bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of ethanol on motor activity of the colon in the rat
Authors: Meshkinpour Hooshang , Yu Jen , Harmon David
Published: January 2005

The present study was designed to evaluate the influence of oral and intravenous ethanol on both resting and neostigmine‐induced motor activity of the colon in the rat. Recording assemblies were implanted in the proximal and distal colon in a chronic preparation. On separate days, 2 ml of normal saline or the same volume of 10% or 25% ethanol was introduced intravenously or into the stomach. Colon motor activity was recorded at resting and after intravenous injection of 0.07 mg/kg neostigmine. Ethanol decreased the number and amplitude of the contractions. This effect occurred within a few minutes after administration of ethanol and lasted for the entire recording period of 30 min. Both concentrations of ethanol significantly (P < 0.05) decreased the motility index of the colon. Injection of neostigmine was signified by a substantial rise in colon motor activity which was significantly inhibited by administration of ethanol. These studies indicate that ethanol, within the human legal intoxication range, inhibits the resting and neostimine‐induced motor activity in the rat colon.
Autoimmunity to cholinergic‐specific antigens of the brain in senile dementia of the Alzheimer's type
Authors: Fillit Howard , Foley P. , Bradford H. F. , Bucht G. , Winblad B. , McEwen B. , Luine V. , Hardy J.
Published: January 2005

Senile dementia is a common and devastating disease of the elderly. The most common type of senile dementia is Alzheimerapos;s type (SDAT). The cause of SDAT is unknown. Considerable evidence indicates that the basal forebrain cholinergic system of the brain is primarily involved in the disease process. The mechanisms which account for this specificity of injury is unknown. Several lines of evidence have suggested that autoimmunity may play a role in SDAT. In particular, the presence of antibrain antibodies in the sera of patients with SDAT has been described. However, their specificity has not been defined. Our hypothesis proposes that cholinergic‐specific autoimmunity might play a role in the immunopathogenesis of SDAT. We previously presented data to suggest that antibrain antibodies in SDAT sera are directed against cholinergic‐specific brain antigens. In the current study, a synaptosomal lysis assay was employed to determine if SDAT sera caused specific complement‐dependent immunolysis of cholinergic synaptosomes. Immunolysis was determined by the release of choline acetyltransferase (ChAT), glutamate decarboxylase (GAD), dopamine‐beta‐hydroxylase (DBH), lactate dehydrogenase (LDH), and the inhibition of high affinity choline uptake. Sera from two (American and Swedish) groups of SDAT patients and controls were pair‐tested in a blinded fashion on a single batch of synaptosomes. The results demonstrated that both groups of SDAT sera caused significant specific immunolysis of cholinergic synaptosomes. ChAT release, LDH release, and inhibition of choline uptake were caused by SDAT sera in the presence of complement, while control sera showed little effect. No effect was noted on GAD or DBH release. These data support the hypothesis that a cholinergic‐specific autoimmune response may play a role in the immunopathogenesis of SDAT. Further studies are needed to define the immunochemistry of the cholinergic‐specific antigens recognized by SDAT sera.
Immune actions in the nervous system: A brief review with special emphasis on Aalzheimer's disease
Authors: Rogers Joseph , Luber‐Narod Judith
Published: January 2005

The traditional dogma of brain immunologic privilege remains entrenched in the neurosciences. Thus the new discipline of neuroimmunology has often been understood as the study of effects of the nervous system on the immune system rather than vice versa. New data, however, are beginning to show potentially important interactions of the immune system in brain, especially in neurologic disease. These neuroimmune mechanisms appear to involve classic peripheral immune cells (e.g., T cells) as well as cells idiosyncratic to brain (e.g., glia).
Learning and memory deficits associated with autoimmunity: Significance in aging and Alzheimer's disease
Authors: Forster Michael J. , Retz Konrad C. , Lal Harbans
Published: January 2005

This review focuses on the significance of brain‐reactive antibodies (BRA) to ageassociated cognitive decline and Alzheimerapos;s disease, drawing on evidence available from both human and animal studies. Human studies suggest a relationship between BRA formation, age, and Alzheimerapos;s disease. Experiments with mice indicate that BRA formation and age‐related learning deficits are accelerated following adoptive transfer of immunity from aged to young mice. Furthermore, mice selected for autoimmunity and early formation of BRA also show accelerated, age‐related learning deficits. It is concluded that a further analysis of the nature of BRA and their targets within the nervous system could reveal important immunological influences in cognitive dysfunctions related to aging and Alzheimerapos;s disease. It is suggested that treatments that delay or prevent age‐related immunological dysfunctions be evaluated for their ability to retard age‐associated cognitive decline.
Gangliosides in treatment of neural injury and disease
Authors: Mahadik Sahebarao P. , Karpiak Stephen K.
Published: January 2005

Gangliosides are being used therapeutically to treat a variety of nervous system disorders including peripheral neuropathies and stroke. Gangliosides (over 70 molecular species) are glycosphingolipids found in highest concentration in neural tissue. They are thought to be functional in such diverse biological processes as embryogenesis and cell death, and specifically in membrane‐mediated processes (cell‐cell interactions, ionic balance, synaptic transmission, and receptor‐mediated information transfer). Their distribution changes during neural development, indicative of differential roles for each molecular species at critical stages of development. Ganglioside distribution differs during abnormal development or after neural injury due to trauma or disease. In vivo and in vitro studies have shown that exogenous gangliosides can substitute (structrally and functionally) for the endogenous molecules. This has made it possible to investigate the molecular mechanisms of ganglioside function in situ. During the genesis of these studies it became clear that exogenous gangliosides were able to protect the chemical and morphological changes associated with neural (CNS and PNS) tissue injury (mechanical, ischemic, and neurotoxic). This protective effect has been characterized by facilitated functional recovery in a number of CNS injury paradigms. The mechanism(s) for the facilitative effect of ganglioside treatment is unidentified. Data support a number of hypotheses. One contends that gangliosides can acutely reduce the extent of CNS injury and pathology by protection of membrane structure/function, thereby leading to reduced functional deficits and therefore to increased potential for functional recovery. Another hypothesis supports the view that these glycosphingolipids may promote neuronal regeneration through modulation of trophic factors. Studying the effects of exogenous gangliosides on CNS injury is leading to further insight into the critical functions of endogenous gangliosides as well as focusing attention on the potential of exogenous gangliosides as a therapeutic treatment of traumatic and degenerative CNS disorders.
Drug discrimination procedures: A method to analyze adaptation level of affective states
Authors: Gauvin David V. , Harland Richard D. , Holloway Frank A.
Published: January 2005

When contrasting drugs (i.e., chlordiazepoxide versus pentylenetetrazol) are examined in drug‐drug, drug‐saline, or drug 1‐drug 2‐saline tasks, one can begin to assess whether such drugs represent orthogonal cues or reflect an underlying cue dimension. Both adaptation level theory and opponent‐process theory are applied to the analysis of drug discriminative performance. Three indices that can differentiate between orthogonal and opponent affective states utilizing drug‐drug discrimination tasks are discussed in relation to these two theories, and a model to characterize further the similarity between pharmacologically and environmentally induced anxiety is proposed.
Stimulant drugs as conditioned and unconditioned stimuli in a classical conditioning paradigm
Authors: Carey Robert J.
Published: January 2005

A number of important ways in which drugs interact with learning processes have been identified in studies of the behavioral pharmacology of centrally active drugs. For example, drugs can act as discriminative and as reinforcement stimuli or as unconditioned stimuli eliciting unconditioned responses. Regarding the latter, it has been shown that a number of drug effects can be conditioned to exteroceptive stimuli, providing a mechanism by which drug effects can be transferred from the drug itself to external environment stimulus control. This paper focuses on the development of conditioned drug responses using drug‐induced rotational behavior in rats with unilateral lesions of dopamine neurons. A particularly useful advantage of this model is that the drug‐induced response is mediated by a specific central nervous system (CNS) substrate and the criterion rotational response is unambiguous and easily quantified. Additionally, different drugs can elicit the same response of rotation but in a different direction (i.e., depending on the drug used to induce rotation, ipsilateral or contralateral to the dopamine‐denervated hemisphere). This difference in directionality of drug‐induced rotation provides an opportunity to condition responses to different stimulant drugs differentially, which is not possible in the intact animal, since these drugs tend to evoke similar responses (e.g., hyperactivity or stereotypy). Another advantage of directionality differences in rotational responses associated with different stimulant drugs is that one can assess conditioning interactions between drugs. For example, if one drug that elicits an ipsilateral rotation is paired with another drug that elicits contralateral rotation, then, through a conditioning paradigm of paired drug presentations, one might shift the direction of rotation of the one drug used as the conditioned stimulus to that of the other drug used as the unconditioned stimulus. A number of procedures are described in which the anticholinergic drug scopolamine (which elicits ipsilateral rotation) is paired as the conditioned stimulus with the dopaminergic drug apomorphine (which elicits contralateral rotation) as the unconditioned stimulus, and, as a result, the scopolamine comes to elicit contralateral rotation when subsequently given alone. Observation of such effects points to the importance of drug–drug interactions influenced by Pavlovian conditioning processes.
Voltage‐ and rate‐dependent reduction of Vmax of cardiac action potentials by SC‐40230
Authors: Martin Cynthia L. , Borowicz Luanne E. , Schniepp Henry C. , Sanguinetti Michael C.
Published: January 2005

The voltage‐, rate‐, and concentration‐dependent effects of a new antiarrhythmic agent, SC‐40230, which is chemically similar to disobutamide, on cardiac action potentials were evaluated. Racemic SC‐40230 and its two stereoisomers caused equipotent reduction of the maximum rate of depolarization (V̇max) of action potentials recorded from guinea pig papillary muscle. Action potential duration and effective refractory period were shortened by the drug in papillary muscle and canine Purkinje fibers, but were not altered in guinea pig atria. Depression of V̇max by racemic drug was similar in all three preparations. SC‐40230 did not cause significant reduction of V̇max following a long rest period (no “rested state” reduction). Rate‐dependent depression of V̇max was observed when papillary muscles were stimulated at rates slower, but not greater than 30 pulses/min. In papillary muscles depolarized by 10 mK Ko+, steady‐state depression of V̇max during a stimulus train of 200 pulses/min was 18% in the absence of drug and 56% in the presence of 30 μM SC‐40230. Onset of V̇max reduction was monoexponential (rate constant = 0.064 [action potentials]−1). Recovery from depression of V̇max following the train of stimuli was monoexponential in both control (tau = 11.0 sec) and in the presence of 30 μM SC‐40230 (tau = 27.8 sec). Thus, SC‐40230 appears to slow recovery from slow inactivation of Na current. Rate‐dependent depression of V̇max was voltage dependent. The V1/2 for the relationship between V̇max and resting membrane potential was shifted by −8 mV when determined at a stimulation rate of 120 pulses/min, but was not altered at 12 pulses/min by the drug. Thus, SC‐40230 has typical class I activity on isolated cardiac muscle, but lacks the toxicity of disobutamide.
Effects of sigma agonist and antagonist drugs on food and/or water intake in rats
Authors: Katz Norman L. , Sobaski Nancy , Sanchez Jenny , Kremer Edna K. , Lee Jamie K. , Schlemmer R. Francis
Published: January 2005

Drugs known to interact with sigma receptors were studied for their effects on food and/or water intake, since the putative sigma receptor agonist N‐allylnormetazocine (NANM) has been reported to both increase and decrease food intake under various conditions. Previous investigators have shown that each enantiomer of racemic NANM [(±)‐NANM] is pharmacologically active. (+)‐NANM appears to interact preferentially with sigma receptors, and (−)‐NANM with both mu and kappa opiate receptor sites. In the present study, the effects of subcutaneously administered (±)‐NANM, (+)‐NANM, and (−)‐NANM on food intake in 20 hr food‐deprived male rats were examined. (±)‐NANM and (−)‐NANM decreased food intake stimulated by food deprivation, while (+)‐NANM exhibited no significant effect. Similarly, both (±)‐NANM and (−)‐NANM decreased water intake in 24 hr water‐deprived rats. (+)‐NANM decreased water intake in doses which may have caused disorientation. Locomotor activity was stimulated by intraperitoneal injection of 10 mg/kg of (+)‐NANM but not by the same dose of (−)‐NANM. The effects of (+)‐NANM and (−)‐NANM on food and water intake paralleled those of narcotic antagonists and did not seem related to an interaction with sigma receptors. (±)‐BMY14802 is a sigma receptor antagonist with potential antipsychotic properties. When administered to female rats by daily injection for 28 days, it did not affect weight gain except at the highest dose, 30 mg/kg. Weight gain of animals given a 30 mg/kg dose was significantly greater compared to controls. However, rats treated orally with a similar dose of (±)‐BMY14802 incorporated into the diet daily for 8 weeks did not exhibit significant weight gain compared to controls. The data argue against a significant role for sigma receptors in mediating ingestive behavior. Should sigma antagonist drugs reach the market, they may be less likely to cause weight gain than most classical antipsychotics.
Cognition enhancement by the acetylcholine releaser DuP 996
Authors: Cook Leonard , Nickolson Victor J. , Steinfels George F. , Rohrbach Kenneth W. , Denoble Victor J.
Published: January 2005

DuP 996, 3,3,‐Bis(4‐pyridinylmethyl)‐1‐phenylindolin‐2‐one, a potent in vitro and in vivo releaser of acetylcholine (ACh), dopamine (DA), and serotonin (5HT) in rat brain, significantly enhanced the performance of rats and mice in several behavioral test procedures. At doses of 0.01–0.1 mg/kg s.c. DuP 996 protected against a hypoxia‐induced passive avoidance deficit in rats. In active avoidance procedures, DuP 996 enhanced acquisition of responses: in rats, at doses between 0.085 and 0.85 mg/kg s.c. and 0.25 and 0.85 mg/kg p.o.; in mice, at doses between 0.85 and 2.5 mg/kg s.c. These effects occurred without any alteration of sensitivity to foot‐shock. In addition, Dup 996 prevented a CO2‐induced retention deficit of a passive avoidance response when administered prior to acquisition testing. In a test for acquisition of lever pressing for food in the rat, DuP 996 increased the proportion of animals acquiring this response. Thus, DuP 996 was active in both the shock‐ and appetitive‐motivated procedures and was shown to enhance performance levels when administered post‐training as well as before training trials. These results suggest that DuP 996 may be useful in the treatment of cognition dysfunction.
Pharmacological validation of ritanserin and risperidone in the drug discrimination test procedure in the rat
Authors: Meert Theo F. , De Haes Patrick L. A. J. , Vermote Patrick C. M. , Janssen Paul A. J.
Published: January 2005

The results presented here indicate that 0.16 mg/kg LSD, 2.50 mg/kg 8‐OHDPAT, 1.25 mg/kg d‐amphetamine, 10.00 mg/kg cocaine, 40.00 mg/kg chlordiazepoxide, 2.50 mg/kg xylazine, and 0.04 mg/kg fentanyl can be used as discriminative stimuli in a two‐lever drug discrimination test procedure in the rat. The central 5‐HT2 antagonist ritanserin and the 5‐HT2 and catecholamine (CA)‐antagonist risperidone were tested for stimulus generalization with, and possible antagonism of, the discriminative stimulus properties of the various training drugs. With both drugs at all doses tested, no stimulus generalization was observed with any of the training drugs. Ritanserin completely blocked the discriminative stimulus properties of LSD at 40.00 mg/kg but was, at doses up to 40.00 mg/kg, unable to block the discriminative stimulus properties of any of the other training drugs. Risperidone completely antagonized the stimulus properties of LSD and d‐amphetamine, partially blocked cocaine, and possessed minor effects on 8‐OHDPAT and fentanyl. Whereas ritanserin was almost without any effects or response rate, risperidone mostly reduced response rate at doses starting between 0.16 and 0.63 mg/kg. However, the complete antagonism of the LSD and d‐amphetamine was observed without effects on response rate. Globally, these results confirm ritanserin to be a selective 5‐HT2 antagonist without any effects on conditioned behaviour. Risperidone was found to be a potent 5‐HT2 and DA antagonist, affecting conditioned behaviour by interfering with response rate and with the response‐reinforcement contingency.
Monosialogangliosides (GM1 and AGF2) reduce acute ethanol intoxication: Sleep time mortality, and cerebral cortical Na+, K+‐ATPase
Authors: Hungund Basalingappa L. , Reddy Mary V. , Bharucha Vandana A. , Mahadik Sahebarao P.
Published: January 2005

Ganglioside pretreatment of mice reduced the sleep time, mortality, and loss of cerebral cortical membrane Na+, K+ ‐ATPase associated with acute ethanol treatment. Gangliosides GM1 and AGF2 (an internal ester of GM1) were optimally effective at a dose of 20 mg/kg when injected 24 hr and 1 hr prior to ethanol injection (3 mg/kg). Blood ethanol levels were slightly lower in GM1‐ and AGF2‐pretreated mice than in the saline‐ethanol group. The sleep times of GM1‐ and AGF2‐injected mice were 32 ± 10 min and 34 ± 12 min respectively vs. 58 ± 15 min for saline‐ethanol‐treated animals. Mortality was 64% and 34% in animals pretreated with GM1 or AGF2 and ethanol, respectively, while in animals treated with saline and ethanol the mortality was 80%. No decrease in crotical membrane Na+, K+ ‐ATPase was seen at 15 min or 40 min after ethanol administration in animals pretreated with AGF2. The decrease in cortical membrane ATPase from GM1‐treated animals was similar to losses in saline‐ethanol‐treated animals (25% after 15 min and 40% min). Pretreatment with either AG4 (asialo GM1) or sialic acid did not affect any of the parameteres tested.
Neuroleptics produce within‐session response decrements: Facts and theories
Authors: Fowler Stephen C.
Published: January 2005

Acute neuroleptic administration results in within‐session decrements for conditioned active avoidance, discriminated lever release (reaction time), fixed‐ratio responding, lever pressing for intracranial electrical stimulation, licking, runway running, and treadmill running. Similarly, catalepsy has been shown to be increased by repeated testing. This paper briefly reviews these findings and reports new results on the effects of haloperidol on the micro‐characteristics of rats' operant behavior maintained by fixed‐ratio 20 food reinforcement. With these methods, within‐session decrements were seen to be produced by abrupt cessation of responding and by response slowing that was evident from the first few responses in the session. It is argued that within‐session decrements can be viewed as manifestations of neuroleptic‐induced pseudoparkinsonism in the rat and that dynamic neurochemical changes in the nigrostriatal dopamine system mediate the behavioral changes.
Drug discrimination and drug stimulus generalization with anxiolytics
Authors: Ator Nancy A.
Published: January 2005

Work with lorazepam in two‐lever food‐maintained drug discrimination procedures with baboons and rats found greater specificity in the generalization profile when this drug was used as a training drug compared to studies with other benzodiazepines (BZ). That is, animals trained to discriminate lorazepam have not reliably made the drug response in tests with barbiturates, although animals trained to discriminate diazepam, chlordiazepoxide, triazolam, oxazepam, and sometimes midazolam commonly have done so. Characterization of the discriminative stimulus effects of lorazepam has included manipulation of species, training dose, and route of administration; drug interaction studies; and tests with a variety of anxiolytics. The time course of the discriminative stimulus effects of lorazepam and other drugs also has been studied using a multiple session procedure in baboons. Some of these results have provided information relevant to the extent to which intermediate levels of the drug response in test sessions at doses that do not reduce response rates may meaningfully reflect threshold or partial drug stimulus effects.
Stimulus functions of drugs and the assessment of abuse liability
Authors: Brady Joseph V. , Hienz Robert D. , Ator Nancy A.
Published: January 2005

The development of a unifying framework for conceptualizing the commonalities in various forms of substance abuse must encompass the data base focused upon the stimulus functions of drugs. In the first instance, for example, the research on drug self‐administration has provided convincing evidence of a remarkable concordance between laboratory animals and human substance abusers in the reinforcing stimulus functions of a range of chemical agents. The recognition of these cross‐species and cross‐drug generalities has radically changed conceptualizations of substance abuse from a reactive to a more active process and has encouraged the kind of functional analysis of drug‐seeking and drug‐taking that has proven productive and useful in the study of other behavioral interactions. In this regard as well, recent refinements in the analysis of the discriminative stimulus functions of drugs have provided a more comprehensive basis for characterizing a chemical agent's spectrum of action and evaluating its abuse liability. While the correlation between the discriminative stimulus functions and the reinforcing stimulus functions is remarkably high for some drug classes, there are notable exceptions. Finally, the assessment of abuse liability requires an analysis of the eliciting stimulus functions of drugs as reflected by the physiological and behavioral changes, both acute and chronic, that follow drug administration. The methods used to evaluate both physiological dependence and behavioral toxicity in relationship to sensory and motor effects for a range of abused drugs have depended heavily upon an assessment of the eliciting stimulus functions of such compounds.
Growth factors in the aqueous humor and their therapeutic implications in glaucoma and anterior segment disorders of the human eye
Authors: Tripathi Ramesh C. , Borisuth Navaneet S. C. , Tripathi Brenda J.
Published: January 2005

The presence of growth‐promoting substances in the aqueous humor has been suspected for the past decade, but it has been only during the last 2 years that the existence of growth factors such as basic fibroblast growth factor, epidermal growth factor, transforming growth factorp, transferrin, and insulin‐like growth factors in the aqueous humor has been demonstrated. The structures that border the anterior and posterior chambers of the eye syn‐ thesize some of these growth factors and release them into the aqueous humor. A breakdown of the blood‐aqueous‐barrier increases the amounts of growth factors and may also bring platelet‐derived growth factor, nerve growth factor, and interleukin‐6 into the aqueous humor. Growth factors maintain the normal function of ocular tissues in health and have a significant role in the pathogenesis and possible management of several disorders of the eye. The outcome of the pathogenetic process and its modulation are determined by a complex coordination and interactions of the growth factors in the aqueous humor and their eventual effect on the target tissues. We discuss the therapeutic implications of growth factors and their antagonists in the treatment of certain disorders of the anterior segment of the eye, including rubeosis iridis, neovascular glaucoma, primary open‐angle glaucoma, sand wound after filtration Surgery.
Topical capsaicin in the treatment of cutaneous disorders
Authors: Carter Richard B.
Published: January 2005

Capsaicin, the primary pungent principle in hot peppers, produces marked alterations in the function of unmyelinated sensory afferent fibers, which are believed to signal pain and to initiate inflammatory responses. Capsaicin first excites and then desensitizes these nerves to subsequent stimulation both by itself and by a variety of physiocochemical stimuli. Accordingly, capsaicin is finding increasing use as a topical therapy for a variety of cutaneous disorders that involve pain and inflammation. Although topical capsaicin has shown therapeutic potential, the utility of capsaicin appears to be limited at present primarily by its irritant properties and secondarily by less than optimal therapeutic response, perhaps resulting from insufficient drug delivery. A capsaicin analogue with diminished irritant properties that retained the critical pharmacologic activities might present a reasonable alternative.
Gastric antisecretory activity of an acid stable H+/K+ ATPase inhibitor, WY‐26,769
Authors: DiJoseph John F. , Palumbo George J. , Crossley Roger , Santilli Arthur A. , Nielsen Susan T.
Published: January 2005

WY‐26,769 (2‐3‐dihydro‐2‐(2‐pyridinyl) thiazolo‐[3,2‐a]benzimidazole) is a gastric antisecretory agent that acts by inhibiting the parietal cell proton pump. In vitro, WY‐26,769 was active against dbcAMP‐stimulated aminopyrine uptake in isolated parietal cells. Preincubating the drug with liver microsomal enzymes increased its potency 50 times, to an IC50 of 6.8 μM. Wy‐26,769 and its oxidative metabolite Wy‐26,876 each inhibited the H+/K+ ATPase (IC50 = 42 μM and 18 μM, respectively). In whole animal studies, Wy‐26,769 inhibited histaminestimulated gastric acid secretion (ID50 = 3 mg/kg) irrespective of whether Wy‐26,769 was administered orally or intravenously. Wy‐26,769 was not degraded in acid and also inhibited gastric acid secretion in the pylorus‐ligated rat. Wy‐26,769 was equiactive after oral or intravenous administration demonstrating that it is an acid stable proton pump inhibitor.
Biochemical, neurophysiological, and behavioral effects of Wy‐45,233 and other identified metabolites of the antidepressant venlafaxine
Authors: Muth Eric A. , Moyer John A. , Haskins J. Thomas , Andree Terrance H. , Husbands G. E. Morris
Published: January 2005

Seven metabolites of venlafaxine, identified in several species, were examined for CNS pharmacological activity in rodents. The O‐desmethyl compound Wy‐45,233, which is the major metabolite in man, had the greatest preclinical activity. This metabolite exhibited an antidepressant profile (monoamine uptake blockade, reversal of reserpine hypothermia, induction of pineal β‐adrenergic subsensitivity) comparable to the parent drug, venlafaxine. This compound also inhibited serotonergic and noradrenergic firing rates like the parent compound, but with less potency. The cyclohexyl ring‐hydroxylated metabolite Wy‐47,877 and the N‐desmethyl metabolite Wy‐45, 494 were also active in reserpine hypothermia, but Wy‐45,494 was a weaker inhibitor of serotonin uptake and both metabolites were weaker inhibitors of norepinephrine uptake than Wy‐45,233. None of the seven metabolites tested exhibited significated binding at dopamine‐2, muscarinic cholinergic, α‐1‐adrenergic, histamine‐1, or opiate (μ) receptors. These results suggest that Wy‐45,233, the O‐desmethyl metabolite of venlafaxine, is an active metabolite which retains the benign side‐effect profile of venlafaxine.
Preclinical anxiolytic versus antipsychotic profiles of the 5‐HT3 antagonists ondansetron, zacopride, 3α‐tropanyl‐1H‐indole‐3‐carboxylic acid ester, and 1αH, 3α, 5αH‐tropan‐3‐yl‐3,5‐dichlorobenzoate
Authors: Dunn Robert W. , Carlezon William A. , Corbett Roy
Published: January 2005

In preclinical studies, the behavioral effects of serotonin antagonists at 5‐HT3 receptor sites suggest potential efficacy in the treatment of anxiety and schizophrenia. The present study shows that 5‐HT3 antagonists were effective in disinhibiting behavior in non‐conditioned rodent models which elicit a behavioral state presumed to be analogous to anxiety, but were generally not effective in conditioned rodent anxiety models or in assays that are traditionally predictive of antipsychotic agents. Ondansetron (0.01–0.1 mg/kg), zacopride (0.1–1.0 mg/kg), ICS 205–930 (3α‐tropanyl‐1H‐indole‐3‐carboxylic acid ester; 0.5 and 1.0 mg/kg), and MDL 72222 (1αH, 3α, 5αH‐tropan‐3‐yl‐3,5‐dichlorobenzoate; 10.0 and 20.0 mg/kg) demonstrated anxiolytic effects in the social interaction and elevated plus maze procedures, while having little or no effect in a modified Cook and Davidson conflict procedure. Ondansetron, zacopride, and ICS 205–930 had no effect in neuroleptic screening procedures, such as the apomorphine climbing mouse assay (CMA), the pole climb avoidance (PCA) procedure, and the intracranial self‐stimulation of the medial forebrain bundle (ICSS‐MFB) assay. MDL 72222 had no effect on CMA but dose‐dependently antagonized PCA (ED50 = 10.9 mg/kg) and ICSS‐MFB (ED50 = 8.8 mg/kg). The results of the present study suggest that MDL 72222 possesses a profile of activity that is different from the other 5‐HT3 antagonists tested and that, in general, 5‐HT3 antagonists may prove to be efficacious in the treatment of certain forms of anxiety in man.
Long‐term follow‐up treatment with sabeluzole in elderly patients with pronounced memory problems of unknown origin
Authors: Clincke Gilbert , Tritsmans Luc , Peelmans Boudewijn
Published: January 2005

In an open follow‐up study, 31 elderly patients with real memory problems of unknown origin were treated for at least 10 months with sabeluzole 10 mg b.i.d. Not only were the same improvements seen as in the preceding double‐blind trial on the cued recall task (CRT) and the word fluency test (WF), but additionally, significantly better results were obtained for the selective reminding procedure after this long‐term treatment: all quantitative (total recall, long‐term storage [LTS], long‐term retrieval [LTR], consistent long‐term retrieval [cLTR]) and qualitative (LTR/total recall, cLTR/total recall) parameters improved in this task. The objective effects were again accompanied by a subjective improvement as reported by the patients and their physician.
U‐80816: A novel partial muscarinic agonist
Authors: Sethy Vimala H. , Francis Jonathan W. , Hyslop Deborah K. , Patrick Sage G. , Oien Timothy T. , Meyer Annette L. , Collins R. James , Russell Roland R. , Heier Richard F. , Hoffmann William E. , Piercey Montford F. , Nichols Nanette F. , Schreur Peggy J. D. , Moon Malcolm W.
Published: January 2005

U‐80816 (1‐(4‐(5‐methyl‐1H‐imidazol‐1‐yl)‐2‐butynyl)‐2‐pyrrolidinone is an acetylenic amine which has been investigated as a partial agonist of muscarinic receptors. In vitro U‐80816 inhibited binding of (3H)‐N‐methylscopolamine [(3H)‐NMS] and (methyl‐3H) oxotremorine‐M acetate [3H)‐Oxo‐M] to the cortical membrance preparation with Ki's of 75 and 3.24 nM, respectively. In the M1 cell line, U‐80816 increased phosphatidylinositol (Pl) hydrolysis. However, the maximum increase in the Pl hydrolysis was significantly (P < 0.01) less than oxotremorine and RS 86. Intraperitoneal administration of U‐80816 dose‐dependently increased striatal acetylcholine (ACh) concentration, and the effect was significant (P < 0.01) at 30 mg/kg. In the presence of hemicholinium‐3 (HC‐3), U‐80816 inhibited the release of (3H)‐ACh from hippocampal slices. On the other hand, in the presence of eserine, U‐80816 increased the release of (3H)‐ACh. In in vivo pharmacological tests, U‐80816 produced hypothermia and tremors in mice. This compound failed to produce lacrimation or salivation in mice when administered up to 100 mg/kg. U‐80816 antagonized oxotremorine‐induced salivation. It is bioavailable to the brain in a significant amount after oral administration and has a sufficiently long duration of action. The in vitro and in vivo pharmacological investigations indicate that U‐80816 is a partial agonist of muscarinic receptors.
Ritanserin, a new therapeutic approach for drug abuse. Part 1: Effects on alcohol
Authors: Meert Theo F. , Janssen Paul A. J.
Published: January 2005

After a period of forced exposure to alcohol, rats developed a preference for alcohol when given the choice to drink either an alcohol solution or water. The development of alcohol preference was dependent on the alcohol concentration but independent of the presence of an alcohol withdrawal phase. The highest alcohol consumption was found with a 3% solution. The serotonin 5‐HT2 antagonist ritanserin reduced alcohol intake and alcohol preference in a dose‐related manner. Changes in test procedures and injection schedules did not affect the effectiveness of ritanserin. The activity of ritanserin started at doses ≥0.04 mg/kg and in the active dose range ritanserin reduced alcohol intake by 46 to 67% and alcohol preference by 33 to 42%. At any time during treatment, the decrease in alcohol drinking was compensated by an increase in water consumption. As a consequence, total fluid intake remained constant. Body weight gain in ritanserin‐treated rats was not different from vehicle‐treated animals. Discontinuation of ritanserin treatment in animals with a very low alcohol intake during ritanserin treatment resulted within one week in a gradual increase in 3% alcohol solution drinking up to 50% of total intake. In rats with a high alcohol preference ritanserin initiated water drinking again. Additional experiments showed that ritanserin neither directly interacted with the discriminative stimulus properties of alcohol nor induced a direct alcohol aversion. The activity of ritanserin against alcohol is discussed in terms of a serotonin 5‐HT2 antagonism that reduces the need for alcohol after a chronic exposure to alcohol.
Binding and uptake studies with [3H]CP‐93, 129, a radiolabeled selective 5‐HT1B receptor ligand
Authors: Koe B. Kenneth , Lebel Lorraine A. , Fox Carol B. , Macor John E.
Published: January 2005

3‐(1,2,5,6‐Tetrahydro‐4‐pyridyl)‐5‐pyrrolo[3,2‐b]pyridone, CP‐93, 129, is a selective agonist ligand for 5‐HT1B receptors. High affinity binding sites of [3H]CP‐93, 129 were found in rat whole brain membranes, which showed KD and Bmax values similar to those for 5‐HT1B sites labeled by [3H]5‐HT. Uptake of [3H]CP‐93, 129 in crude rat synaptosomes was also observed, which was potently inhibited by 5‐HT uptake blockers and 5‐HT but not by desipramine (NE uptake blocker) or tametraline (NE and DA uptake blocker). Because of this sensitivity to 5‐HT uptake inhibitors and the structural similarity of CP‐93, 129 to serotonin, [3H]CP‐93, 129 uptake probably occurred in 5‐HT neurons.
Ganglioside modulation of CD4 does not block T‐helper cell function as compared to antagonism by anti‐CD4 antibody
Authors: Morrison William J. , Offner Halina , Vandenbark Arthur A.
Published: January 2005

Gangliosides (GM1) modulate CD4 from the surface of T‐helper lymphocytes and have been shown to block CD4‐mediated HIV‐1 infection in vitro. However, the effects of GM1 on CD4 are neutralized in the presence of serum. We sought to make a GM1 derivative which would resist serum neutralization and to determine whether modulation of CD4 by GM1 would affect T‐helper lymphocyte function. Study of GM1 and GM1‐derivatives in the presence of serum indicated that the active conformation involves intact sialic acid hydroxyl groups and intermolecular ganglioside interactions. All chemical modifications directed toward the sialic acid moiety reduced the ability of GM1 to modulate CD4. Elution profiles of GM1 in the presence and absence of albumin indicate that the active form of GM1 is represented by micelles that are disrupted by albumin. Function studies show that CD4 T‐helper cells made CD− by GM1 treatment continued to proliferate in culture and recognize antigen (Ag) through the T cell receptor (TcR). Moreover, T‐helper cell mediated inflammation assessed by Ag‐specific, delayed type hypersensitivity (DTH) was enhanced after passive transfer of GMl‐treated T‐helper cells to naive animals. In comparison, CD4 blockade by anti‐CD4 antibody decreased Ag‐stimulated T‐helper cell proliferation and DTH reactions. These results demonstrate that (1) CD4 modulation involves an active conformation that arises from sialic acid effector molecules organized by micellar GM1 conformations; and (2) the mechanism by which GM1 modulates CD4 is different from CD4 antagonism seen with anti‐CD4 antibody treatment. © 1992 Wiley‐Liss, Inc.
Ethopharmacological studies differentiate the effects of various serotonergic compounds on aggression in rats
Authors: Mos J. , Olivier B. , Tulp M. T. H. M.
Published: January 2005

A series of experiments was performed to investigate the effects on aggression of various drugs affecting serotonergic transmission in rats. Using ethologically derived behavioural categories, the behaviour of treated animals was described. Drug effects were observed in two aggression models: resident–intruder aggression (RI) in male rats, and maternal aggression in lactating females during the postpartum period (MA). The 5‐HT1A agonists, buspirone, iosapirone, and 8‐OH‐DPAT, decreased aggression in RI and MA but simultaneously led to a marked decrease in social interest and activity, indicative of a nonspecific anti‐aggressive profile. Nonselective 5‐HT agonists, such as RU 24969, eltoprazine (DU 28853), and TEMPP, reduced aggression quite specifically and did not decrease social interest or exploration, but sometimes even increased these behaviours. In RI and MA, the behavioural effects of these drugs were roughly similar. By contrast, MA was more sensitive to the treatment with the 5‐HT reuptake blocker fluvoxamine, which blocked RI aggression only nonspecifically at the highest dose. DOI, a 5‐HT2 and 5‐HT1C agonist, decreased aggressive behaviour and increased inactivity, without affecting social interest and exploration in RI as well as MA. This was, however, accompanied by “wet dog shaking,” characteristic of 5‐HT2‐receptor stimulation. The nonspecific 5‐HT agonist (and 5‐HT3 antagonist) quipazine also induced “wet dog shaking” at doses that suppressed aggression, social interest and exploration but increased inactive behaviours (sitting and lying). The discussion attempts to delineate a role for 5‐HT receptor subtype involvement in the modulation of aggression, with the restrictions we clearly face with regard to the lack of specific serotonergic agonists and antagonists for certain receptor subtypes. By and large, male and female rats react similarly to treatment with serotonergic drugs stressing the consistent role of 5‐HT in different forms of aggression. © 1992 wiley‐Liss, Inc.
Endothelin mechanisms in the central nervous system: A target for drug development
Authors: Gulati Anil , Srimal Rikhab C.
Published: January 2005

Endothelin (ET), a vasoconstrictor peptide, was isolated and characterized in 1988. Since then extensive studies have been done in different animal species to identify its receptors in central nervous system (CNS) and peripheral tissues. Three forms of ETs have been identified: ET‐1, ET‐2, and ET‐3. Their distribution pattern and pharmacological functions have been defined. ET‐1 and ET‐2 are mainly distributed in the CNS, including spinal cord and the peripheral tissues, while ET‐3 although present in other tissues is mainly concentrated in the pituitary. ET receptors have been found to be coupled to intracellular pathways involving stimulation of Ca++ fluxes, through phospholipase C and inhibition of adenyl cyclase. The literature concerning central actions of ET has been reviewed. The bulk of the evidence shows that it may be a regulator of regional cerebral blood flow, and a modulator of the release of posterior pituitary hormones (oxytocin and vasopressin). It may also regulate the release of prolactin, growth, thyroid stimulating, or luteinizing hormones. The regulatory role of ET on cardiovascular system can be exerted by central as well as peripheral actions. Besides direct regulation, ET modulates the release of endothelium derived relaxing factor/nitric oxide (EDRF/NO) and increases the sensitivity of peripheral α‐adreno‐ceptors. Thus ET appears to establish a balance between vasodilatation induced by EDRF/NO release and vasoconstriction due to increased sensitivity of vascular a‐adrenoceptors. The level of ET was found to be raised in several pathological conditions like subarachnoid hemorrhage, myocardial infarction, cardiogenic and septic shock, Raynaud's disease, and pulmonary hypertension. Its level was also raised in patients undergoing chronic hemodialysis. On the other hand, the level of ET was significantly lower in the cerebrospinal fluid (CSF) of patients of depression. The available data suggest that ET has a neuromodulatory role in the CNS and may be involved in the pathophysiological processes of several diseases. ET mechanisms in the CNS could provide potential targets for the development of newer drugs. © 1992 Wiley‐Liss, Inc.
Effects of serotonergic agonists on micturition and sexual function in the rat
Authors: Steers William D. , Albo Michael , van Asselt Els
Published: January 2005

Behavioral and electrophysiological methods were used to study the role of 5‐hydroxytryptamine (5‐HT) receptors on bladder and erectile function in the male rat. Postulated 5‐HT1A [p‐aminophenylethyl‐m‐trifluoromethylphenylpiperazine (PAPP), 5‐methoxydimethyltyramine (5‐MeODMT)] and 5‐HT1C/2 [MK212, m‐trifluoromethylphenylpiperazine (TFMPP)] agonists did not consistently alter sensitivity voiding frequency (VF) in awake rats or affect micturition threshold (0.4 vs. 0.3 cc) in anesthetized rats. The 5‐HT1B agonist Organon 6997 (ORG 6997) had no effect on pelvic nerve‐induced detrusor contraction or evoked responses in bladder nerves. 5‐HT1C/2 agonists abolished reflexly evoked bladder contractions by inhibiting efferent firing in the pelvic nerve. 5‐HT1C/2 agonists also produced penile erections (2–5/30 min) via firing in cavernous nerves mediated by preganglionics in the pelvic nerve. Neural activity in the cavernous nerves following administration of MK212 and TFMPP was abolished by the 5‐HT1C/2 antagonist mianserin. 5‐HT1A, 5‐HT1B, 5‐HT1C/2 agonists failed to influence synaptic transmission in the pelvic ganglion. These data support a functional diversity of 5‐HT receptor subtypes with selective excitation or inhibition of central autonomic pathways regulating pelvic visceral function. These observations suggest that 5‐HT1C/2 agonists could be clinically useful for managing impotence or urinary incontinence. © 1992 Wiley‐Liss, Inc.
Role of GABA during the multiple consolidation of memory
Authors: Brioni Jorge D.
Published: January 2005

Alzheimer's disease (AD) is the most common form of senile dementia and it is a neurodegenerative disorder associated with a progressive deterioration of memory and cognitive capacity. Although one of the most characteristic abnormalities in AD patients is the reduced cholinergic input to the cortex, AD is a disorder that affects different neuronal populations in the brain, including the GABAergic neurons. The data regarding the participation of the central GABAergic system on memory indicate that: (1) drugs that facilitate GABA‐A and GABA‐B neurotransmission impair memory in experimental animals and in humans; (2) drugs that reduce GABA‐A neurotransmission facilitate memory in rodents; (3) the facilitatory effect of thee drugs has not been corroborated at the clinical level, as they show a small therapeutic window, but new drugs are presently being evaluated in clinical studies; (4) the cognitive effects of the GABAergic agents are dose‐ and time‐related, and cannot be explained by state‐dependency; (5) the effects of the GABAergic antagonists are centrally mediated, as peripherally acting drugs are ineffective in memory tests; (6) GABA and endogenous benzodiazepines are released in different brain areas during learning of different tasks and after the induction of long‐term potentiation (LTP); (7) GABA‐A antagonists facilitate LTP while diazepam blocks LTP in hippocampal slices; and (8) the amygdala, the basal forebrain, the septo‐hippocampal pathway, the trisynaptic circuit and the entorhinal cortex are likely candidate regions for the central actions of GABAergic drugs. The consolidation process of memory storage can be presently envisioned as multiple consolidation process that takes place in different brain circuits and at different times after the learning experience. The anatomical evidence on the presence of GABAergic neurons in brain areas relevant to memory (and affected in Alzheimer's patients) like the cortex, amygdala, septum, hippocampus and NBM, together with the electrophysiological and biochemical changes induced by the learning experience, suggest that the GABAergic neurons can critically modulate the electrical activity of these brain areas during the “multiple consolidation” process of memory storage. © 1993 Wiley‐Liss, Inc. © 1993 Wiley‐Liss, Inc.
Cardiovascular and pharmacokinetic drug interactions between acute tirilazad mesylate and chronic nimodipine in conscious dogs
Authors: Humphrey Stephen J. , Weber Dennis J. , Smith Michael P. , Brown W. Patrick , Steenwyk Rick C. , Lund John E.
Published: January 2005

In support of prospective human tests, the cardiovascular, pharmacokinetic, and histopathologic drug interactions between the dihydropyridine calcium channel blocker nimodipine and the lipid peroxidase inhibitor tirilazad mesylate were examined in conscious beagle dogs. Chronic arterially cannulated dogs first received repeated oral doses of nimodipine (1 mg/kg q 4 h × 2 days) to establish its steady‐state pharmacokinetics prior to 30 min iv infusions of a citrate buffered vehicle (4 and 20 ml/kg) and tirilazad mesylate (6 and 30 mg/kg). Both vehicle and tirilazad infusions were very well tolerated in the placebo‐ and nimodipine‐pretreated dogs, and resulted in negligible changes in the plasma kinetics of the test agents. Nimodipine's phasic hypotensive response was largely unaffected by tirilazad, although its reflex tachycardia was moderately prolonged. Electrocardiographic and routine clinical parameters were within the range seen with the nimodipine plus citrate buffer combination. Plasma cholesterol, total lipids, and triglyceride levels increased slightly with tirilazad, independent of oral nimodipine therapy. Gross necropsy findings were limited to slight inflammatory liver changes in all dogs, which were attributed to the doses of heparin used to maintain catheter patency. This study demonstrates that in normal conscious dogs, standard and supratherapeutic iv doses of tirilazad mesylate can safely be combined with chronic oral nimodipine without untoward cardiovascular, pharmacokinetic, or histopathologic drug interactions. © 1993 Wiley‐Liss, Inc.