sincalide and Dyskinesia--Drug-Induced

We investigated whether pretreatment with the neuropeptide cholecystokinin-8 affected methamphetamine (METH)-induced behavioral changes and dopaminergic neurodegeneration in male C57/BL6 mice. CCK-8 pretreatment alone had no effect on locomotion and stereotypic behavior and could not induce behavioral sensitization; however, it attenuated, in a dose-dependent manner, hyperlocomotion and behavioral sensitization induced by a low dose of METH (1mg/kg). CCK-8 attenuated METH-induced stereotypic behavior at a dose of 3mg/kg but not at 10mg/kg. CCK-8 pretreatment attenuated METH (10mg/kg)-induced hyperthermia, the decrease of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum, and TH in the substantia nigra. CCK-8 alone had no effect on rectal temperature, TH and DAT expression in the nigrostriatal region. In conclusion, our study demonstrated that pretreatment with CCK-8 inhibited changes typically induced by repeated exposure to METH, such as hyperlocomotion, behavioral sensitization, stereotypic behavior, and dopaminergic neurotoxicity. These findings make CCK-8 a potential therapeutic agent for the treatment of multiple symptoms associated with METH abuse.

Topics: Amphetamine-Related Disorders; Animals; Body Temperature; Cholecystokinin; Corpus Striatum; Dopamine Agents; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Male; Methamphetamine; Mice, Inbred C57BL; Motor Activity; Neurodegenerative Diseases; Neuroprotective Agents; Peptide Fragments; Random Allocation; Stereotyped Behavior; Substantia Nigra; Tyrosine 3-Monooxygenase

To clarify the role of neuropeptides in dyskinesia induced by iminodipropionitrile (IDPN), the levels of five representative neuropeptides were examined in discrete regions of the rat brain 4 weeks after intraperitoneal injection of IDPN. The five neuropeptides examined were methionine-enkephalin (Met-Enk), substance P (SP) and somatostatin, which are closely related to extrapyramidal function, and thyrotropin-releasing hormone (TRH) and cholecystokinin octapeptide (CCK-8), which are closely related to the neural mechanism of the dopamine system. IDPN pretreatment significantly increased Met-Enk in the basal ganglia but not SP or somatostatin; however, all three neuropeptide levels were increased in the hindbrain. In IDPN-treated rats, TRH and CCK-8 levels were increased in the nucleus accumbens, and the frontal cortical CCK-8 level was extremely increased. These findings, together with previous reports, suggest that neuropeptides in the basal ganglia, hindbrain and cerebral cortex play important roles in the manifestation of dyskinetic symptoms.

Topics: Animals; Brain; Catecholamines; Dyskinesia, Drug-Induced; Enkephalin, Methionine; Neuropeptides; Nitriles; Rats; Sincalide; Somatostatin; Substance P; Thyrotropin-Releasing Hormone

We have previously demonstrated that intraperitoneal cholecystokinin (CCK-8S) suppresses the vacuous chewing mouth movements (VCM's) elicited by chronic neuroleptic administration in the rat, a possible model of tardive dyskinesia (TD) in humans. The studies described here were undertaken in order to better determine whether this effect is mediated centrally or peripherally. In the first set of experiments, CCK-8S (10, 30 or 50 ng, i.c.v.) was found to have no effect on VCM's elicited by 20 weeks treatment with fluphenazine decanoate (25 mg/kg, i.m., every 3 weeks). A second set of experiments was then performed to determine if the previously observed effects of intraperitoneal CCK-8S were vagally mediated. As previously described, CCK-8S (10, 30 or 60 micrograms/kg, i.p.) suppressed neuroleptic-induced VCM's in sham-operated animals without affecting the baseline VCM rate. Bilateral subdiaphragmatic vagotomy alone unexpectedly suppressed neuroleptic-induced VCM's to control levels and CCK-8S had no further effect. Vagotomy also prevented the suppressive effects of peripherally administered CCK-8S on rearing and grooming. We conclude that neuroleptic-induced VCM's may depend upon tonic activity in the vagus nerve and/or its central projections and that the effects of CCK-8S on this behavioural response are likely to be peripherally mediated.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Dyskinesia, Drug-Induced; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mastication; Rats; Rats, Sprague-Dawley; Sincalide; Vagotomy; Vagus Nerve

Systemic administration of CCK-8S (1 or 10 micrograms/kg IP) markedly inhibited L-dopa-induced dyskinesias in parkinsonian monkeys, but did not interfere with locomotor stimulation by L-dopa. CCK analogues may be useful antidyskinetic agents for improved control of Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Dyskinesia, Drug-Induced; Levodopa; Parkinson Disease, Secondary; Saimiri; Sincalide