Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC

We investigated the effect of successive administrations of SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride), a novel cognitive enhancer with high affinity and selectivity for the sigma1 receptor subtype, on the cortical cholinergic dysfunction-induced impairment of the spatial learning performance in the Morris water maze (MWM) task in rats. The impairment of the spatial learning performance was produced by the ibotenic acid-induced lesion of the basal forebrain (BF) area in rats. Escape latencies to find the platform during the training trials of the MWM task were significantly prolonged in the BF-lesioned rats compared with the sham-operated rats. Daily treatment with SA4503 (0.1-0.5 mg/kg, P.O./day) for 13 days ameliorated this learning deficit. In the probe trial, BF-lesioned rats reduced the number of times each rat crossed the former platform location during the training trials (goal area) in comparison with sham-operated rats. Successive administrations of SA4503 (0.25 mg/kg, P.O./day) also significantly increased the BF lesion-induced reduction of the number of times each rat crossed the goal area. These results suggest that the successive administrations of SA4503 attenuate the impairment of the spatial learning performance in rats with cortical cholinergic dysfunction, and that SA4503 is useful as a therapeutic drug for Alzheimer's disease.     

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.     

Effects of the dopamine D3 antagonist PD 58491 and its interaction with the dopamine D3 agonist PD 128907 on brain dopamine synthesis in rat

The dopamine (DA) D3 receptor antagonist PD 58491 [3-[4-[1-[4-[2-[4-(3-diethylaminopropoxy)phenyl]benzoimidazol++ +-1-yl-butyl]-1H-benzoimidazol-2-yl]phenoxy]propyl]diethylamine] bound with high affinity and selectivity to recombinant human DA D3 versus D2L and D4.2 receptors transfected into Chinese hamster ovary cells: Ki values of 19.5 nM versus 2,362 and >3,000 nM, respectively. In contrast, the putative DA D3 receptor antagonist (+)-AJ76 displayed low affinity and selectivity for D3 versus D2L and D4.2 receptors (91 nM vs. 253 and 193 nM, respectively). In vitro, PD 58491 (1 nM-1 microM) exhibited D3 receptor antagonist activity, reversing the quinpirole (10 nM)-induced stimulation of [3H]thymidine uptake in D3 CHOpro-5 cells, but did not have any significant intrinsic activity by itself in this assay. PD 58491 did not decrease the gamma-butyrolactone-induced increase in DA synthesis (L-3,4-dihydroxyphenylalanine accumulation) in rat striatum, indicating that the compound possessed no in vivo DA D2/D3 receptor agonist action at DA autoreceptors. PD 58491 (3-30 mg/kg, i.p.) generally did not alter DA or serotonin synthesis in either the striatum or mesolimbic region of rat brain. The D3-preferring agonist PD 128907 decreased DA synthesis in striatum and mesolimbic regions, and this effect was attenuated by pretreatment with PD 58491. These findings support the hypothesis that DA D3 autoreceptors may in part modulate the synthesis and release of DA in striatum and mesolimbic regions.     

Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated

The 5-HT2B receptor agonist, BW 723C86 (10, 30(mg/kg i.p. 30 min pre-test), increased the number of punishments accepted in a rat Vogel drinking conflict paradigm over 3 min, as did the benzodiazepine anxiolytics, chlordiazepoxide (2.5-10 mg/kg p.o. 1 h pre-test) and alprazolam (0.2-5 mg/kg p.o. 1 h pre-test), but not the 5-HT2C/2B receptor agonist, m-chlorophenylpiperazine (mCPP, 0.3-3 mg/kg i.p) or the 5-HT1A receptor agonist, buspirone (5-20 mg/kg p.o. 1 h pre-test). The effect of BW 723C86 was unlikely to be secondary to enhanced thirst, as BW 723C86 did not increase the time that rats with free access to water spent drinking, nor did it reduce sensitivity to shock in the apparatus. The anti-punishment effect of BW 723C86 was opposed by prior treatment with the 5-HT2/2B receptor antagonist, SB-206553 (10 and 20 mg/kg p.o. 1 h pre-test), and the selective 5-HT2B receptor antagonist, SB-215505 (1 and 3 mg/kg p.o. 1 h pre-test), but not by the selective 5-HT2C receptor antagonist, SB-242084 (5 mg/kg p.o.), or the 5-HT1A receptor antagonist, WAY 100635 (0.1 or 0.3 mg/kg s.c. 30 min pre-test). Thus, the anti-punishment action of BW 723C86 is likely to be 5-HT2B receptor mediated. This is consistent with previous reports that BW 723C86 exhibited anxiolytic-like properties in both the social interaction and Geller-Seifter conflict tests.     

Role of rpoS in the regulation of glutathione oxidoreductase (gor) in Escherichia coli

Caffeine (10-40 mg/kg, p.o.) enhanced locomotor activity (LA). Administration of GABA antagonist, bicuculline (0.5-1.0 mg/kg, i.p.), potentiated this caffeine-induced increase of LA, as well as LA of control rats. Treatment with the GABA agonist, muscimol (0.25-1 mg/kg, i.p.) or dopaminergic antagonist, haloperidol (0.25-1 mg/kg, i.p.) or muscarinic receptor blocker, atropine (3.75-5 mg/kg, i.p.), or inhibitor of acetylcholine esterase physostigmine (0.05-0.30 mg/kg, i.p.) or nicotine (0.5-1.5 mg/kg, i.p.) an nicotinic receptor agonist all decreased the LA of both caffeine-treated and control rats. Haloperidol-induced reduction in caffeine-induced increase in LA was found to be withdrawn with higher dose of caffeine. The dopamine agonist L-Dopa (75-150 mg/kg, p.o.) along with carbidopa (10 mg/kg, p.o.) increased the LA in control rats and potentiated the LA of caffeine treated rats. The haloperidol attenuated the bicuculline-induced increase in LA and atropine or physostigmine attenuated the bicuculline or L-Dopa + carbidopa-induced increase in LA in both caffeine treated and control rats when those drugs were administered concomitantly with bicuculline or L-Dopa+carbidopa. These results suggest that (a) the GABAergic system has direct role in the regulation of LA, and (b) caffeine potentiates LA by antagonism of the adenosine receptor and activation of the dopaminergic system which, in turn, reduces GABAergic activity through the reduction of cholinergic system.     

Dopaminergic modulation of kappa opioid-mediated ultrasonic vocalization, antinociception, and locomotor activity in the preweanling rat.

The purpose of this study was to determine whether dopamine (DA) systems modulate kappa opioid-mediated ultrasonic vocalizations (USVs), antinociception, and locomotion in young rats. Seventeen-day-old rats were injected with the kappa agonist U-50,488 (0.0-7.5 mg/kg) and saline, the D?-like receptor agonist R(-)-propylnorapomorphine (NPA; 0. 1 or 1.0 mg/kg), the indirect DA agonist cocaine (10 or 20 mg/kg), or the DA antagonist flupenthixol (0.25 or 0.5 mg/kg). USVs and locomotion were measured for 6 min, with antinociception being assessed with a tail-flick test. Kappa receptor stimulation produced analgesia and increased USVs and locomotion. U-50,488-induced analgesia was potentiated by NPA, whereas U-50,488-induced USVs were attenuated by both DA agonists. NPA and flupenthixol depressed U-50,488's locomotor effects. These results show that DA systems interact with kappa opioid systems to modulate USVs, antinociception, and locomotion in preweanling rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Hippocampal formations imaging with axial sections parallel to their longitudinal axis

Previous studies have indicated that corticostriatal glutamatergic pathways are implicated in the regulation of neuroleptic catalepsy. To obtain a better understanding of the way in which dopamine (DA) and glutamate interact within the caudate-putamen (CP) in the development of catalepsy, we investigated the regional distribution within the rat CP of the cataleptogenic effect of haloperidol and its antagonism by D(-)-2-amino-5-phosphonopentanoic acid (D(-)AP5), a selective antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype. Bilateral injections of haloperidol (3 micrograms/side) into the rostral ventromedial (VM) CP induced potent catalepsy with a short latency after the injection. In contrast, only a weak cataleptic response, of slower onset, was observed after haloperidol injections into the rostral ventrolateral (VL), rostral dorsomedial (DM), or rostral dorsolateral (DL) CP, or into the nucleus accumbens. D(-)AP5 (5 micrograms/side) injected bilaterally into the dorsorostral CP (DM and DL) strongly inhibited the catalepsy induced by systemic haloperidol (1 mg/kg, i.p.), and this effect lasted longer when the drug was injected into the DM than when it was injected into the DL. D(-)AP5 did not affect haloperidol-induced catalepsy when injected into the ventrorostral (VM and VL) or intermediate dorsal CP. D(-)AP5 injected into the DM, the region most sensitive to the anticataleptic effect of the drug, had no effect on basal levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, or on the modification of these levels by haloperidol in either the DM or VM. These findings suggest that, while the catalepsy resulting from DA receptor blockade by haloperidol originates mainly from the VM, the expression of this phenomenon depends on an intact glutamatergic transmission within the dorsorostral CP. In the development of neuroleptic catalepsy, the mesencephalostriatal DAergic and corticostriatal glutamatergic pathways seem to be functionally linked through an indirect, rather than a direct, interaction.     

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.     

Systemic administration of CCK-8S, but not CCK-4, enhances dopamine turnover in the posterior nucleus accumbens: a microdialysis study in freely moving rats

The present study was carried out to examine the effects of peripheral administration of sulfatedcholecystokinin octapeptide (CCK-8S) on dopamine (DA) turnover in the posterior nucleus accumbens (PNAc) and the caudate-putamen (CP) in awake rats. Microdialysis was used to quantify the extracellular concentrations of DA and its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Intraperitoneal injections of CCK-8S (0.3 mg/kg b.wt.) caused a significant increase in DOPAC and HVA concentrations in the PNAc, but did not affect the DA level. Such increases in the metabolite contents were not found in the CP. Similar injections of vehicle (1% NaHCO3 solution, 1 ml/kg b.wt.) did not have an effect in either brain region. In an attempt to determine the type of receptor involved in the CCK-8S-induced changes, CCK tetrapeptide (CCK-4, 0.3 mg/kg b.wt.) known to have high affinity for CCKB subtype or vehicle (10% DMSO-saline, 1 ml/kg b.wt.) was administered intraperitoneally. Neither CCK-4 nor vehicle caused significant changes in any of extracellular DA, DOPAC and HVA contents in the PNAc. These results suggest that peripherally administered CCK-8S has stimulatory effects on the dopaminergic system in the PNAc, and raise the possibility that the effect appears to be mediated via CCKA receptors.     

Importance of the noradrenaline-dopamine coupling in the locomotor activating effects of D-amphetamine

The locomotor hyperactivity induced by systemic or local (nucleus accumbens) D-amphetamine injections can be blocked by systemic or local (prefrontal cortex) injections of prazosin, an alpha1-adrenergic antagonist (Blance et al., 1994). Microdialysis studies performed on freely moving animals indicated that prazosin (0.5 mg/kg, i.p.) does not modify the increase in the extracellular dopamine (DA) levels in the nucleus accumbens that are induced by D-amphetamine (2.0 mg/kg, i.p.), but it inhibits the D-amphetamine-induced locomotor hyperactivity (-63%, p < 0.0001). No behavioral activation occurred after the bilateral local perfusion of 3 microM D-amphetamine in the nucleus accumbens, although it led to a fivefold increase in extracellular DA levels. This increase in extracellular DA levels was not affected by prazosin (0.5 mg/kg, i.p.). When an intraperitoneal injection of D-amphetamine (0.5 mg/kg) was superimposed to the continuous local perfusion of 3 microM D-amphetamine, it induced a 64% increase in the extracellular DA levels in the nucleus accumbens, and this response was associated with simultaneous behavioral activation. Both the increases in extracellular DA levels and in locomotor activity were completely blocked by a pretreatment with prazosin, injected either systemically (0.5 mg/kg, i.p.) or locally and bilaterally into the prefrontal cortex (500 pmol/side). Complementary experiments indicated that the focal application of D-amphetamine requires at least a 4.8-fold higher increase in DA output compared with systemic D-amphetamine for the behavioral effects to be elicited. Altogether, these results suggest that locomotor activating effects of D-amphetamine are caused by the stimulation of cortical alpha1-adrenergic receptors by noradrenaline, which increases the release of a functional part of subcortical DA.     

Relationship between nitric oxide and platelet-activating factor in castor-oil induced mucosal injury in the rat duodenum

The modulation of platelet activating factor (PAF) formation in duodenal tissue by nitric oxide (NO) released in response to castor oil was studied in rats pretreated with NG-nitro-L-arginine methyl ester (L-NAME, 6.25-25 mg/kg, i.p.), an inhibitor of NO synthase, NG-nitro-D-arginine methyl ester (D-NAME, 25 mg/kg, i.p.), the inactive enantiomer of L-NAME or isosorbide-5-mononitrate (IMN, 30-90 mg/kg, p.o.), a NO donating compound. Castor oil (2 ml/rat orally) increased PAF production in the rat duodenum 3 h after challenge. L-NAME, but not D-NAME, enhanced the amount of PAF formed by duodenal tissue, while IMN (30-90 mg/kg) counteracted the effects of L-NAME (12.5 mg/kg) and also reduced PAF release in the tissue of rats treated with castor oil. L-NAME 12.5 mg/kg, but not D-NAME, enhanced both macroscopic damage and acid phosphatase release induced by castor oil. These effects were reduced by a PAF antagonist BN 52021 (3-t-Butyl-hexahydro-4, 7b, 11-trihydroxy-8-methyl-9H-1, 7a-epoxymethano-1H, 6aH-cyclopenta [c] furo [2, 3b] furo [3'2':3,4] cyclopenta [1.2-d]furan-5,9,12(4H)trione) 10 and 20 mg/kg i.p. Such findings suggest that endogenous nitric oxide could reduce PAF biosynthesis in castor oil-treated rats.     

Intramuscular osteoinduction and bone marrow formation by the implantation of rhBMP-2 with atelopeptide type I collagen

The atypical neuroleptic, clozapine, has been shown to have encouraging, but mixed, effects on prefrontal cortical (PFC) cognitive deficits in schizophrenia, a stress-exacerbated disorder involving dopamine (DA) dysregulation. The current study examined the effects of acute clozapine pretreatment on the spatial working memory deficits induced by the pharmacological stressor, FG7142, in monkeys. Previous research has shown that FG7142 impairs spatial working memory in rats and monkeys through excessive DA receptor stimulation in the PFC (Murphy et al. 1996). Lower clozapine doses (1-3 mg/kg p.o.) reversed the FG7142-induced spatial working memory deficits, whereas doses in the clinical range (e.g., 6 mg/kg, p.o.) did not improve cognitive function in most animals. Clozapine alone produced a dose-related impairment in delayed response performance. These results from nonhuman primates suggest that the clozapine doses commonly used to treat schizophrenia may not be optimal for treating the PFC cognitive deficits associated with this illness.     

Differential effects of clozapine and haloperidol on dopamine receptor mRNA expression in rat striatum and cortex

The regulation of the dopamine (DA) receptors is of considerable interest, in part because treatment with antipsychotic drugs is known to upregulate striatal D2-like receptors. While previous studies have focused on the regulation of striatal DA receptors, less is known about the pharmacological regulation of cortical DA receptors. The purpose of this study was to examine the regulation of DA mRNA receptor expression in the cortex compared to the striatum following treatment with antipsychotic agents. Adult male Sprague-Dawley rats were injected daily with haloperidol (2 mg/kg/day), clozapine (20 mg/kg/day) or a control vehicle for a period of 14 days. Following treatment, brains were subjected to in situ hybridization for the mRNAs encoding the five dopamine receptors; only D1, D2, and D3 receptor mRNAs were detected in these regions. Haloperidol tended to either modestly upregulate or have no effect on dopamine receptor mRNAs detected in striatal structures, while clozapine generally downregulated these mRNAs. On the other hand, in the cortex, both drugs had striking effects on D1 and D2 mRNA levels. Cortical D1 mRNA was upregulated by haloperidol, but this effect was primarily restricted to cingulate cortex; clozapine also upregulated D1 mRNA, but primarily in parietal regions. Haloperidol downregulated D2 mRNA in the majority of cortical regions, but most dramatically in frontal and cingulate regions; clozapine typically upregulated this mRNA, but primarily in regions other than frontal and cingulate cortex. These results indicate that clozapine and haloperidol each have regionally-specific effects, and differentially regulate dopamine receptor mRNA expression in striatal and cortical regions of the rat brain.     

Extracellular striatal concentrations of endogenous 3,4-dihydroxyphenylalanine in the absence of a decarboxylase inhibitor: a dynamic index of dopamine synthesis in vivo

Basal levels of endogenous 3,4-dihydroxyphenylalanine (DOPA) were detected by HPLC coupled with coulometric detection in dialysates from freely moving rats implanted 48-72 h earlier with transversal dialysis fibers in the dorsal caudate. Because decarboxylase inhibitor is absent in the Ringer's solution, this method allows monitoring of basal output of dopamine (DA) and 3,4-dihydroxyphenylacetic acid, as well as DOPA. Extracellular DOPA concentrations were reduced by the tyrosine hydroxylase inhibitor alpha-methylparatyrosine (200 mg/kg, i.p.) and by the dopaminergic agonist apomorphine (0.25 mg/kg, s.c.). The dopaminergic antagonist haloperidol (0.2 mg/kg, s.c.) stimulated DOPA output by about 60% over basal values. Gamma-Butyrolactone, at doses of 700 mg/kg, i.p., which are known to block dopaminergic neuronal firing and which reduce DA release, stimulated DOPA output maximally by 130% over basal values. Tetrodotoxin, which blocks DA release by blocking voltage-dependent Na+ channels, increased DOPA output maximally by 100% over basal values. The results indicate that basal DOPA can be detected and monitored in the extracellular fluid of the caudate of freely moving rats by transcerebral dialysis and can be taken as a dynamic index of DA synthesis in pharmacological conditions.     

Increased reactivity to endothelin of pulmonary arteries in long-term post-obstructive pulmonary vasculopathy in rats

Some sigma receptor ligands have been shown to bind with low affinity to the dopamine transporter and to inhibit [3H]dopamine uptake. It has not previously been shown whether any of these compounds influence release of dopamine via facilitated exchange diffusion. To further examine the nature of the interaction between sigma receptor ligands and the dopamine transporter, the effects of sigma receptor ligands on amphetamine-stimulated [3H]dopamine release were examined in slices prepared from rat caudate putamen. In the absence of exogenous Ca2+, both (+)-pentazocine and (-)-pentazocine potentiated amphetamine-stimulated [3H]dopamine release at concentrations consistent with their affinities for sigma2 receptors. In contrast, BD737 (1S.2R-(-)-cis-N-?2-(3,4-dichlorophenyl)ethyl?-N-methyl-2-(1-pyrrolidiny l)cyclohexylamine), a sigma1 receptor agonist, had no effect on amphetamine-stimulated release. Neither isomer of pentazocine alone had any effect on basal [3H]dopamine release under these conditions. Three antagonists at sigma receptors, one of which is non-selective for subtypes, and two of which are sigma2-selective, all blocked the enhancement of stimulated release produced by (+)-pentazocine. Enhancement of stimulated release by (-)-pentazocine was similarly blocked by sigma2 receptor antagonists. Our data support the contention that it is possible to regulate transporter-mediated events with drugs that act at a subpopulation of sigma receptors pharmacologically identified as the sigma2 subtype.     

Suppression of neocortical high-voltage spindles by nicotinic acetylcholine and 5-HT2 receptor stimulation

To investigate the roles of the nicotinic acetylcholine receptor and the serotonin (5-hydroxytryptamine; 5-HT) subtype 2 receptor in the modulation of rat thalamocortical oscillations, the effects of systemic (s.c.) administration of nicotine, a nicotinic acetylcholine receptor agonist, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 receptor agonist, on neocortical high-voltage spindle activity occurring during quiet waking-immobility behavior in aged (28 months of age) and adult (7 months of age) rats were studied. Nicotine 0.1 and 0.3 mg/kg alleviated the age-related increase of neocortical high-voltage spindles, whereas in adult rats only nicotine 0.3 mg/kg was effective. DOI 0.3, 1.0 and 2.0 mg/kg suppressed high-voltage spindles in both aged and adult rats. In aged rats, a combination of subthreshold doses of nicotine (0.03 mg/kg) and DOI (0.1 mg/kg) decreased neocortical high-voltage spindles, whereas in adult rats two different subthreshold dose combinations (nicotine 0.03 or 0.1 mg/kg+DOI 0.1 mg/kg) had no effect. p-Chlorophenylalanine (400 mg/kg/day i.p. for 3 consecutive days) treatment decreased brain serotonin concentration (> 80% reduction), but did not affect high-voltage spindles. However, in both aged and adult rats, p-chlorophenylalanine treatment blocked the decrease in high-voltage spindle activity produced by DOI 0.3 mg/kg, though not the decrease produced by higher doses of DOI (1.0 and 2.0 mg/kg). It is important that, in adult rats, p-chlorophenylalanine treatment was able to abolish the decrease in high-voltage spindle activity seen after a relatively high dose of nicotine (0.3 mg/kg). The results suggest that nicotinic acetylcholine and 5-HT2 receptors may act in concert to suppress neocortical high-voltage spindling in rats, and that intact brain serotonergic systems may be important for some of the therapeutic effects of nicotine.     

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.     

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.     

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.