piperidines and Ataxia

Recent data demonstrated that activation of the muscarinic M

Topics: Allosteric Regulation; Amphetamine; Animals; Ataxia; Diarrhea; Dogs; Donepezil; Drug Design; Female; Humans; Indans; Isoindoles; Lactams; Male; Mice, Inbred C57BL; Microsomes, Liver; Oxazoles; Piperidines; Rats, Wistar; Receptor, Muscarinic M1; Scopolamine; Seizures; Structure-Activity Relationship; Sulfonamides; Thiadiazoles; Vomiting

N-methyl-D-asparate (NMDA)-mediated glutamatergic neurotransmission is strongly involved in the development of trauma-induced behavioral dysfunctions, and indirect evidence suggests that NR2B subunit-expressing NMDA receptors are primarily involved in this process. Earlier studies showed that NR2B blockers inhibit the acquisition of conditioned fear, a frequently used model of post-traumatic stress disorder, but their effects on the expression of conditioned fear was poorly studied. We investigated here the effects of the selective serotonin reuptake blocker, fluoxetine, the NMDA blocker, MK-801, and the NR2B subunit blocker, Ro25-6981 on the expression of conditioned fear. Rats received 10 foot shocks administered over 5 min and were tested 24 h later in the shocking context. Treatments were administered 1 h before testing. Shocks dramatically increased freezing and reduced exploration. MK-801 and Ro25-6981 significantly ameliorated both changes. The effects of fluoxetine were less pronounced. In the open field, MK-801 increased locomotion, ataxia, and stereotypy (effects typical of NMDA blockade). Neither fluoxetine nor Ro25-6981 affected locomotion in the open field. Thus, the NR2B-specific NMDA blockade preserved the beneficial effects of general NMDA antagonists on the expression of conditioned fear but did not produce the locomotor side-effects typical of the latter. These findings warrant further studies on the effects of NR2B antagonists in models of post-traumatic stress disorder.

Topics: Animals; Ataxia; Disease Models, Animal; Dizocilpine Maleate; Electroshock; Excitatory Amino Acid Antagonists; Exploratory Behavior; Fear; Fluoxetine; Freezing Reaction, Cataleptic; Locomotion; Male; Phenols; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Selective Serotonin Reuptake Inhibitors; Stereotypic Movement Disorder; Stress Disorders, Post-Traumatic

We investigated the effects of the centrally acting antitussives dextromethorphan and cloperastine on urinary bladder dysfunction 24 h after cerebral infarction in rats using the cystometry technique. First, cystometrography was performed in conscious male Sprague-Dawley rats. Cerebral infarction was then induced by occlusion of the left middle cerebral artery. Twenty-four hours after cerebral infarction, the effect of each drug on micturition disorder was estimated for 5 parameters: bladder capacity, maximum voiding pressure, micturition latency, flow rate, and urethral resistance. Cerebral infarction markedly reduced bladder capacity, micturition latency, and flow rate and increased urethral resistance. After cerebral infarction, intravenous dosing of saline had no effect on these parameters. Dextromethorphan (20 mg/kg) and cloperastine (2.5 and 5.0 mg/kg) at antitussive effective doses significantly increased bladder capacity and micturition latency. Unlike dextromethorphan, cloperastine ameliorated decreases in flow rate and increases in urethral resistance caused by cerebral infarction. These results suggest that cloperastine may have therapeutic value for the treatment of disorders of the micturition reflex associated with cerebral infarction, and that the drug may become a base compound from which to develop more active drugs for such disorders.

Topics: Animals; Antitussive Agents; Ataxia; Dextromethorphan; Diagnostic Techniques, Urological; Infarction, Middle Cerebral Artery; Male; Piperidines; Rats; Rats, Sprague-Dawley; Urinary Bladder; Urinary Bladder, Overactive; Urination

Melanin-concentrating hormone (MCH)1 receptors are widely expressed in limbic structures and cortex. Their inactivation is associated with anxiolytic and antidepressive properties but little information is available concerning cognition. This issue was addressed using the selective antagonists, SNAP-7941 and GW3430, in a social recognition paradigm in rats. The muscarinic blocker, scopolamine (1.25 mg/kg s.c.), reduced social recognition, an action dose-dependently blocked by SNAP-7941 and GW3430 (0.63-10.0 and 20.0-80.0 mg/kg i.p., respectively) which did not themselves display amnesic properties. Further, in a protocol where a spontaneous deficit was induced by a prolonged inter-session delay, SNAP-7941 and GW3430 dose-dependently enhanced social recognition. In dialysis studies, SNAP-7941 (0.63-40.0 mg/kg i.p.) and GW3430 (10.0-40.0 mg/kg i.p.) elevated extracellular levels of acetylcholine (ACh) in the frontal cortex (FCX) of freely moving rats. The SNAP-7941 effect was specific, as it did not increase levels of ACh in ventral and dorsal hippocampus: moreover, it did not modify levels of noradrenaline, dopamine, serotonin and glutamate in FCX. Active doses of SNAP-7941 and GW3430 corresponded to doses (2.5-40.0 and 10.0-80.0 mg/kg i.p., respectively) exerting anxiolytic properties in Vogel conflict and ultrasonic vocalization tests, and antidepressant actions in forced swim, isolation-induced aggression and marble-burying procedures. In contrast to SNAP-7941 and GW3430, the benzodiazepine, diazepam, decreased social recognition and dialysate levels of ACh, while the tricyclic, imipramine, reduced social recognition and failed to enhance cholinergic transmission. In conclusion, at anxiolytic and antidepressant doses, SNAP-7941 and GW3430 improve social recognition and elevate extracellular ACh levels in FCX. This profile differentiates MCH1 receptor antagonists from conventional anxiolytic and antidepressant agents.

Topics: Acetylcholine; Aggression; Animals; Anxiety; Ataxia; Brain Chemistry; Conflict, Psychological; Data Interpretation, Statistical; Depression; Diazepam; Hypnotics and Sedatives; Microdialysis; Motor Activity; Muscarinic Antagonists; Piperidines; Prefrontal Cortex; Pyrimidines; Rats; Rats, Wistar; Receptors, Somatostatin; Recognition, Psychology; Scopolamine; Social Behavior; Swimming

The authors present a case of a patient with dementia with mood symptoms and multiple neurological manifestations of fragile X-associated tremor/ataxia syndrome (FXTAS). Despite a gradually deteriorating neurological course, he was managed for 2 years with combination therapy of donepezil and venlafaxine, which resulted in improvement and relative stabilization of his psychiatric status. Psychiatrists are hereby alerted to the description of a novel dementia syndrome that may respond to pharmacological intervention commonly used for other dementias.

Topics: Aged; Antidepressive Agents, Second-Generation; Ataxia; Atrophy; Brain; Cyclohexanols; Dementia; Dominance, Cerebral; Donepezil; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genetic Carrier Screening; Humans; Image Processing, Computer-Assisted; Indans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Mood Disorders; Neurologic Examination; Neuropsychological Tests; Nootropic Agents; Piperidines; Tremor; Trinucleotide Repeats; Venlafaxine Hydrochloride

Forty captive wapiti (Cervus elaphus) and thirty-two bison (Bison bison bison) were tested in April and October 1988, respectively, for their response to the sedative R51163. Treatment animals were injected with either 0.1, 0.2, or 0.3 mg of R51163/kg and then observed for 72 hr. Behavior was significantly altered by the drug. Hyperactive, aggressive, and milling behavior was characteristic of treated wapiti and they were extremely dangerous and reared when hind quarters were touched. Although treated plains bison displayed some milling behavior, they were generally more calm than wapiti. There was a marked difference between sexes in plains bison for all behavioral categories. Male bison were more ataxic, often observed in sternal or lateral recumbency, less conscious, and were slower to respond than females or controls. Respiratory rate increased in treated wapiti and plains bison, and heart rates of treated wapiti increased. Because of the powerful sedative effect on large, male bison, R51163 may be useful for handling unmanageable or dangerous animals and warrants further studies.

Topics: Aggression; Animals; Ataxia; Behavior, Animal; Bison; Deer; Female; Gait; Handling, Psychological; Heart Rate; Hypnotics and Sedatives; Male; Motor Activity; Piperidines; Respiration; Salivation; Sex Characteristics; Species Specificity; Transportation

Aromatic and heterocyclic esters of 1-methyl-4-piperidinol and 1,4-dimethyl-4-piperidinol and aromatic esters of (dialkylamino)alkanols were prepared and evaluated for antiepileptic activity by the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (scMet) assays and for minimal central neurotoxicity by the rotorod ataxia test. The most potent compound, namely the 2-phenylbenzoate (57) of 3-(diethylamino)propanol, was slightly more potent than diphenylhydantoin in the MES assay, while the 2-phenylbenzoate (24) of 1-methyl-4-piperidinol and the 2-phenylbenzoate (56) of (diethylamino)ethanol displayed activity comparable to that of diphenylhydantoin. The 2-phenethylbenzoate ester (6) of 1-methyl-4-piperidinol exhibited one-third the activity of diphenylhydantoin. The 2,4,5-trimethylbenzoate 40 and 2,4,6-trimethylbenzoate 41 of 1-methyl-4-pieridinol were even less potent, but did display activity in the phenobarbital-methsuximide range. Certain compounds interact with sites associated with the GABA receptor-chloride channel complex, but their potencies as anticonvulsant agents do not correlate with interaction at sites on the channel complex. Certain analogues antagonize binding of a batrachotoxin analogue to sodium channel sites, a property indicative of local anesthetic activity. There are structural similarities between 2-phenylbenzoates 57, 56, and 24 and diphenylhydantoin, and the latter anticonvulsant also antagonizes binding of the batrachotoxin analogue.

Topics: Amino Alcohols; Animals; Anticonvulsants; Ataxia; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Diazepam; Electroshock; Esters; Muscimol; Pentylenetetrazole; Phenytoin; Piperidines; Rats; Receptors, GABA-A; Structure-Activity Relationship

Cows, ewes, and mares varied considerably in susceptibility to toxicoses from the oral administration of the piperidine alkaloid, coniine. Cows were most susceptible and ewes least. Only calves had teratogenic effects from maternal administration of coniine during gestation; lambs and foals were apparently resistant. Results suggest that the marked differences between cattle and sheep are probably not due to variation in gut absorption or rumen metabolism.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Alkaloids; Animals; Ataxia; Cattle; Cattle Diseases; Female; Horse Diseases; Horses; Piperidines; Plants, Toxic; Pregnancy; Sheep; Sheep Diseases

Topics: Ataxia; Humans; Male; Middle Aged; Perhexiline; Piperidines

Topics: Amphetamine; Analgesics; Anesthetics; Animals; Ataxia; Atropine; Azocines; Behavior, Animal; Cyclazocine; Levallorphan; Lysergic Acid Diethylamide; Male; Mescaline; Morphine; Motor Activity; Movement Disorders; Nalorphine; Narcotic Antagonists; Pentazocine; Phencyclidine; Piperidines; Psilocybin; Psychopharmacology; Rats