties of dopamine autoreceptor agonists is mostly attenuated between 2 and 14 days of treatment. The ability of chronic CGS 15855A treatments to increase dopamine levels and, with acute CGS 15855A, to decrease DOPAC levels, indicates that autoreceptor control of dopamine metabolism is partly retained after chronic autoreceptor agonism.     

Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis

Kynurenic acid (KYNA) is an endogenous NMDA receptor antagonist as well as a blocker of the α7* nicotinic receptor and mounting evidence suggests that the compound participates in the pathophysiology of schizophrenia. Previous studies have shown that elevated levels of endogenous KYNA are associated with an increased firing of midbrain dopamine (DA) neurons. In the present study, utilizing extracellular single unit cell recording techniques, the mechanism involved in this excitatory action of the compound was analyzed in male Sprague–Dawley rats. Administration of 4-chlorokynurenine (4-Cl-KYN; 25 mg/kg, i.p.), which is converted to the selective NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), was found to increase firing rate and per cent burst firing activity of ventral tegmental area (VTA) DA neurons to the same magnitude as pretreatment of kynurenine (causing a 25-fold elevation in extracellular brain KYNA). Intravenous administration of the selective antagonist at the α7* nicotinic receptor methyllycaconitine (MLA; 1–4 mg/kg) did not affect firing of VTA DA neurons, whereas intraperitoneal administration of this drug in a high dose (6 mg/kg) was associated with a decreased firing rate and per cent burst firing activity. Administration of SDZ 220-581 (10 mg/kg, i.v.), a competitive antagonist at the glutamate recognition-site of the NMDA receptor, was found to increase firing rate and per cent burst firing. Present results have potential implications for the treatment of schizophrenia, and indicate that the increased activity of VTA DA neurons following elevation of brain KYNA is mediated through glutamatergic rather than by nicotinergic mechanisms.     

Nigral-induced decrease in striatal blood flow and the influence on this decrease of several drugs in reserpinized and non-reserpinized cats

The effect of nigral electrical stimulation on regional blood flow in the caudate nucleus and the cerebral cortex, and the influence of several drugs on these effects were examined in reserpinized or non-reserpinized cats. A double-thermistor element was inserted into the left caudate nucleus, and a plate-type thermocouple element was put on the left cerebral cortex. The left substantia nigra was electrically stimulated for 10 sec through a concentric bipolar electrode with a diameter of 0.3 mm (30 Hz, 1 msec, 10-30 V). In non-reserpinized cats, the nigral stimulation caused a decrease in striatal blood flow, increase in cortical blood flow and rise in mean blood pressure. Hexamethonium (3 mg/kg, i.v.) blocked completely the rise in mean blood pressure following nigral stimulation, but did not affect a decrease in striatal blood flow, indicating that a decrease in striatal blood flow following nigral stimulation was not due to the activation of the peripheral sympathetic nervous system. Nigral-induced decrease in striatal blood flow in non-reserpinized cats was blocked by haloperidol (0.1 mg/kg, i.v.), methysergide (1 mg/kg, i.v.) and reserpine (2 mg/kg, i.v.), but not by phentolamine (7 mg/kg, i.v.). In reserpinized cats, nigral stimulation caused an increase in striatal blood flow in contrast to a decrease in non-reserpinized cats. After administration of 5-HTP (50 mg/kg, i.v.) in reserpinized cats, nigral stimulation decreased the striatal blood flow. On the other hand, after administration of L-DOPA (30 mg/kg, i.v.) in reserpinized cats, nigral stimulation increased striatal blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)