cholecystokinin and Amphetamine-Related-Disorders

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

Neuropeptide cholecystokinin (CCK) interacts with dopamine in the regulation of motor activity and motivations. Therefore, in CCK(2) receptor deficient mice the behavioural effects of repeated amphetamine administration and changes in dopamine-related gene expression were studied. Four-day amphetamine (1 mg/kg) treatment induced a significantly stronger motor sensitization in homozygous mice compared to their wild-type littermates. However, in the conditioned place preference test the action of amphetamine was more pronounced in wild-type animals. As opposed to wild-type mice, amphetamine (1-3 mg/kg) did not cause a significant conditioned place preference in homozygous mice. The expression of Tyhy gene was elevated in the mesolimbic structures and Drd2 gene was down-regulated in the mesencephalon of saline-treated homozygous mice in comparison with respective wild-type group. Four-day treatment with amphetamine induced a significant increase in the expression of Tyhy in the mesencephalon, striatum and mesolimbic structures of wild-type mice, whereas in homozygous mice a similar change was evident only in the mesencephalon. Also, the expression of Drd1 gene in the striatum and Drd2 gene in the mesolimbic structures of wild-type mice were up-regulated under the influence of amphetamine. In conclusion, the present study established differences in the behavioural effects of amphetamine in wild-type and homozygous mice. The increased tone of dopaminergic projections from the mesencephalon to mesolimbic structures is probably related to increased amphetamine-induced motor sensitization in homozygous mice. The lack of development of up-regulation of Drd1 and Drd2 genes after repeated treatment with amphetamine probably explains the reduced place conditioning in CCK(2) receptor deficient mice.

Topics: Amphetamine; Amphetamine-Related Disorders; Animals; Behavior, Animal; Brain; Cholecystokinin; Conditioning, Psychological; Disease Models, Animal; Dopamine; Dopamine Uptake Inhibitors; Gene Expression Regulation; Homozygote; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Pathways; Nucleus Accumbens; Receptor, Cholecystokinin B; Receptors, Dopamine; Tyrosine 3-Monooxygenase; Up-Regulation; Ventral Tegmental Area