GDNF improves dopamine function in the substantia nigra but not the putamen of unilateral MPTP-lesioned rhesus monkeys

Microdialysis measurements of dopamine (DA) and DA metabolites were carried out in the putamen and substantia nigra of unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rhesus monkeys that received intraventricular injections of vehicle or glial-derived neurotrophic factor (GDNF, 300 microg) 3 weeks prior to the microdialysis studies. Following behavioral measures in the MPTP-lesioned monkeys, they were anesthetized with isoflurane and placed in a stereotaxic apparatus. Magnetic resonance imaging (MRI)-guided sterile stereotaxic procedures were used for implantations of the microdialysis probes. Basal extracellular levels of DA and the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were found to be decreased by >95% in the right putamen of the MPTP-lesioned monkeys as compared to normal animals. In contrast, basal DA levels were not significantly decreased, and DOPAC and HVA levels were decreased by only 65% and 30%, respectively, in the MPTP-lesioned substantia nigra. Significant reductions in d-amphetamine-evoked DA release were also observed in the MPTP-lesioned substantia nigra and putamen of the monkeys as compared to normal animals. A single intraventricular administration of GDNF into one group of MPTP-lesioned monkeys elicited improvements in the parkinsonian symptoms in these animals at 2-3 weeks post-administration. In addition, d-amphetamine-evoked overflow of DA was significantly increased in the substantia nigra but not the putamen of MPTP-lesioned monkeys that had received GDNF. Moreover, post-mortem brain tissue studies showed increases in whole tissue levels of DA and DA metabolite levels primarily within the substantia nigra in MPTP-lesioned monkeys that had received GDNF. Taken together, these data support that single ventricular infusions of GDNF produce improvements in motoric behavior in MPTP-lesioned monkeys that correlate with increases in DA neuronal function that are localized to the substantia nigra and not the putamen.     

Human cortical responses evoked by dichotically presented tones of different frequencies

In vivo brain microdialysis was used to investigate the influence of lobeline on dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) overflow in the core of the nucleus accumbens of freely-moving rats pretreated with nicotine (0.4 mg x kg(-1), s.c., once per day for 5 days). Locomotion was also recorded. Lobeline, at doses of 0.7, 4.0 and 10.0 mg x kg(-1), i.p., failed to elicit any significant changes in extracellular dopamine or dihydroxyphenylacetic acid levels during the 60 min following its administration and did not stimulate locomotor. The dopamine responses to nicotine (0.4 mg x kg(-1), s.c.), were abolished (P<0.01) if the nicotine challenge was administered 10 min but not 60 min, after lobeline doses of 4.0 and 10.0 mg kg(-1), i.p., but were unaffected following lobeline at the lowest dose tested (0.7 mg x kg(-1), i.p.) at either time. The increase in locomotor activity was significantly attenuated (P<0.01), to a similar extent, when the nicotine was injected 10 min, but not 60 min, after all three doses of lobeline (0.7, 4.0 and 10.0 mg kg(-1), i.p.) when compared with the saline-treated rats. The results suggest that lobeline is a short-acting antagonist of the nicotinic AChRs which mediate the effects of nicotine on mesolimbic dopamine activity and locomotor stimulation.     

Hexadecylphosphocholine and 2-modified 1,3-diacylglycerols as effectors of phospholipase D

The effects of mesulergine (100 and 200 microg/kg s.c.), SB 206553 (1 and 2.5 mg/kg i.p.), RP 62203 (2.5 and 4 mg/kg i.p.) and ritanserin (630 microg/kg i.p.) were studied on the extracellular concentration of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens of chloral hydrate-anesthetized rats, using intracerebral microdialysis. Mesulergine, a non selective serotonin2C/2B/2A (5-HT2C/2B/2A) receptor antagonist, significantly increased DA release, which reached a peak level (+ 20%) 60 min after drug injection and slowly returned back to baseline values. Mesulergine also caused a dose-dependent increase in DOPAC outflow. Pretreatment with mesulergine (200 microg/kg) did not change the inhibition of DA release induced by apomorphine (100 microg/kg), whereas it prevented the reduction of DOPAC outflow induced by apomorphine (100 microg/kg). Administration of SB 206553, a selective blocker of 5-HT2C/2B receptors, dose-dependently increased DA outflow. The dose of 2.5 mg/kg SB 206553 caused a linear increase of DA output which reached a peak (+75%) 40 min after injection, while 1 mg/kg induced a more gradual increase of DA release which peaked (+54%) 60 min after administration of the drug. Treatment with RP 62203, a selective 5-HT2A receptor antagonist, did not produce any significant effect on DA outflow. Administration of ritanserin, a mixed 5-HT2A/2C receptor antagonist, did not cause any significant change of DA and DOPAC outflow. Taken together, these data indicate that selective blockade of 5-HT2/2B receptor subtypes increases DA release in the rat nucleus accumbens.     

Control of virulence gene expression by plant calcium in the phytopathogen Erwinia carotovora

1. The authors performed both microdialysis and behavioral measurement in each of rats, in order to examine effects of nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (LNAME;30 mg/kg,i.p.) on striatal dopamine (DA) release and stereotypy induced by a single administration of methamphetamine (MA)(4 mg/kg,s.c.), simultaneously. 2. LNAME administered prior to MA significantly decreased level of locomotion-stereotypy rating scores induced by MA. 3. In the same animals, LNAME had no effect on MA-induced striatal DA release. 4. The results suggest that NO synthesis inhibition attenuated MA-induced stereotypy by modulating neuronal process subsequent to activation of postsynaptic DA receptors.     

Serotonin 5-HT2C agonists selectively inhibit morphine-induced dopamine efflux in the nucleus accumbens

In vivo microdialysis was used to compare the effects of serotonergic drugs on morphine- and cocaine-induced increases in extracellular dopamine (DA) concentrations in the rat nucleus accumbens (NAc). Systemic administration of the 5-HT2A/2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (2.5 mg/kg, s.c. ) prevented the increase in extracellular DA in the NAc produced by morphine (5 mg/kg, i.p.). In contrast, this dose of DOI had no effect on the ability of cocaine (10 mg/kg, i.p.) to increase extracellular DA concentrations in the NAc. A 5-HT2C selective agonist, 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212, 5 mg/kg, s.c.) also inhibited morphine-induced increases in extracellular DA concentrations in the NAc. Pretreatment of rats with the selective 5-HT2A antagonist, amperozide, had no effect on morphine-induced elevation of NAc DA concentrations. In order to determine if inhibition of the firing of 5-HT neurons contributes to the serotonin agonist-mediated inhibition of morphine-induced accumbens DA release, rats were pretreated with the 5-HT1A agonist, 8-OHDPAT. At a dose of 100 microg/kg (sc), 8-OHDPAT did not interfere with morphine's ability to increase DA concentrations in the NAc. These results suggest that the activation of 5-HT2C receptors selectively inhibits morphine-induced DA release in the NAc in a manner which is independent of the inhibition of 5-HT neurons.     

Sigma 1 receptor subtype is involved in the facilitation of cortical dopaminergic transmission in the rat brain

Our previous studies have shown that three sigma (sigma) receptor ligands, (+)-N-allylnormetazocine ((+)-SKF-10,047), (+/-)-pentazocine and 1,3-di(2-tolyl)guanidine (DTG) differently regulated the dopamine (DA) transmission in the rat brain. In the present study, we attempted to clarify the role of sigma 1 receptor subtype in the regulation of DA transmission using a novel and selective sigma 1 receptor agonist, 1-(3,4-dimethoxyphenethyl)-4(3-phenylpropyl)piperazine dihydrochloride (SA4503) in the rat brain. Acute administration of SA4503 (1.0 mg/kg, p.o.) significantly increased DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the rat frontal cortex, but not in the other six regions, hippocampus, striatum, midbrain, cerebellum, medulla/pons and hypothalamus. The increase of cortical DA level elicited by SA4503 was fully reversed by N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) (0.25 mg/kg, p.o.), a putative sigma 1 receptor antagonist. In addition, SA4503 (1.0 mg/kg, p.o.) showed an increase of cortical L-3,4-dihydroxyphenylalanine (L-DOPA) accumulation under the inhibition of dopa decarboxylase activity with m-hydrobenzylhydrazine (NSD-1015), suggesting that SA4503 has activated the cortical DA synthesis rate. These results suggest that the sigma 1 receptor subtype plays an important role in the facilitation of cortical DA transmission. In addition, this phenomenon is partially involved in the augmentation of DA synthesis rate.     

Evidence that an OX-2-positive cell can inhibit the stimulation of type 1 cytokine production by bone marrow-derived B7-1 (and B7-2)-positive dendritic cells

The present study was designed to compare the effects of typical and atypical antipsychotic drugs on extracellular dopamine (DA) levels in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis with dual probe implantation in awake, freely moving rats. Amperozide (2 and 10 mg/kg), clozapine (5 and 20 mg/kg), and olanzapine (10 mg/kg), all of which are atypical antipsychotics, produced greater increases in extracellular DA levels in the mPFC than in the NAC. Olanzapine (1 mg/kg), risperidone (0.1 and 1 mg/kg), also an atypical antipsychotic, and S-(-)-sulpiride (25 mg/kg), a typical antipsychotic, produced comparable increases in extracellular DA levels in the mPFC and the NAC. S-(-)-sulpiride (10 mg/kg) and haloperidol (0.1 and 1 mg/kg), another typical antipsychotic, significantly increased extracellular DA levels in the NAC but not in the mPFC. The effects of the six antipsychotic drugs to increase extracellular DA levels in the mPFC relative to those in the NAC was positively correlated with the difference between their pKi values for serotonin (5-hydroxytryptamine, 5-HT2A) and DA-D2 receptors and was inversely correlated to their pKi values for D2 or D3 receptors, but was not for 5-HT2A receptors alone. These results are consistent with the hypothesis that the ability of antipsychotic drugs to produce a greater increase in prefrontal compared with NAC extracellular DA levels may be related, in part, to weak D2 and D3 receptor affinity relative to 5-HT2A receptor antagonism.     

Rapid tyrosine phosphorylation of HS1 in the response of mouse lymphoma L5178Y-R cells to photodynamic treatment sensitized by the phthalocyanine Pc 4

The repeated administration of methamphetamine (METH) can result in long-lasting decreases in dopamine (DA) levels, tyrosine hydroxylase activity and DA uptake sites in the striatum. However, whether these changes lead to functional alterations in the dynamics of DA release and uptake has not been extensively examined. The present study used in vivo electrochemistry and microdialysis to examine potassium- and amphetamine-evoked release of DA in the striatum and nucleus accumbens (NAc) of METH-treated rats. Male Fischer-344 rats were administered METH (5 mg/kg s.c.) or saline four times in 1 day, at 2-hr intervals. One week later the animals were anesthetized with urethane and prepared for in vivo electrochemical recordings. The METH treatment resulted in dramatic decreases in potassium-evoked release of DA and in the rate of DA clearance in the striatum, whereas the NAc was not significantly affected. In vivo microdialysis studies demonstrated significant decreases in basal DA levels and in potassium- and amphetamine-evoked overflow of DA in the striatum of METH-treated animals. Basal and evoked DA levels in the NAc were not altered. Post-mortem levels of tissue DA were decreased by 41 to 67% in the striatum and 25 to 31% in the NAc. These results indicate that the striatum is more sensitive than the NAc to the neurotoxic effects of METH, both in measures of functional dynamics of DA signaling and in tissue levels of DA. It remains to be determined whether these functional changes in DA release and uptake are permanent or tend to recover over time.     

Rapid method for obtaining high-quality chromosome banding in the study of hematopoietic neoplasia

The antiemetic effects of six serotonergic 5-HT1A-receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetrarin (8-OH-DPAT), 4-(4-[4-(2-pyrimidinyl)piperazin-1-yl]butyl)-2,3,4,5- tetrahydro-1,4-benzoxazepine-3,5-dione (SUN8399), buspirone, gepirone, ipsapirone and tandospirone, against motion sickness were investigated in Suncus murinus. Subcutaneous injection of all six agonists completely and dose-dependently suppressed motion-induced emesis. Pretreatment with 8-OH-DPAT or SUN8399 dose-dependently inhibited emesis elicited by nicotine (4.0 mg/kg, s.c.), veratrine (0.7 mg/kg, s.c.), cisplatin (20 mg/kg, i.p.) and copper sulfate (40 mg/kg, p.o.). These results suggest that serotonergic 5-HT1A-receptor agonists are effective as anti-motion sickness drugs, and these drugs may block a common mechanism(s) for the emetic reflex of the suncus because the antiemetic effects of the 5-HT1A-receptor agonists were exerted irrespective of the stimulus.     

The aminoacceptor stem of the yeast tRNA(Lys) contains determinants of mitochondrial import selectivity

The effect of quinine, a cinchona alkaloid, was studied on gastrointestinal transit in mice. Intraperitoneal (i.p.) administration of quinine inhibited the intestinal propulsion of a charcoal suspension at a dose of 100 mg/kg, comparing favorably with 5 mg/kg morphine. In an attempt to probe into the mechanism underlying this inhibition, a possible modulation by minoxidil (1 mg/kg, p.o.) and glibenclamide (1 mg/kg, p.o.), the drugs that, respectively, open and close ATP-sensitive K+ channels was tested on gastrointestinal transit in animals treated or not with quinine or morphine. While minoxidil produced no significant change of normal transit, glibenclamide significantly increased it. However, both drugs blocked the quinine-induced reduction in gastrointestinal transit. In contrast, the inhibitory effect of morphine on gastrointestinal transit was not modified by either drug. The effects of quinine as well as of morphine on gastrointestinal transit were significantly antagonized by naloxone (2 mg/kg, s.c.), a mu-opioid receptor antagonist but not by yohimbine (1 mg/kg, i.p.), an alpha2-adrenoceptor antagonist. Furthermore, quinine at a lower dose (25 mg/kg) that showed no per se effect on gastrointestinal transit, significantly potentiated the response to 2.5 mg/kg morphine. Although the role of ATP-sensitive K+ channels in the action of quinine and morphine was not clarified by the present results, a possible involvement of endogenous opioid(s) in the quinine-induced inhibition of gastrointestinal transit can be suggested.     

Clozapine, haloperidol, and the D4 antagonist PNU-101387G: in vivo effects on mesocortical, mesolimbic, and nigrostriatal dopamine and serotonin release

With in vivo microvoltammetry, the dopamine (DA) receptor antagonists, clozapine (D4/D2), haloperidol (D2) and the selective D4 antagonist, PNU-101387G, were evaluated for their effects on DA and serotonin (5-HT) release within A10 neuronal terminal fields [mesocortical, prefrontal cortex (PFC), mesolimbic, nucleus accumbens, (NAcc)] and within A9 neuronal terminal fields [nigrostriatal, caudate putamen (CPU)], in chloral hydrate anesthetized rats. Clozapine, which also has 5-HT2 receptor antagonist properties, significantly (p < 0.001) increased DA release within A10 terminal fields, PFC and NAcc; DA release was not increased by clozapine within A9 terminals, CPU. Serotonin release was significantly (p < 0.001) increased by clozapine within A10 and A9 terminal fields. Haloperidol significantly (p < 0.001) increased DA release within PFC, dramatically and significantly (p < 0.001) increased DA release within CPU, but not within NAcc; haloperidol had a small but statistically significant (p < 0.05) increase on 5-HT release within PFC [only at the highest dose studied (2.5 mg/kg)] and within CPU [only at the lowest dose studied 1.0 mg/kg) (p < 0.05)]. The selective D4 antagonist, PNU-101387G dramatically and significantly (p < 0.001) increased DA release within PFC, modestly, but significantly (p < 0.001) increased DA release within CPU, did not alter DA release within NAcc at the lowest dose studied (1.0 mg/kg) and significantly (p < 0.05) decreased DA release within NAcc at the highest dose studied (1.0 mg/kg). The selective D4 antagonist did not affect 5-HT release within either A10 or A9 terminal fields. The present data are discussed in terms of the neurochemistry, antipsychotic activity, and side effect profiles of clozapine and haloperidol, in order to provide comparative profiles for a selective D4 antagonist, PNU-101387G.     

Effect of alpha 2-adrenergic drugs dexmedetomidine and atipamezole on extracellular amino acid levels in vivo

alpha 2-Adrenoceptors are known to be involved in a variety of physiological functions and pathological conditions, including epilepsy and the extent of excitotoxin-induced cell death. In this study we evaluated whether selective alpha 2-adrenergic drugs can modulate the release of neurotransmitter amino acids. The effect of the alpha 2-adrenoceptor agonist dexmedetomidine (5 micrograms/kg, s.c.) and the alpha 2-adrenoceptor antagonist atipamezole (0.1 mg/kg and 1 mg/kg, s.c.) on the release of extracellular glutamate, aspartate and gamma-aminobutyric acid (GABA) was studied with microdialysis in the hippocampus of freely moving rats under basal and K(+)-evoked conditions. Atipamezole (1 mg/kg) decreased K(+)-evoked glutamate efflux by 30% compared to the control group (P < 0.05) but did not affect significantly the effluxes of aspartate and GABA. Dexmedetomidine and the lower dose of atipamezole (0.1 mg/kg) did not significantly alter the evoked overflow of amino acids. The results suggest that alpha 2-adrenergic drugs have only modest effects on the K(+)-stimulated overflow of extracellular neurotransmitter amino acids in rat hippocampus.     

Effects of 5-hydroxytryptamine and bradykinin in cat dorsal horn neurones activated by noxious stimuli

The levels of homovarillic acid and 3,4-dihydroxyphenylacetic acid in rat c. striatum after acute and 10 day administration of clozapine (30 and 100 mg/kg p.o.), thioridazine (100 mg/kg p.o.), haloperidol (1 mg/kg p.o.), and chlorpromazine (30 mg/kg p.o.), were estimated. With clozapine and haloperidol, the mesolimbic area was also investigated. With all these neuroleptics, the levels of both dopamine metabolites were reduced after a 10 day treatment as compared to acute administration, sometimes almost to control values. With clozapine, however, such a reduction occurred only with the higher dose of 100 mg/kg p.o., acting for a period longer than 24 h. This tolerance phenomenon was also observed with clozapine and haloperidol in the mesolimbic area. We conclude that clozapine is not qualitatively different from classical neuroleptics with respect to development of biochemical tolerance.     

Effects of AF102B and tacrine on delayed match-to-sample in monkeys

1. Object working memory, a function which declines in aging and dementia, was tested in young and aged pretrained monkeys using a delayed match-to-sample task. 2. During drug treatment, monkeys were given the m 1 muscarinic agonist AF102B (0.1-2.1 mg/kg i.m.), the cholinesterase inhibitor tacrine (0.5-2.0 mg/kg p.o.), or vehicle controls in a repeated measures design to assess putative cognitive enhancement. 3. Both agents improved task performance in both young and aged monkeys, AF102B yielding equivalent or greater, and less variable, improvement than tacrine. 4. AF102B may represent a low-toxicity alternative to tacrine for the treatment of age-related memory disorders.     

N alpha-methylhistamine inhibits intestinal transit in mice by central histamine H1 receptor activation

The effects of (R)alpha-methylhistamine and N alpha-methylhistamine on intestinal transit were examined in mice. The passage of a charcoal meal in the gastrointestinal tract was dose dependently inhibited by N alpha-methylhistamine (1-20 mg/kg i.p.), but not by a selective H3 receptor agonist (R)alpha-methyl-histamine (1-50 mg/kg i.p.). The inhibitory effect of N alpha-methylhistamine (20 mg/kg) was attenuated by pretreatment with H1 receptor antagonists (mepyramine 5 mg/kg i.p. or 5 micrograms i.c.v. and triprolidine 5 mg/kg i.p.), but not by cimetidine (10 mg/kg i.p.), zolantidine (5 mg/kg i.p.), a brain-penetrating H2 receptor antagonist, or thioperamide (5 mg/kg i.p.), a selective H3 receptor antagonist. The effect of N alpha-methylhistamine was also attenuated by combined treatment with phentolamine and propranolol (5 and 15 mg/kg s.c., respectively) and by pretreatment with 6-hydroxydopamine (20 mg/kg i.p., 2 days before). N alpha-Methylhistamine markedly decreased histamine turnover in the mouse brain. These findings suggest that intestinal transit is inhibited by N alpha-methylhistamine via stimulation of central H1 but not H3 receptors and that stimulation of the sympathetic system is involved in this effect.     

In vivo functional interaction between phencyclidine binding sites and sigma receptors to produce head-weaving behavior in rats

To investigate the in vivo functional interaction between phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP) binding sites and sigma receptors, we examined the effects of sigma receptor ligands on stereotyped head-weaving behavior induced by PCP, a putative PCP/sigma receptor ligand, and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclo-hepten-5,10-imin e ((+)-MK-801; dizocilpine), a selective PCP binding site ligand, in rats. PCP (7.5 mg/kg, i.p.)-induced head-weaving behavior was inhibited by both N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine (NE-100; 0.03-1.0 mg/kg, p.o.), a selective sigma1 receptor ligand, and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperidine butanol (BMY-14802; 3 and 10 mg/kg, p.o.), a prototype sigma receptor ligand, in a dose-dependent manner, whereas NE-100 (0.1-1.0 mg/kg, p.o.) and BMY-14802 (3 and 10 mg/kg, p.o.) did not inhibit dizocilpine (0.25 mg/kg, s.c.)-induced head-weaving behavior. These results suggest that NE-100 and BMY-14802 act via sigma receptors. Dizocilpine-induced head-weaving behavior was potentiated by 1,3-di-o-tolyl-guanidine (DTG; 0.03-0.3 microg/kg, i.v.) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP; 3 and 6 mg/kg, i.p.), sigma1/sigma2 receptor ligands, as well as by (+)-N-allyl-normetazocine ((+)-SKF-10,047: 8 mg/kg, i.p.), a sigma1 receptor ligand, while DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) did not induce this behavior. Potentiation of dizocilpine-induced head-weaving behavior by DTG (0.3 microg/kg, i.v.), (+)-3-PPP (6 mg/kg, i.p.) and (+)-SKF-10,047 (8 mg/kg, i.p.) was completely blocked by NE-100 (0.1 mg/kg, p.o.) and BMY-14802 (10 mg/kg, p.o.). These results suggest that PCP binding sites and sigma receptors are involved in PCP-induced head weaving behavior, and that sigma1 receptors play an important role in modulation of the head-weaving behavior.     

Gestational exposure to cocaine or pharmacologically related compounds: effects on behavior and striatal dopamine receptors

Gestational cocaine (COC) exposure has been reported to alter behavior and possibly dopamine (DA) receptors. In this paper, we further examined the effects of prenatal COC (40 mg/kg, s.c.) on DA receptor binding and the behavioral response to quinpirole, a DA D2 receptor agonist. In an attempt to elucidate possible mechanisms of such effects, we exposed pregnant dams to specific reuptake blockers; fluoxetine 12.5 mg/kg, a serotonin reuptake blocker; desipramine 10 mg/kg, a norepinephrine reuptake blocker; GBR-12909 10 mg/kg, a DA reuptake blocker; or to a local anesthetic, lidocaine 40 mg/kg. Drugs were administered once daily over gestational days 8-20. Control dams were injected with saline (SAL) or pair-fed to the COC group. Quinpirole challenge was performed in the offspring on post natal day 19. Two pups per litter were injected (s.c.) with 0.03 or 0.09 mg/kg quinpirole-HCl on post-natal day 19. The remaining pups in each litter were sacrificed for analysis of striatal DA receptors. Results showed that only COC exposure altered the behavioral response to the quinpirole challenge by increasing quinpirole-induced stereotypy and motor activity relative to SAL controls. DA receptor analysis showed no alteration in K(D) or B(MAX) for striatal D1 or D2 sites in any group. These results suggest that prenatal COC exposure produces alterations in function of the D2 receptor complex which are not reflected in K(D) or B(MAX) and that these effects are not fully mimicked by exposure to specific monoamine reuptake blockers or a local anesthetic.     

Emergency coronary artery surgery after failed PTCA: myocardial protection with continuous coronary perfusion of beta-blocker-enriched blood

MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate antagonist, induces dystonia in monkeys at doses of 0.08 mg/kg. This syndrome was tested with the dopamine D1 receptor antagonist NNC 756, the DA D2 receptor antagonist raclopride, the atypical antipsychotic clozapine, the dopamine D1 receptor agonist SKF 81297, the dopamine D2/D3 receptor agonist quinpirole, the anticholinergic biperiden, amphetamine, and the benzodiazepine midazolam in 7 Cebus apella monkeys previously treated with dopaminergic agents. NNC 756 (0.004 and 0.01 mg/kg), raclopride (0.004 and 0.01 mg/kg), SKF 81297 (0.3 and 0.6 mg/kg), quinpirole (0.1 and 0.2 mg/kg), amphetamine (0.25 and 0.5 mg/kg), and biperiden (0.125 and up to 1.0 mg/kg), had no significant effect on MK-801-induced dystonia. In contrast, both clozapine (2.0 mg/kg) and midazolam (0.4 and 1.0 mg/kg) reduced the dystonia caused by MK-801. Dystonia induced by dopamine D1 and D2 antagonists is easily antagonized by biperiden and dopamine agonists, whereas these drugs had no significant effect on MK-801-induced dystonia. It has been proposed that dystonia may be caused by a sudden drop in the output from the basal ganglia that is primarily GABAergic. Midazolam's enhancing effect on the GABAergic tone is consistent with this hypothesis. The effect of clozapine is more difficult to explain, but this drug has a rich pharmacology and suggests an agonistic glutamatergic effect.     

Dopaminergic regulation of striatal acetylcholine release: the critical role of acetylcholinesterase inhibition

This study examined the effects of different levels of acetylcholinesterase (AChE) inhibition on dopaminergic regulation of striatal acetylcholine (ACh) release as estimated by in vivo brain microdialysis. Systemic administration of d-amphetamine (2 or 10 mg/kg) increased the striatal output of ACh when the AChE inhibitor neostigmine (0.1 microM) was present in the perfusion fluid. In contrast, when the same experiments were conducted at 0.01 microM neostigmine, d-amphetamine failed to affect (2 mg/kg) or significantly decreased (10 mg/kg) striatal ACh output. The inhibitory action of the D2 receptor agonist quinpirole (0.2 mg/kg) was significantly greater at 0.01 microM than at 0.1 microM neostigmine. Similarly, there was a nonsignificant trend for the D2 antagonist raclopride (1 mg/kg) to stimulate ACh release to a greater extent at the low neostigmine concentration. In contrast, the stimulant effects of systemic administration of the D1 agonist A-77636 (1.46 mg/kg) on striatal ACh release were the same at the two neostigmine concentrations. These results demonstrate that the concentration of an AChE inhibitor in the perfusion solution can quantitatively and even qualitatively influence the manner in which dopaminergic agents regulate ACh overflow in the striatum. On comparing the present results with earlier reports concerning the effects of d-amphetamine on tissue concentrations of ACh, it is tentatively concluded that a low neostigmine concentration is the more physiologically relevant condition. Under such conditions, at moderate doses d-amphetamine does not appear to alter striatal ACh release, with this likely being due to the opposing actions of D1 and D2 receptors. Nevertheless, until the endogenous interstitial concentrations of striatal ACh can be measured by other methods, the physiological relevance of ACh microdialysis studies in the striatum will remain uncertain.     

S 18126 ([2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl methyl]indan-2-yl]), a potent, selective and competitive antagonist at dopamine D4 receptors: an in vitro and in vivo comparison with L 745,870 (3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2, 3b]pyridine) and raclopride

The novel benzoindane S 18126 possessed > 100-fold higher affinity at cloned, human (h) D4 (Ki = 2.4 nM) vs. hD2 (738 nM), hD3 (2840 nM), hD1 (> 3000 nM) and hD5 (> 3000 nM) receptors and about 50 other sites, except sigma1 receptors (1.6 nM). L 745,870 similarly showed selectivity for hD4 (2.5 nM) vs. hD2 (905 nM) and hD3 (> 3000 nM) receptors. In contrast, raclopride displayed low affinity at hD4 (> 3000 nM) vs. hD2 (1.1 nM) and hD3 receptors (1.4 nM). Stimulation of [35S]-GTPgammaS binding at hD4 receptors by dopamine (DA) was blocked by S 18126 and L 745,870 with Kb values of 2.2 and 1.0 nM, respectively, whereas raclopride (> 1000 nM) was inactive. In contrast, raclopride inhibited stimulation of [35S]-GTPgammaS binding at hD2 sites by DA with a Kb of 1.4 nM, whereas S 18126 (> 1000 nM) and L 745,870 (> 1000 nM) were inactive. As concerns presynaptic dopaminergic receptors, raclopride (0.01-0.05 mg/kg s.c. ) markedly enhanced DA synthesis in mesocortical, mesolimbic and nigrostriatal dopaminergic pathways. In contrast, even high doses (2. 5-40.0 mg/kg s.c.) of S 18126 and L 745,870 were only weakly active. Similarly, raclopride (0.016 mg/kg i.v.) abolished inhibition of the firing rate of ventrotegmental dopaminergic neurons by apomorphine, whereas even high doses (0.5 mg/kg i.v.) of S 18126 and L 745,870 were only weakly active. As regards postsynaptic dopaminergic receptors, raclopride potently (0.01-0.3 mg/kg s.c.) reduced rotation elicited by quinpirole in rats with unilateral lesions of the substantia nigra, antagonized induction of hypothermia by PD 128, 907, blocked amphetamine-induced hyperlocomotion and was effective in six further models of potential antipsychotic activity. In contrast, S 18126 and L 745,870 were only weakly active in these models (5.0-> 40.0 mg/kg s.c.). In six models of extrapyramidal and motor symptoms, such as induction of catalepsy, raclopride was likewise potently active (0.01-2.0 mg/kg s.c.) whereas S 18126 and L 745,870 were only weakly active (10.0-80.0 mg/kg s.c.). In freely moving rats, raclopride (0.16 mg/kg s.c.) increased levels of DA by + 55% in dialysates of the frontal cortex. However, it also increased levels of DA in the accumbens and striatum by 70% and 75%, respectively. In contrast to raclopride, at a dose of 0.16 mg/kg s.c. , neither S 18126 nor L 745,870 modified frontal cortex levels of DA. However, at a high dose (40.0 mg/kg s.c.), S 18126 increased dialysate levels of DA (+ 85%) and noradrenaline (+ 100%), but not serotonin (+ 10%), in frontal cortex without affecting DA levels in accumbens (+ 10%) and striatum (+ 10%). In conclusion, S 18126 and L 745,870 behave as potent and selective antagonists of cloned, hD4 vs. other dopaminergic receptor types in vitro. However, their in vivo effects at high doses probably reflect residual antagonist actions at D2 (or D3) receptors. Selective blockade of D4 receptors was thus associated neither with a modification of dopaminergic transmission nor with antipsychotic (antiproductive) or extrapyramidal properties. The functional effects of selective D4 receptor blockade remain to be established.