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  • 1
    Electronic Resource
    Electronic Resource
    BAY 38–7271: A Novel Highly Selective and Highly Potent Cannabinoid Receptor Agonist for the Treatment of Traumatic Brain Injury (2003)
    Oxford, UK : Blackwell Publishing Ltd
    CNS drug reviews 9 (2003), S. 0 
    Details
    ISSN: 1527-3458
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Traumatic brain injury (TBI) is the most common cause of mortality and morbidity in adults under 40 years of age in industrialized countries. Worldwide the incidence is increasing, about 9.5 million people are hospitalized per year due to TBI, and the death rate is estimated to be more than one million people per year. Recently BAY 38–7271 has been characterized as a structurally novel, selective and highly potent cannabinoid CB1/CB2 receptor agonist in vitro and in vivo with pronounced neuroprotective efficacy in a rat traumatic brain injury model, showing a therapeutic window of at least 5 h. Furthermore, neuroprotective efficacy was also found in models of transient and permanent occlusion of the middle cerebral artery and brain edema models as well. In this article we review the in vitro and in vivo pharmacology of BAY 38–7271, the results from acute and subacute toxicity studies, pharmacokinetics and drug metabolism in animals and healthy male volunteers. In phase I studies BAY 38–7271 was safe and well tolerated when administered by i.v. infusion for either 1 or 24 h.As the doses of BAY 38–7271 in animals needed for maximal neuroprotective efficacy were significantly lower than those inducing typical cannabinoid-like side effects, it is to be expected that the compound will offer a novel therapeutic approach with a favorable therapeutic window for the treatment of TBI or cerebral ischemia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3458.2003.tb00259.x
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  • 2
    Electronic Resource
    Electronic Resource
    Ipsapirone and 8-OH-DPAT reduce ethanol preference in rats: involvement of presynaptic 5-HT1A receptors (1993)
    Springer
    Psychopharmacology 112 (1993), S. 100-110 
    Details
    ISSN: 1432-2072
    Keywords: Alcoholism ; Dorsal raphe nucleus ; Ethanol intake ; Ethanol preference ; 5-HT, 5-HT1A receptor ; Ipsapirone ; Nucleus accumbens ; 8-OH-DPAT ; pCPA ; Rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The selective serotonin(5-HT)1A receptor agonists 8-OH-DPAT and ipsapirone were tested in selectively inbred Wistar rats, with high preference [70–90%: defined as the ratio of ethanol (EtOH) to total fluid intake] for EtOH (10% v/v) over water in a two-bottle free choice situation. Rats were injected shortly before the overnight test session (8:00p.m.–8:00a.m.). EtOH and water consumption were determined in 20-min intervals; food consumption after the session. 8-OH-DPAT (ED50: 2.4 mg/kg, SC) and ipsapirone (ED50: 12.5 mg/kg, SC) reduced EtOH preference in a dose-dependent manner. In addition, 8-OH-DPAT increased total fluid intake, whereas ipsapirone enhanced total food intake. The EtOH preference reduction was time-dependent and reached a maximum within the second 4 h after application of 8-OH-DPAT (−73%) and ipsapirone (−72%). The preference reducing effect of ipsapirone (20 mg/kg, PO) was completely blocked by the nonselective 5-HT1A antagonist spiperone (0.05 mg/kg, SC). Local application of 8-OH-DPAT (10 µg, 0.5 µl) into the dorsal raphe nucleus (DRN, a brain area rich in somatodendritic 5-HT1A autoreceptors), reduced the EtOH preference significantly as compared to the saline injection in the same animal (−12%, 8:00–12:00p.m.). Only marginal effects on ingestion behavior were observed after micro-injection into the nucleus accumbens. Reduction of brain 5-HT levels by pretreatment with the 5-HT synthesis inhibitor pCPA (2×150 mg/kg, IP) resulted in a short lasting, marked reduction (−54%) and a long lasting, small attenuation of the EtOH preference. Total food consumption was strongly decreased but returned soon to normal; total fluid intake was only slightly decreased. The EtOH preference reducing effect of ipsapirone (5 and 20 mg/kg, SC) was attenuated in pCPA-pretreated rats. The present data suggest that 5-HT1A receptor ligands reduce EtOH preference via stimulation of 5-HT1A receptors in the DRN. The possibility of additional mechanism(s) is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02247369
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  • 3
    Electronic Resource
    Electronic Resource
    Effects of training dose on discrimination and cross-generalization of chlordiazepoxide, pentobarbital and ethanol in the rat (1986)
    Springer
    Psychopharmacology 88 (1986), S. 341-345 
    Details
    ISSN: 1432-2072
    Keywords: Drug discrimination ; Drug generalization ; Training dose ; Chlordiazepoxide ; Ethanol ; Pentobarbital ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Six groups of rats (N=8), trained to discriminate chlordiazepoxide (5 or 20 mg/kg), pentobarbital (5 or 15 mg/kg) or ethanol (750 or 1500 mg/kg) from saline in a two-lever food-reinforced procedure, were tested for stimulus generalization with the three drugs. Training drug, but not training dose, affected the extent of generalization to a test drug; symmetrical generalization between chlordiazepoxide and pentobarbital and asymmetrical generalization between chlordiazepoxide and ethanol and between pentobarbital and ethanol was observed. Training dose level affected (1) slope and ED50 of the generalization gradients of training drugs and substitution drugs, (2) discriminative performance, (3) response bias and (4) threshold dose for response suppression. Indices of lever selection and percentage drug-appropriate lever responses yielded similar generalization maxima, slopes and ED50s. The potency of chlordiazepoxide relative to the potency of pentobarbital to induce drug stimulus generalization varied across the experimental groups. The results indicate differences between the discriminative effects of chlordiazepoxide, pentobarbital and ethanol. It is suggested that the discriminative effects of chlordiazepoxide, pentobarbital and ethanol are not based on their response rate modulating effects and that training dose is not a determinant for the extent of cross-generalization between these compounds.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00180836
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  • 4
    Electronic Resource
    Electronic Resource
    The calcium channel agonist BAY k 8644 reduces ethanol intake and preference in alcohol-preferring AA rats (1996)
    Springer
    Psychopharmacology 127 (1996), S. 302-310 
    Details
    ISSN: 1432-2072
    Keywords: Key words Ethanol intake ; L-type calcium channels ; AA rats ; Dihydropyridines ; BAY k8644 ; Nimodipine ; Stereoselectivity ; Subchronic ; Antagonism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Applying a 12-h limited access, two-bottle choice procedure, antialcohol effects of the 1,4-dihydropyridine (DHP) L-type calcium (Ca2+) channel agonist BAY k8644 were investigated in alcohol-preferring AA rats. In this Wistar line, selectively bred for a high 10% v/v ethanol (EtOH) preference in a free choice situation, effects on EtOH preference and intake, as well as on food and total fluid intake were evaluated for racemic BAY k8644 (0.1–1 mg/kg IP; 0.25–2 mg/kg PO), its agonistic (−)-enantiomer (0.1–1 mg/kg IP and PO) and its antagonistic (+)-enantiomer (10–50 mg/kg IP and PO). Irrespective of route of application, BAY k8644 was found to be effective in reducing both EtOH intake and preference (minimal effective dose: 0.5 mg/kg; maximum effect: approximately 60% of baseline levels). The (+)-enantiomer, acting as a low-potency Ca2+ channel antagonist, also reduced EtOH intake and preference, but the effects were not very selective as food intake was also substantially reduced. Moreover, the effects were only obtained at relatively high doses (50 mg/kg). The essential enantiomer involved in the antialcohol effects of BAY k8644 seems to be the (−)-enantiomer, acting as a strong Ca2+ channel agonist. This latter compound was potent (minimal effective dose: 0.3 mg/kg), very effective in reducing EtOH intake (maximum effect: 29% of baseline level) and preference (26% of baseline) and apparently more selective. Although slightly decreasing over days, effects of (−)-BAY k8644 on EtOH intake and preference were shown to remain after repeated treatment (10 successive days, 0.3 mg/kg IP). Interestingly, the acute antialcohol effects of (−)-BAY k8644 (0.3–1 mg/kg IP) could not be antagonized with the DHP L-type Ca2+ channel antagonists nimodipine (0.01–1 mg/kg IP) and (−)-nimodipine (1–30 mg/kg IP). The present results suggest thata mechanism of action other than L-type Ca2+ channel agonism is involved in the antialcohol effects of (±)- and (−)-BAY k8644. Alternatively, it is possible that the previously described antialcohol effects of DHP Ca2+ channel antagonists are not related to antagonistic activity at Ca2+ channels. Finally, it cannot be excluded that a mechanism unrelated to Ca2+ channels is responsible for the antialcohol effects of both DHP Ca2+ channel agonists and antagonists.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050090
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  • 5
    Electronic Resource
    Electronic Resource
    Stimulus control induced by benzodiazepine antagonist Ro 15-1788 in the rat (1985)
    Springer
    Psychopharmacology 85 (1985), S. 483-485 
    Details
    ISSN: 1432-2072
    Keywords: Drug discrimination ; Stimulus control ; Benzodiazepine antagonist ; Ro 15-1788 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The imidazodiazepine Ro 15-1788 is a proposed benzodiazepine receptor antagonist. Recently however, behavioural effects of Ro 15-1788 have been demonstrated. In the present study, rats (n=12) were trained to discriminate Ro 15-1788 (10 mg/kg, IP, t=15 min) from vehicle in a two-lever food-reinforced procedure. All rats showed a reliable discrimination (mean injection-appropriate lever responding 〉85%) after about 60 daily training sessions. Drug stimulus control was evidenced by an orderly generalization gradient obtained with 0.01–30 mg/kg Ro 15-1788 (ED50 for stimulus generalization: 0.12 mg/kg). Since even low doses of Ro 15-1788 have discriminative effects in the rat, it is concluded that Ro 15-1788 may have potent behavioural activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00429669
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  • 6
    Electronic Resource
    Electronic Resource
    Effects of chlordiazepoxide training dose on the mixed agonist-antagonist properties of benzodiazepine receptor antagonist Ro 15-1788, in a drug discrimination procedure (1986)
    Springer
    Psychopharmacology 88 (1986), S. 177-183 
    Details
    ISSN: 1432-2072
    Keywords: Drug discrimination ; Chlordiazepoxide ; Benzodiazepine antagonism ; Ro 15-1788 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In experiment 1, rats (n=12) were trained to discriminate the benzodiazepine (BDZ) compound chlordiazepoxide (CDP, 20 mg/kg, IP) from saline in a two-lever food-reinforced procedure, and subsequently were tested for stimulus control with different doses of CDP, Ro 15-1788 (a proposed BDZ receptor antagonist) and Ro 15-1788 plus 20 mg/kg CDP. Ro 15-1788 (0.63–40 mg/kg) dose-dependently antagonized CDP, and induced predominantly saline appropriate responding when administered alone. Thereafter, the same rats were retrained by progressively decreasing the training dose, to discriminate 2.5 mg/kg CDP from saline, and were tested again with the same compounds. Ro 15-1788 (0.16–40 mg/kg) now failed to antagonize CDP (2.5 mg/kg) and increased the percentage of drug-appropriate responding in a dose-related manner when administered alone. In experiment 2, separate groups of rats (n=10) were similarly trained to discriminate either 15 or 3 mg/kg CDP from saline. Tests with CDP, Ro 15-1788 and Ro 15-1788 plus CDP (either 15 or 3 mg/kg) yielded similar results to experiment 1, suggesting that the training dose effects on generalization and antagonism of Ro 15-1788 were not affected by the manner in which the lower CDP dose acquired drug stimulus control. It is concluded that mixed agonist-antagonist properties are apparent after-variations of the BDZ training dose in a drug discrimination procedure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00652236
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  • 7
    Electronic Resource
    Electronic Resource
    Substitution of the selective serotonin reuptake inhibitors fluoxetine and paroxetine for the discriminative stimulus effects of ethanol in rats (1997)
    Springer
    Psychopharmacology 130 (1997), S. 404-406 
    Details
    ISSN: 1432-2072
    Keywords: Key words 5-HT receptor subtypes ; Alcoholism ; Drug discrimination ; MDL 100 ; 907 ; WAY-100635
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rats trained to discriminate ethanol (EtOH, 1 g/kg IP) from saline in a two-lever procedure completely generalized to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine. Substitution of fluoxetine was completely blocked by the selective 5-HT2A receptor antagonist MDL 100,907 and not affected by the selective 5-HT1A receptor antagonist WAY-100635. It is suggested that the previously reported effectiveness of SSRIs in reducing EtOH consumption could be based on similarities in discriminative stimulus effects of SSRIs and EtOH. Stimulation of 5-HT2A receptors may underlie these stimulus similarities and contribute to the EtOH intake-reducing effects of SSRIs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050257
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  • 8
    Electronic Resource
    Electronic Resource
    Effects of drug-induced differences in reinforcement frequency on discriminative stimulus properties of fentanyl (1984)
    Springer
    Psychopharmacology 83 (1984), S. 257-261 
    Details
    ISSN: 1432-2072
    Keywords: Drug discrimination ; Reinforcement variables ; Fentanyl ; Morphine ; Sufentanil ; Naloxone ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats were trained to discriminate between fentanyl (0.04 mg/kg) and saline in a two-lever procedure. Using a FR 10 schedule of food reinforcement, drug-induced differences between the number of reinforcers obtained under fentanyl and saline conditions were observed. The effect of eliminating these differences on the outcome of generalization tests was investigated by different manipulations. In one group (N=10), the FR 10 schedule used during saline sessions was changed to FR 6 during drug sessions. In a second group (N=12), saline sessions ended after the number of reinforcers obtained was equal to the number obtained during the preceding drug session. A control group (N=10) was trained using a FR 10 schedule under both conditions. Elimination of differences in reinforcement frequency 1) accelerated the acquisition of the discrimination, 2) diminished response bias, 3) flattened the slope and reduced the ED50 value of generalization gradients of fentanyl, morphine and sufentanil and 4) increased the ED50 value of naloxone in antagonizing 0.04 mg/kg fentanyl. It is concluded that the unconditioned effects of 0.04 mg/kg fentanyl on response rate in a FR 10 procedure lead to differences between saline and drug sessions which contribute to the apparent discriminative stimulus properties of fentanyl.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00464790
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  • 9
    Electronic Resource
    Electronic Resource
    Oestradiol enhances the vulnerability threshold for schizophrenia in women by an early effect on dopaminergic neurotransmission (1991)
    Springer
    European archives of psychiatry and clinical neuroscience 241 (1991), S. 65-68 
    Details
    ISSN: 1433-8491
    Keywords: Schizophrenia ; Onset of schizophrenia ; Gender differences in schizophrenia ; Oestradiol effect on dopamine receptor sensitivity ; Vulnerability threshold in schizophrenia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In a representative sample of 392 first hospital admissions for schizophrenia from a population of 1.5 million we assessed the “true” age of onset by a semistandardized interview “IRAOS”. We demonstrated that the mean age at onset of the disease is 3–4 years higher in females than in males, with the lifetime risk being exactly equal. In males, the rates of onset show a steep increase — starting from school age and reaching their maximum value in the age group 15–24 years — followed by a steady decrease. Females reach the first peak with a clear delay between 20 and 29 years. After the decrease, a second smaller peak is observed consistently in females within the age group 45–49 years and over. After having excluded competing explanations, we hypothesized that the effect of oestradiol on the dopaminergic system enhances the vulnerability threshold, which is lowered again during the menopause. Alternatively, we assumed that testosterone reduces the vulnerability threshold and thus furthers the earlier onset of the disease in males. We tested the hypotheses in three animal models by examining the effect of gonadal hormones on haloperidol-induced catalepsy and on apomorphine-induced stereotypies in both neonatal and adult rats. No clear influence by testosterone was shown. Oestradiol caused a significant reduction of both dopamine-agonist and dopamine-antagonist induced behaviour. The effects were stronger in neonatal rats. Since oestradiol caused the dopamine (DA) receptor affinity for sulpiride to be reduced by a factor of 2.8, we assumed that the behavioural changes due to oestradiol were accounted for by a down-regulation of DA receptor sensitivity. The higher age at onset and the second peak of onsets after menopause in females may therefore be due to a functional effect and possibly also to an additional structural effect of oestrogens already exerted on the development of the brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02193758
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  • 10
    Electronic Resource
    Electronic Resource
    The role of 5-HT receptor subtypes in the anxiolytic effects of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test (1998)
    Springer
    Psychopharmacology 135 (1998), S. 383-391 
    Details
    ISSN: 1432-2072
    Keywords: Key words 5-HT1A receptors ; 5-HT2A receptors ; Anxiety ; Paroxetine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We evaluated whether the anxiolytic effects of selective serotonin reuptake inhibitors (SSRIs) in the rat ultrasonic vocalization (USV) test are preferentially mediated by (indirect) activation of 5-HT1A, 5-HT1B/1D, 5-HT2A, 5-HT3 or 5-HT4 receptors. The SSRIs, paroxetine (ED50 in mg/kg, IP: 6.9), citalopram (6.5), fluvoxamine (11.7) and fluoxetine (〉30), dose dependently reduced shock-induced USV. The effects of paroxetine (3.0 mg/kg, IP) were not blocked by the selective 5-HT1A receptor antagonist, WAY-100635 (3.0 mg/kg, IP), the 5-HT1B/1D receptor antagonist, GR 127935 (30 mg/kg, IP), the nonselective 5-HT2A receptor antagonists, ritanserin (3.0 mg/kg, IP) and ketanserin (1.0 mg/kg, IP), the 5-HT3 receptor antagonist, ondansetron (0.1 mg/kg, IP), or the 5-HT4 receptor antagonist, GR 125487D (3.0 mg/kg, SC). In contrast, the selective 5-HT2A receptor antagonist, MDL 100,907 (0.1 mg/kg, IP), completely prevented the paroxetine-induced reduction of USV. Under similar conditions, WAY-100635 blocked the anxiolytic-like effects of the selective 5-HT1A receptor agonist, 8-OH-DPAT [(±)-8-hydroxy-2-(di-n-propylamino)tetralin, 1.0 mg/kg, IP], and ritanserin, ketanserin, and MDL 100,907 blocked the anxiolytic-like effects of the mixed 5-HT2A/2C receptor agonist, DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, 3.0 mg/kg, IP]. WAY-100635 (1.0 mg/kg, IP) in combination with ritanserin (3.0 mg/kg, IP), but not ondansetron (0.1 mg/kg, IP), GR 125487D (3.0 mg/ kg, SC), or GR 127935 (30 mg/kg, IP), attenuated the USV reducing effects of paroxetine. Although the results suggest that selective stimulation of 5-HT1A and 5-HT2A receptors produces a decrease of USV, we postulate that only 5-HT2A receptors play a pivotal role in the effects of SSRIs in this model of anxiety.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050526
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