piperidines and Tourette-Syndrome

Serotonin uptake inhibitors (SUIs) have been established as the first-line pharmacotherapy of obsessive compulsive disorder (OCD). However, approximately one half of patients who receive an adequate trial with these agents remain clinically unchanged. The addition of drugs that enhance serotonin (5-HT) neurotransmission, such as lithium and buspirone, to ongoing treatment in SUI-refractory patients has generally proved to be an ineffective strategy. The addition of dopamine antagonists to the regimens of SUI-resistant patients appears to be a useful approach for OCD patients with a comorbid chronic tic disorder (e.g., Tourette's syndrome) and possibly for those with concurrent psychotic spectrum disorders. These drug response data suggest that both the 5-HT and dopamine systems may be involved in the treatment, and possibly the pathophysiology, of specific subtypes of OCD.

Topics: Adult; Antipsychotic Agents; Clinical Trials as Topic; Clomipramine; Clozapine; Dopamine Antagonists; Drug Therapy, Combination; Female; Fluvoxamine; Haloperidol; Humans; Isoxazoles; Male; Obsessive-Compulsive Disorder; Piperidines; Risperidone; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Tic Disorders; Tourette Syndrome

Topics: Adrenergic alpha-2 Receptor Agonists; Attention Deficit Disorder with Hyperactivity; Child; Comorbidity; Delayed-Action Preparations; Drug Therapy, Combination; Guanfacine; Humans; Male; Piperazines; Piperidines; Tourette Syndrome

Topics: Adolescent; Disorders of Excessive Somnolence; Histamine; Humans; Male; Piperidines; Receptors, Histamine H3; Synaptic Transmission; Tourette Syndrome

Topics: Adolescent; Cholinesterase Inhibitors; Donepezil; Electroencephalography; Female; Follow-Up Studies; Humans; Indans; Piperidines; Tourette Syndrome

We have previously reported that acute and chronic donepezil and nicotine administration significantly attenuate DOI-induced head twitch response (HTR) in mice. This behavior, primarily mediated by stimulation of 5-HT2A receptors, has been proposed to model tic symptoms seen in Tourette's syndrome (TS). Haloperidol, a drug widely used to treat symptoms of TS, has also been reported to reduce DOI-induced head shakes in rodents when administered acutely. These findings suggest an inhibitory interaction of these drugs with 5-HT2A receptors. To test this hypothesis, we evaluated the effects of chronic donepezil, nicotine and haloperidol on expression levels of 5-HT2A mRNA and 5-HT2A receptor density in select brain regions. Initially, we established a dose-response relationship for the acute and chronic haloperidol and DOI-induced HTR. Male ICR mice were treated twice daily with donepezil (0.1 mg/kg), nicotine (0.5 mg/kg), and once daily with haloperidol (0.4 mg/kg) for 14 days and were sacrificed 16-18 h after the last injection. These drug regimens were chosen because of their significant effects on DOI-induced HTR. Donepezil significantly increased 5-HT2A mRNA level, but not the receptor density in the striatum. In the midbrain, donepezil significantly decreased the receptor density without affecting the 5-HT2A mRNA level. In the frontal cortex, only haloperidol significantly reduced the 5-HT2A receptor density. The cortex was the only area where donepezil, nicotine and haloperidol significantly reduced the 5-HT2A receptor density. The results suggest that the anti-tic properties of donepezil, nicotine and haloperidol in this paradigm might be due to antagonism of cortical 5-HT2A receptors. Thus, further investigation of involvement of cortical 5-HT2A receptors in TS as well as evaluation of selective 5-HT2A receptor antagonists in this disorder is warranted.

Topics: Amphetamines; Animals; Behavior, Animal; Binding, Competitive; Cerebral Cortex; Corpus Striatum; Donepezil; Dose-Response Relationship, Drug; Frontal Lobe; Gene Expression; Haloperidol; Humans; Indans; Ketanserin; Male; Mesencephalon; Mice; Mice, Inbred ICR; Nicotine; Piperidines; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serotonin Antagonists; Tourette Syndrome

Tourette syndrome (TS) is a neurological disorder characterized by persistent motor and phonic tics. Administration of the selective 5-HT(2A/2C) agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induces head twitches in mice that have been proposed to model tics seen in TS. Previous studies have demonstrated that nicotine markedly attenuates DOI-induced head twitch response (HTR). This and the reports that nicotine may have clinical efficacy in reducing symptoms of TS suggest possible involvement of the nicotinic cholinergic system in this disorder. Donepezil is an acetylcholinesterase inhibitor approved for use in mild to moderate Alzheimer's disease. The purpose of this study was to investigate whether donepezil might also reduce DOI-induced HTR, and whether its combination with nicotine might result in an additive or synergistic effect. Moreover, to elucidate the possible role of nicotinic receptors in this paradigm, the effects of mecamylamine, a nicotinic antagonist, was also evaluated. Acute and chronic administration of donepezil (0.1 mg/kg) or nicotine (0.5 mg/kg base), significantly reduced DOI-induced HTR. No additive or synergistic effects of donepezil and nicotine were observed. Acute mecamylamine administration (0.5-5.0 mg/kg) dose-dependently inhibited DOI-induced HTR. None of the mecamylamine doses blocked the inhibitory effects of donepezil or nicotine on DOI-induced HTR. These results suggest that donepezil may have therapeutic potential in treating motor tic symptoms of TS. Moreover, the action of donepezil and nicotine may be mediated through the same mechanism.

Topics: Amphetamines; Animals; Donepezil; Drug Synergism; Head Movements; Indans; Male; Mecamylamine; Mice; Mice, Inbred ICR; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Nootropic Agents; Piperidines; Serotonin Receptor Agonists; Tics; Time Factors; Tourette Syndrome

Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Child; Comorbidity; Donepezil; Humans; Indans; Male; Nootropic Agents; Piperidines; Tourette Syndrome

Topics: Adult; Antipsychotic Agents; Comorbidity; Depressive Disorder; Drug Therapy, Combination; Fluoxetine; Humans; Isoxazoles; Male; Obsessive-Compulsive Disorder; Piperidines; Risperidone; Tourette Syndrome; Treatment Outcome

Topics: Antipsychotic Agents; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Tourette Syndrome

Topics: Adult; Antipsychotic Agents; Humans; Isoxazoles; Male; Piperidines; Risperidone; Severity of Illness Index; Tourette Syndrome

Topics: Adult; Antipsychotic Agents; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Isoxazoles; Male; Middle Aged; Neurologic Examination; Pilot Projects; Piperidines; Risperidone; Serotonin Antagonists; Tourette Syndrome

Topics: Child; Child, Preschool; Clonidine; Haloperidol; Humans; Penfluridol; Pimozide; Piperidines; Tourette Syndrome