Human apolipoprotein E4 modulates the expression of Pin1, Sirtuin 1, and Presenilin 1 in brain regions of targeted replacement apoE mice.

The apolipoprotein E4 (apoE4) allele is consistently associated with increased risk for Alzheimer's disease (AD). We investigated the molecular mechanism of this susceptibility by analyzing the levels of genes involved in AD pathogenesis in transgenic mice expressing human apoE3 or apoE4 isoforms. mRNA and protein levels of Pin1, Sirtuin 1 (Sirt1), Presenilin 1 (PS1), and pro-Brain-derived Neurotrophic Factor (BDNF) were analyzed in brain regions affected by neuropathological changes in AD. Pin1 mRNA was significantly higher in the hippocampus of apoE4 mice than in apoE3 controls, whereas lower expression was detected in the entorhinal and parietal cortices. Reduced Pin1 levels may increase neurofibrillary degeneration and amyloidogenic processes, while compensatory mechanisms may take place in the hippocampus to balance spatial memory deficits. Sirt1 levels were significantly reduced in the frontal cortex of apoE4 mice. Sirt1 reduction may hinder its protective role against the formation of plaques and tangles and diminish its anti-inflammatory actions. Sirt1 decrease may also play a role in apoE4-associated memory impairments. Moreover, in apoE4 mice PS1 mRNA levels were lower in the frontal cortex. Lower PS1 expression may hamper γ-secretase function, thus affecting amyloid precursor protein processing. Pro-BDNF mRNA levels did not differ between apoE3 and apoE4 mice in any region analyzed. This study showed dysregulated expression of Pin1, Sirt1, and PS1 genes in different cerebral areas of apoE4 mice, suggesting that these changes may play a role in the mechanism of AD vulnerability.

Modulation of voluntary ethanol consumption by beta-arrestin 2.

Beta-arrestin 2 is a multifunctional key component of the G protein-coupled receptor complex and is involved in mu-opiate and dopamine D2 receptor signaling, both of which are thought to mediate the rewarding effects of ethanol consumption. We identified elevated expression of the beta-arrestin 2 gene (Arrb2) in the striatum and the hippocampus of ethanol-preferring AA rats compared to their nonpreferring counterpart ANA line. Differential mRNA expression was accompanied by different levels of Arrb2 protein. The elevated expression was associated with a 7-marker haplotype in complete linkage disequilibrium, which segregated fully between the lines, and was unique to the preferring line. Furthermore, a single, distinct, and highly significant quantitative trait locus for Arrb2 expression in hippocampus and striatum was identified at the locus of this gene, providing evidence that genetic variation may affect a cis-regulatory mechanism for expression and regional control of Arrb2. These findings were functionally validated using mice lacking Arrb2, which displayed both reduced voluntary ethanol consumption and ethanol-induced psychomotor stimulation. Our results demonstrate that beta-arrestin 2 modulates acute responses to ethanol and is an important mediator of ethanol reward.

Plasticity and impact of the central renin-angiotensin system during development of ethanol dependence.

Pharmacological and genetic interference with the renin-angiotensin system (RAS) seems to alter voluntary ethanol consumption. However, understanding the influence of the RAS on ethanol dependence and its treatment requires modeling the neuroadaptations that occur with prolonged exposure to ethanol. Increased ethanol consumption was induced in rats through repeated cycles of intoxication and withdrawal. Expression of angiotensinogen, angiotensin-converting enzyme, and the angiotensin II receptor, AT1a, was examined by quantitative reverse transcription polymerase chain reaction. Increased ethanol consumption after a history of dependence was associated with increased angiotensinogen expression in medial prefrontal cortex but not in nucleus accumbens or amygdala. Increased angiotensinogen expression also demonstrates that the astroglia is an integral part of the plasticity underlying the development of dependence. The effects of low central RAS activity on increased ethanol consumption were investigated using either spirapril, a blood-brain barrier-penetrating inhibitor of angiotensin-converting enzyme, or transgenic rats (TGR(ASrAOGEN)680) with reduced central angiotensinogen expression. Spirapril reduced ethanol intake in dependent rats compared to controls. After induction of dependence, TGR(ASrAOGEN)680 rats had increased ethanol consumption but to a lesser degree than Wistar rats with the same history of dependence. These data suggest that the central RAS is sensitized in its modulatory control of ethanol consumption in the dependent state, but pharmacological or genetic blockade of the system appears to be insufficient to halt the progression of dependence.

c-fos reduces corticosterone-mediated effects on neurotrophic factor expression in the rat hippocampal CA1 region.

The transcription of neurotrophic factors, i.e., basic fibroblast growth factor (bFGF) and brain-derived neurotrophic factor (BDNF) is regulated by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation despite the lack of a classical glucocorticoid response element in their promoter region. A time course for corticosterone (10 mg/kg, s.c.) in adrenalectomized rats revealed a peak hormone effect at the 4 hr time interval for bFGF (110-204% increase), BDNF (53-67% decrease), GR (53-64% decrease), and MR (34-56% decrease) mRNA levels in all hippocampal subregions using in situ hybridization. c-fos mRNA levels were affected exclusively in the dentate gyrus after 50 min to 2 hr (38-46% decrease). Furthermore, it was evaluated whether corticosterone regulation of these genes depends on interactions with the transcription factor complex activator protein-1. c-fos antisense oligodeoxynucleotides were injected into the dorsal hippocampus of adrenalectomized rats. Corticosterone was given 2 hr later, and the effects on gene expression were measured 4 hr later. In CA1, antisense treatment significantly and selectively enhanced the hormone action on the expression of bFGF (44% enhanced increase) and BDNF (38% enhanced decrease) versus control oligodeoxynucleotide treatment. In addition, an upregulation of c-fos expression (89% increase) was found. There were no effects of c-fos antisense on hippocampal GR and MR expression. Thus it seems that a tonic c-fos mechanism exists within CA1, which reduces GR- and MR-mediated effects on expression of bFGF and BDNF.

Blockade of central neuropeptide Y (NPY) Y2 receptors reduces ethanol self-administration in rats.

Activation of central neuropeptide Y (NPY) receptors is known to produce several behavioral effects, including feeding, modulation of memory and antagonism of behavioral effects of stress. In addition, experiments in knock-out and transgenic mice have suggested a possible role of NPY regulation of voluntary ethanol intake. NPY receptors involved in this action are not known. Here, we examined the effects of a selective NPY-Y2 receptor antagonist, BIIE0246, on operant responding for ethanol in a sweetened solution, or the sweetened solution without ethanol, during 30 min sessions of free choice between the two. BIIE0246 produced a robust suppression of responding for ethanol (40% reduction, P=0.013) at an intracerebroventricular dose of 1.0 nmol, but not 0.3 nmol. Responding for the saccharin solution was not significantly affected. The dose range examined was selected since preliminary experiments with doses of 3 nmol and higher indicated sedative effects, but such effects were absent up to 1.0 nmol, as shown by unaffected exploratory locomotor activity. In summary, antagonism at central NPY-Y2 receptors seems to selectively suppress operant self-administration of ethanol. This suggests that Y2 receptors might be candidate targets for developing novel pharmacological treatments of alcoholism.

Effects of tiagabine and diazepam on operant ethanol self-administration in the rat.

OBJECTIVE: Benzodiazepines (BDZ) are widely used in the treatment of anxiety and ethanol withdrawal. It has been suggested that this class of compounds may increase the reinforcing value of ethanol; however, the literature is scarce. Tiagabine has recently been introduced into clinical use as an anti-epileptic drug. It acts through inhibiting gamma-aminobutyric acid (GABA) reuptake, and thus represents a pharmacodynamically novel principle for potentiating GABAergic transmission. The objective of the present study was to examine whether these two manners of modulating GABAergic transmission would affect ethanol self-administration in rats. METHOD: Rats were trained on an operant oral ethanol self-administration task in a two-lever free-choice paradigm. When trained, subjects were treated with tiagabine (2, 6 and 18 mg/kg, intraperitoneally [i.p.]) or diazepam (0.5, 1.5 and 4.5 mg/kg, i.p.). Postsession blood alcohol concentrations and locomotor activity measures also were obtained. RESULTS: At nonsedating doses, neither tiagabine nor diazepam affected operant ethanol self-administration. At the highest doses (18 and 4.5 mg/kg, respectively), both drugs suppressed ethanol self-administration but also induced significant suppression of locomotion, indicative of sedation. CONCLUSIONS: Systemic administration of either the GABA-uptake blocker, tiagabine, or the GABA/BDZ agonist, diazepam, at nonsedating doses does not seem to affect oral ethanol self-administration.

Leptin suppression of hypothalamic NPY expression and feeding, but not amygdala NPY expression and experimental anxiety.

Leptin decreases food intake through actions in the hypothalamus, partly through interactions with neuropeptide Y (NPY). However, NPY also produces behavioral antistress effects mediated inter alia through the amygdala. If leptin generally suppresses NPY function, the utility of leptin-mimics for treatment of obesity might be limited. Here, we therefore compared the effects of intracerebroventricular leptin on hypothalamic and amygdala NPY expression, as well as the respective related behaviors, i.e., feeding and experimental anxiety. Rats were injected intracerebroventricularly with leptin once daily for 6 days. Leptin-treated subjects consumed significantly less chow and had reduced body weight at the end of the treatment period compared to saline-treated controls. This was accompanied by a significant suppression of hypothalamic NPY expression. In contrast, the expression of NPY within the amygdala was unaffected by leptin. In parallel, in an established animal model of anxiety, the elevated plus-maze, no effect of leptin on anxiety-related behaviors was observed. In conclusion, leptin selectively affects the hypothalamic NPY system and its functional outflow, i.e., feeding and endocrine stress responses. Despite modifying endocrine responses, leptin treatment does not affect behavioral measures of experimental anxiety.

Differential expression of NPY and its receptors in alcohol-preferring AA and alcohol-avoiding ANA rats.

BACKGROUND: Central neuropeptide Y (NPY) is known to control feeding and stress responses. Recently, it has been suggested that NPY also has a role in regulation of alcohol consumption. METHODS: NPY and NPY receptor expression in genetically selected alcohol-preferring (AA), alcohol-nonpreferring (ANA), and Wistar rats were investigated. Expression was assessed using in situ hybridization histochemistry with riboprobes specific for preproNPY, Y1, and Y2 receptors. Effects of central NPY administration on ethanol self-administration were also examined in AA, ANA, and Wistar rats by using oral operant self-administration. RESULTS: NPY mRNA expression was higher in ANA than in both AA and Wistar rats in the hippocampal CA region and dentate gyrus, whereas AA and Wistar did not differ from each other. No differences in NPY expression were found in the other regions analyzed: cingulate cortex, medial nucleus of the amygdala, arcuate, and paraventricular nuclei of the hypothalamus. Y1 receptor mRNA expression did not differ between the three lines. Y2 expression was higher in the dentate gyrus of both AA and ANA rats than in Wistar subjects. In the medial amygdala, Y2 mRNA was reduced in the AA line, compared to both ANA and Wistar rats. NPY injected intracerebroventricularly (1.5-3.0 nmol) did not affect operant ethanol self-administration in any of the three lines examined. CONCLUSION: The NPY system seems to differ in several respects between rat lines with different levels of alcohol preference. Differences observed within the hippocampus could be related to behavioral traits other than alcohol intake but it is also possible that elevated hippocampal expression of NPY in the ANA rats contributes to the low alcohol intake of this line. Aberrant NPY expression and/function within the amygdala complex could contribute to alcohol preference and constitute an anatomic substrate of the effects of NPY expression on alcohol intake observed previously in genetically modified animals.

Adenosine/dopamine interaction: implications for the treatment of Parkinson's disease.

Evidence for a role of dopaminergic neurotransmission in the motor effects of adenosine antagonists, such as caffeine, is reviewed, based on the existence of specific antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the striatum. Both adenosine A(1) and adenosine A(2A) receptor antagonists induce motor activation in rodents. At least a certain degree of dopaminergic activity is required to obtain adenosine antagonist-induced motor activation, with adenosine A(1) antagonists being the most sensitive and non-selective adenosine antagonists the most resistant to striatal dopamine depletion. When considering long-term treatment with adenosine antagonists concomitant administration of dopamine agonists might be required in order to obtain strong motor effects (cross-sensitization) and to avoid the development of telerance.

Local 5,7-dihydroxytryptamine lesions of rat amygdala: release of punished drinking, unaffected plus-maze behavior and ethanol consumption.

Several serotonergic drugs are effective for anxiety disorders, but underlying mechanisms are unclear, and findings in experimental animals are difficult to reconcile with human data. It has been proposed that differential effects of serotonin within specific anatomical systems may account for these difficulties, and the amygdala has been suggested as one of the structures involved. To examine this hypothesis, the neurotoxin 5,7-dihydroxytryptamine was administered locally in rat amygdala. Within the amygdala, serotonin was depleted by approximately 80%, with other transmitters unaffected, and serotonin transporter labelling was decreased by approximately 85%. Cortical areas near the lesion site were also affected, although to a lesser degree. Other forebrain areas were unaffected. Lesions resulted in a specific anti-conflict effect in a punished drinking test, but did not influence elevated plus-maze behavior (under baseline conditions and after restraint stress), locomotor activity or ethanol intake. These data suggest that the punished drinking test and the elevated plus-maze may activate different components of fear circuitry, and that the serotonergic input to the amygdala specifically participates in fear-related behavioral suppression mediated by this structure.

Behavioral insensitivity to restraint stress, absent fear suppression of behavior and impaired spatial learning in transgenic rats with hippocampal neuropeptide Y overexpression.

Exogenous neuropeptide Y (NPY) reduces experimental anxiety in a wide range of animal models. The generation of an NPY-transgenic rat has provided a unique model to examine the role of endogenous NPY in control of stress and anxiety-related behaviors using paradigms previously used by pharmacological studies. Locomotor activity and baseline behavior on the elevated plus maze were normal in transgenic subjects. Two robust phenotypic traits were observed. (i) Transgenic subjects showed a markedly attenuated sensitivity to behavioral consequences of stress, in that they were insensitive to the normal anxiogenic-like effect of restraint stress on the elevated plus maze and displayed absent fear suppression of behavior in a punished drinking test. (ii) A selective impairment of spatial memory acquisition was found in the Morris water maze. Control experiments suggest these traits to be independent. These phenotypic traits were accompanied by an overexpression of prepro-NPY mRNA and NPY peptide and decreased NPY-Y1 binding within the hippocampus, a brain structure implicated both in memory processing and stress responses. Data obtained using this unique model support and extend a previously postulated anti-stress action of NPY and provide novel evidence for a role of NPY in learning and memory.

Stimulation of adenosine A1 receptors attenuates dopamine D1 receptor-mediated increase of NGFI-A, c-fos and jun-B mRNA levels in the dopamine-denervated striatum and dopamine D1 receptor-mediated turning behaviour.

Adenosine A1 receptors antagonistically and specifically modulate the binding and functional characteristics of dopamine D1 receptors. In the striatum this interaction seems to take place in the GABAergic strionigro-strioentopeduncular neurons, where both receptors are colocalized. D1 receptors in the strionigro-strioentopeduncular neurons are involved in the increased striatal expression of immediate-early genes induced by the systemic administration of psychostimulants and D1 receptor agonists. Previous results suggest that a basal expression of the immediate-early gene c-fos tonically facilitates the functioning of strionigro-strioentopeduncular neurons and facilitates D1 receptor-mediated motor activation. The role of A1 receptors in the modulation of the expression of striatal D1 receptor-regulated immediate-early genes and the D1 receptor-mediated motor activation was investigated in rats with a unilateral lesion of the ascending dopaminergic pathways. The systemic administration of the A1 agonist N6-cyclopentyladenosine (CPA, 0.1 mg/kg) significantly decreased the number of contralateral turns induced by the D1 agonist SKF 38393 (3 mg/kg). Higher doses of CPA (0.5 mg/kg) were necessary to inhibit the turning behaviour induced by the D2 agonist quinpirole (0.1 mg/kg). By using in situ hybridization it was found that CPA (0.1 mg/kg) significantly inhibited the SKF 38393-induced increase in the expression of NGFI-A and c-fos mRNA levels in the dopamine-denervated striatum. The increase in jun-B mRNA expression could only be inhibited with the high dose of CPA (0.5 mg/kg). A stronger effect of the A1 agonist was found in the ventral striatum (nucleus accumbens) compared with the dorsal striatum (dorsolateral caudate-putamen). The results indicate the existence of antagonistic A1-D1 receptor-receptor interactions in the dopamine-denervated striatum controlling D1 receptor transduction at supersensitive D1 receptors.

Multiple intramembrane receptor-receptor interactions in the regulation of striatal dopamine D2 receptors.

Adenosine A2A, group I mGlu and neurotensin receptors have been previously found to modulate the binding characteristics of dopamine D2 receptors in membrane preparations from rat striatum. In the present study it is shown that stimulation of different combinations of striatal A2A, group I mGlu and neurotensin receptors induce different effects on the modulation of D2 receptor binding to those obtained when they are separately stimulated using maximal effective concentrations. In competitive inhibition experiments of dopamine versus the D2 receptor antagonist [3H]raclopride the addition of the A2A receptor agonist CGS 21680, the group I mGlu receptor agonist DHPG or neurotensin induced a decrease in the affinity of the high affinity state of the dopamine D2 receptors for dopamine. When added together CGS 21680 plus neurotensin induced the same effect as when administered alone, CGS 21680 plus DHPG induced a synergistic effect and DHPG plus neurotensin lost their modulating effect on D2 receptor binding. These results demonstrate the existence of multiple intramembrane receptor-receptor interactions in the regulation of striatal D2 receptors.

Adenosine A2A and group I metabotropic glutamate receptors synergistically modulate the binding characteristics of dopamine D2 receptors in the rat striatum.

There is experimental evidence for the existence of interactions between metabotropic glutamate (mGlu), adenosine and dopamine receptors in the striatum. In membrane preparations from rat striatum the group I and II mGlu receptor agonist 1-aminocyclopentane-1S-3R-dicarboxylic acid (1S-3R-ACPD) was found to modulate the binding characteristics of D2 receptors in a similar manner as the A2A receptor agonist 2-[p-(2-carboxyethyl)phenthylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680), with a significant decrease in the affinity of the high-affinity state of D2 receptors for dopamine. The effect of 1S-3R-ACPD was mimicked by (+/-)-trans-ACPD (t-ACPD; a racemic mixture of 1S-3R-ACPD and its inactive isomer 1R-3S-ACPD) and by the selective group I mGlu receptor agonist 3,5-dihydroxyphenylglycine (DHPG) and it was counteracted by the selective group I mGlu receptor antagonist 1-aminoindan-1,5-dicarboxilic acid (AIDA), but not by the the group II and III mGlu receptor antagonist (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG) or the adenosine receptor antagonist 8-phenyltheophylline. Furthermore, a strong synergistic effect was observed when the striatal membranes were exposed to both CGS 21680 and 1S-3R-ACPD. In agreement with the biochemical results, in unilaterally 6-OH-dopamine lesioned rats 1S-3R-ACPD counteracted the turning behaviour induced by the D2 receptor agonist quinpirole, but not by the D1 receptor agonist SKF 38393, and it synergistically potentiated the antagonistic effect of CGS 21680 on quinpirole-induced turning behaviour.

Differential effects of selective adenosine A1 and A2A receptor agonists on dopamine receptor agonist-induced behavioural responses in rats.

The effects of the systemic (i.p.) administration of the selective adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and the selective adenosine A2A receptor agonist sodium 2-p-carboxyethyl)phenylamino-5'-N-carboxamidoadenosine (CGS 21680) on different dopamine receptor agonist-induced behaviours were studied in the male rat. CGS 21680 (1 micromol/kg), but not CPA, was found to counteract the stereotypies induced by the non-selective dopamine receptor agonist apomorphine (0.25 mg/kg s.c.). Low doses of CGS 21680 (0.1 micromol/kg) and high doses of CPA (3 micromol/kg) counteracted yawning induced by the dopamine D2 selective agonist quinpirole (0.05 mg/kg). On the other hand, low doses of CPA (0.3 micromol/kg) antagonized grooming induced by the selective dopamine D1 receptor-selective agonist SKF 38393 (10 mg/kg i.p.), while CGS 21680 was ineffective. These results are consistent with the proposed existence of a selective antagonistic modulation of dopamine D1 and D2 receptors by adenosine A1 and A2A receptors, respectively. The ability of CGS 21680 to counteract apomorphine-induced stereotypies is weaker compared to its previously reported antagonistic effect of amphetamine-induced motor activity. This supports the hypothesis that adenosine A2A receptor agonists may be potential antipsychotic drugs with a low potential for extrapyramidal side effects.

Age-related alteration of the adenosine/dopamine balance in the rat striatum.

An antagonistic interaction between adenosine A2A- and dopamine D2-receptors has been described. Radioligand binding experiments showed a predominant reduction in the number of D2 vs. A2A-receptors in the striatum of aged compared to young rats. The A2A-receptor-mediated antagonistic modulation of D2-receptor binding remained unchanged in aged animals. In striatal homogenates a significant increase in adenosine and no change in dopamine content was found in aged vs. young rats. These results reveal the existence of an age-dependent imbalance of adenosine vs. dopamine in favor of adenosine, which involves both presynaptic and postsynaptic mechanisms.

Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine.

Release of the neurotransmitter dopamine in the mesolimbic system of the brain mediates the reinforcing properties of several drugs of abuse, including nicotine. Here we investigate the contribution of the high-affinity neuronal nicotinic acetylcholine receptor to the effects of nicotine on the mesolimbic dopamine system in mice lacking the beta2 subunit of this receptor. We found that nicotine stimulates dopamine release in the ventral striatum of wild-type mice but not in the ventral striatum of beta2-mutant mice. Using patch-clamp recording, we show that mesencephalic dopaminergic neurons from mice without the beta2 subunit no longer respond to nicotine, and that self-administration of nicotine is attenuated in these mutant mice. Our results strongly support the idea that the beta2-containing neuronal nicotinic acetylcholine receptor is involved in mediating the reinforcing properties of nicotine.

"Atypical" neuromodulatory profile of glutapyrone, a representative of a novel 'class' of amino acid-containing dipeptide-mimicking 1,4-dihydropyridine (DHP) compounds: in vitro and in vivo studies.

Glutapyrone, a disodium salt of 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)- glutaric acid, is a representative of a novel 'class' of amino acid-containing 1,4-dihydropyridine (DHP) compounds developed at the Latvian Institute of Organic Synthesis, Riga, Latvia. Conceptually, the glutapyrone molecule can be regarded as a dipeptide-mimicking structure formed by the "free" amino acid (glutamate) moiety and "crypto" (built into the DHP cycle) amino acid ("GABA") elements. Both of these amino acids are joined by the peptide bond. This compound unlike classical DHPs lacks calcium antagonistic or agonistic properties. Our previous studies revealed a profound and long-term anticonvulsant, stress-protective and neurodeficit-preventive activities of glutapyrone. In view of structural properties the role of glutamatergic mechanisms in the mediation of central effects of glutapyrone was considered. In the present study glutapyrone at the concentration range of 1 microM(-1) mM failed to effect both NMDA ([3H]TCP) and non-NMDA ([3H]KA and [3H]AMPA) receptor ligand binding in the rat cortical membranes in vitro. The compound markedly enhanced motor hyperactivity induced by the NMDA antagonist PCP and the dopamine releasing compound D-amphetamine in the rats. Glutapyrone displayed activity in a variety of animal models relevant for affective/depressive disorders in humans i.e. reserpine-induced ptosis and hypothermia, forced swimming test and open field test. These data indicate that the unusually "broad" pharmacological spectrum of glutapyrone might involve concomitant actions on multiple neurotransmitter systems, particularly, GABA-ergic and the catecholamines. It is discussed whether these functional properties are secondary to action on intracellular events, predominantly, G protein-related since glutapyrone appears to lack direct interactions with a number of receptors including ionotropic glutamate and GABA(A)/Bzd receptors.

Adenosine A2A agonists: a potential new type of atypical antipsychotic.

The systemic intraperitoneal (i.p.) administration of the adenosine A2A agonist CGS 21680 was found to dose-dependently antagonize spontaneous and amphetamine-induced (1 mg/kg i.p.) motor activity with similar ED50 values (about 0.2 mg/kg). The ratios between the ED50 values for induction of catalepsy and for antagonizing amphetamine-induced motor activity for CGS 21680, haloperidol, and clozapine were 12, 2, and > 30, respectively. Furthermore, CGS 21680 was comparably much stronger than haloperidol or clozapine at antagonizing the motor activity induced by phencyclidine (2 mg/kg subcutaneously) than motor activity induced by amphetamine (1 mg/kg i.p.). In conclusion, the present results show a clear "atypical" antipsychotic profile of the adenosine A2A agonist CGS 21680 in animal models.

Endothelin-1 induced lesions of the frontoparietal cortex of the rat. A possible model of focal cortical ischemia.

Endothelin-1 (ET-1) was unilaterally applied onto the surface of the dorsal frontoparietal cortex of the rat. Cortical blood flow measurements using laser-Doppler flowmetry demonstrated dose-dependent reductions of frontoparietal cortical blood flow. Histological analysis demonstrated dose-related lesions and the time course was followed using MRI. The lesions appear to be associated with a large penumbra area indicated by morphological characteristics. Thus, cortical surface exposure to ET-1 may produce graded lesions of the frontoparietal cortex related to local ischemia.