tetragastrin and Disease-Models--Animal

Spinocerebellar ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia and neurodegeneration, often in cerebellar Purkinje neurons. A SCA1 mouse model, Pcp2-ATXN1[30Q]D776, has severe ataxia in absence of progressive Purkinje neuron degeneration and death. Previous RNA-seq analyses identify cerebellar upregulation of the peptide hormone cholecystokinin (Cck) in Pcp2-ATXN1[30Q]D776 mice. Importantly, absence of Cck1 receptor (Cck1R) in Pcp2-ATXN1[30Q]D776 mice confers a progressive disease with Purkinje neuron death. Administration of a Cck1R agonist, A71623, to Pcp2-ATXN1[30Q]D776;Cck

Topics: Animals; Ataxin-1; Atrophy; Behavior, Animal; Calbindins; Chemokines, CC; Cholecystokinin; Disease Models, Animal; Female; Genetic Predisposition to Disease; Guanine Nucleotide Exchange Factors; Male; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Nerve Degeneration; Neuropeptides; Purkinje Cells; Signal Transduction; Spinocerebellar Ataxias; Tetragastrin

Pain is associated with negative emotions such as anxiety, but the underlying neurocircuitry and modulators of the association of pain and anxiety remain unclear. The neuropeptide cholecystokinin (CCK) has both pronociceptive and anxiogenic properties, so we explored the role of CCK in anxiety and nociception in the central amygdala (CeA), a key area in control of emotions and descending pain pathways. Local infusion of CCK into the CeA of control rats increased anxiety, as measured in the light-dark box test, but had no effect on mechanical sensitivity. By contrast, intra-CeA CCK infusion 4 days after Complete Freund's Adjuvant (CFA) injection into the hindpaw resulted in analgesia, but also in loss of its anxiogenic capacity. Inflammatory conditions induced changes in the CeA CCK signaling system with an increase of CCK immunoreactivity and a decrease in CCK1, but not CCK2, receptor mRNA. In CFA rats, patch-clamp experiments revealed that CCK infusion increased CeA neuron excitability. It also partially blocked the discharge of wide dynamic range neurons in the dorsal spinal cord. These effects of CCK on CeA and spinal neurons in CFA rats were mimicked by the specific CCK2 receptor agonist, gastrin. This analgesic effect was likely mediated by identified CeA neurons projecting to the periaqueductal gray matter that express CCK receptors. Together, our data demonstrate that intra-CeA CCK infusion activated a descending CCK2 receptor-dependent pathway that inhibited spinal neuron discharge. Thus, persistent pain induces a functional switch to a newly identified analgesic capacity of CCK in the amygdala, indicating central emotion-related circuit controls pain transmission in spinal cord.

Topics: Amygdala; Animals; Cholecystokinin; Dark Adaptation; Disease Models, Animal; Exploratory Behavior; Freund's Adjuvant; Gastrins; Glutamate Decarboxylase; Inflammation; Male; Neurons; Nociception; Pain; Pain Threshold; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Signal Transduction; Sincalide; Tetragastrin

We investigated the involvement of neuropeptide Y (NPY) in the modulation of cholecystokinin-4 (CCK-4)-evoked anxiety and depression. Adult male mice were injected with vehicle, CCK-4, NPY, NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY or antagonist BIBP3226, via intracerebroventricular route, and subjected to social interaction or forced swim test (FST) for the evaluation of anxiety- and depression-like phenotypes, respectively. To assess the interactions between the two systems, if any, NPYergic agents were administered prior to CCK-4 and the animals were subjected to these behavioral tests. Treatment with CCK-4 or BIBP3226 dose-dependently reduced social interaction time, while NPY or [Leu(31), Pro(34)]-NPY produced opposite effect. CCK-4 treatment increased immobility time in FST. This effect was reversed by NPY and [Leu(31), Pro(34)]-NPY, although BIBP3226 per se did not alter the immobility time. In a combination study, the anxiogenic or depressive effects of CCK-4 were attenuated by NPY or [Leu(31), Pro(34)]-NPY and potentiated by BIBP3226. The brains of CCK-4 treated rats were processed for NPY immunohistochemistry. Following CCK-4 treatment, the nucleus accumbens shell (AcbSh), ventral part of lateral division of the bed nucleus of stria terminalis (BSTLV), hypothalamic paraventricular nucleus and locus coeruleus showed a reduction in NPY-immunoreactive fibers. Population of NPY-immunopositive cells was also decreased in the AcbSh, BSTLV, prefrontal cortex and hypothalamic arcuate nucleus (ARC). However, NPY-immunoreaction in the fibers of the ARC and cells of the central nucleus of amygdala was unchanged. We conclude that, inhibition of NPY signaling in the brain by CCK-4 might be causal to anxiety- and depression-like behaviors.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Arginine; Brain; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Immunohistochemistry; Male; Mice; Motor Activity; Neuropeptide Y; Neuropsychological Tests; Psychotropic Drugs; Receptors, Neuropeptide Y; Social Behavior; Swimming; Tetragastrin

This study investigated the roles of cholecystokinin (CCK)(A) and CCK(B) receptors on CCK-4-induced anxiety-like behaviors in mice through behavioral and neural evaluations. Anxiety-like behaviors in mice were induced by an intracerebroventricular (i.c.v.) administration of CCK-4, which can bind to both CCK(A) and CCK(B) receptors. The effects of CCK(A) and CCK(B) receptor antagonists (devazepide and CI-988, respectively) were examined using mouse anxiety tests (elevated-plus maze and light-dark box) and also by examining neuronal activities through EEG monitoring and c-Fos immunohistochemistry in the cortex and amygdala. CCK-4 (3 μg/kg of body weight i.c.v.) significantly induced mouse anxiety-like behaviors in the anxiety tests and also affected their EEG patterns with respect to pre-drug tracing, resulting in increase in spectral power in relative power distribution in the delta and theta bands (0.5-5 Hz frequency bands) and also in increase in c-Fos immunopositive neuron counts. These CCK-4 effects were completely suppressed by 1.0mg/kg CCK(B) receptor antagonist, CI-988, while the same amount of CCK(A) receptor antagonist, devazepide was partly able to suppress the same effects. These findings indicated that not only CCK(B) receptors but also CCK(A) receptors in the brain play important roles in regulating anxiety-like behaviors in mice. The present study also proposed a possibility that cortical EEG is useful for assessing anxiety.

Topics: Adaptation, Physiological; Analysis of Variance; Animals; Anxiety; Behavior, Animal; Brain; Brain Mapping; Brain Waves; Devazepide; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Gene Expression Regulation; Indoles; Injections, Intraventricular; Male; Maze Learning; Meglumine; Mice; Mice, Inbred C57BL; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Spectrum Analysis; Tetragastrin

The effects of GB-115 dipeptide, a retroanalog of endogenous CCK-4, on the behavioral indices in "elevated plus maze" (EPM) test and on the content of biogenic amines in the brain structures after discontinuation of a chronic administration of benzodiazepine (BZ) derivatives phenazepam (2.0 mg/kg, i.p.) and diazepam (4.0 mg/kg, i.p.) have been studied in outbred and inbred MR/MNRA rats. It is established that, in 24-48 h following BZ withdrawal, GB-115 dipeptide administered in doses of 0.1 and 0.5 mg/kg, i.p., produced an anxiolytic effect in all animals, which was manifested by increasing the stay time and number of entries in EPM. In the striatum of outbred rats, GB-115 increased DOPAC (+25%) and DA (+31.6%) levels that were decreased during diazepam withdrawal syndrome. The obtained results showed the GB-115 efficiency in attenuating the anxiety caused by BZ withdrawal.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Animals, Outbred Strains; Anti-Anxiety Agents; Anxiety Disorders; Behavior, Animal; Benzodiazepines; Brain Chemistry; Diazepam; Dipeptides; Disease Models, Animal; Dopamine; Exploratory Behavior; Male; Maze Learning; Rats; Substance Withdrawal Syndrome; Tetragastrin; Tranquilizing Agents

Cholecystokinin (CCK) has been implicated in anxiety disorders. The midbrain periaqueductal gray (PAG), which modulates anxiety and panic reactions, contains CCK-immunoreactive fibers and CCK(2) receptors. The present study investigated the involvement of CCK(2) receptors of the PAG dorsolateral subdivision (dlPAG) in the regulation of inhibitory avoidance and escape, two defensive behaviors that have been related in terms of psychopathology to generalized-anxiety and panic disorders, respectively. Male Wistar rats were microinjected in the dlPAG with the CCK(2) receptor agonist cholecystokinin-tetrapeptide (CCK-4; 0.08-0.32 nmol/0.2 microL), the CCK(2) receptor antagonist LY-225910 (0.05-0.20 nmol/0.2 microL) or LY-225910 prior to CCK-4. Inhibitory avoidance and escape behaviors were evaluated in the elevated T-maze. Whereas CCK-4 facilitated escape, indicating a panic-like action, LY-225910 had the opposite effect. Pretreatment with a non-effective dose of LY-225910 prevented the panic-eliciting action of CCK-4. Neither CCK-4 nor LY-225910 affected inhibitory avoidance acquisition. The present results substantiate the view that dlPAG CCK(2) receptors modulate panic-related behaviors.

Topics: Animals; Avoidance Learning; Behavior, Animal; Cholecystokinin; Disease Models, Animal; Exploratory Behavior; Fear; Male; Maze Learning; Motor Activity; Neural Pathways; Panic Disorder; Periaqueductal Gray; Quinazolines; Quinazolinones; Rats; Rats, Wistar; Receptor, Cholecystokinin B; Tetragastrin

This study investigated a role of cholecystokinin (CCK) in the anxiolytic-like action of morphine, an agonist of mu-opioid receptors, in the rat plus-maze model of anxiety. The acute administration of morphine (1 mg/kg) induced a significant increase of exploratory activity in the plus-maze, but did not affect the locomotor activity in the motility test. The higher dose of morphine (2.5 mg/kg) tended to decrease the locomotor activity and, therefore, did not cause the anxiolytic-like action in the plus-maze. The other drugs (naloxone, BOC-CCK-4, L-365,260) and their combinations with morphine (0.5-1 mg/kg) did not affect the locomotor activity of rats. The opioid antagonist naloxone itself (0.5 mg/kg) did not change the exploratory activity in the plus-maze, but potently antagonized the anxiolytic-like action of morphine (1 mg/kg). An agonist of CCK(B)receptors BOC-CCK-4 (1-50 microgram/kg) induced a dose-dependent anxiogenic-like action in the plus-maze. Nevertheless, only one dose of BOC-CCK-4 (10 microgram/kg) completely reversed the action of morphine. Also, one dose of CCK(B)receptor antagonist L-365,260 (10 microgram/kg) was effective to modify the behaviour of rats in the elevated plus-maze. Namely, this dose of L-365,260 increased the ratio between open and total arm entries, a behavioural measure believed to reflect the anxiolytic-like action in the elevated plus-maze. The combination of L-365,260 (100 microgram/kg) with the sub-effective dose of morphine (0.5 mg/kg) caused the anxiolytic-like action in the plus-maze not seen if the drugs were given alone. In conclusion, morphine induces a potent anxiolytic-like action in the elevated plus-maze and CCK is acting as an endogenous antagonist of this effect of morphine.

Topics: Analgesics, Opioid; Animals; Anti-Anxiety Agents; Anxiety; Benzodiazepinones; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Fear; Injections, Subcutaneous; Locomotion; Male; Maze Learning; Morphine; Naloxone; Narcotic Antagonists; Phenylurea Compounds; Rats; Rats, Wistar; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Tetragastrin

This study was conducted to determine what, if any, role L-NAME (inhibitor of nitric oxide synthase) plays in the behavioral effects induced by sulfated cholecystokinin octapeptide CCK-8) and cholecystokinin tetrapeptide (CCK-4) in adult male rats. The motility, stereotypy, anxiety, extinction of conditioned avoidance responses and recall of passive avoidance behavior were estimated. CCK-8 (but not CCK-4) injected intracerebroventricularly (icv) at the dose 0.1 nmole decreased of locomotor activity in the "open field" test. Administration of CCK-8 intensified stereotypy evoked by apomorphine (1 mg/kg, i.p.). The CCK-4 was ineffective in this test. Both, CCK-8 and CCK-4 did not make any significant differences in passive avoidance behavior. Examine the influence of CCK-8 and CCK-4 on the extinction of conditioned avoidance responses (CAR) proved that both peptide tended to facilitate extinction of CAR's. CCK-8 and CCK-4 induced anxiogenic-like effect in the elevated 'plus' maze behavior. Application of L-NAME alone (50 nmole,-icv) decreased of motility and stereotypy behavior in control rats. It was ineffective in a passive avoidance behavior and extinction of CAR's. In elevated 'plus' maze behavior injection of L-NAME, similarly to cholecystokinin, induced anxiogenic-like effect. L-NAME induced of motility decreases in the "open field" test were blocked by injection of CCK-8 and CCK-4. Our results indicate that observed behavioral activity of CCK-8 and CCK-4 (except of influence on motility) is probably independent of NO concentration in the brain.

Topics: Analysis of Variance; Animals; Behavior, Animal; Brain; Disease Models, Animal; Dopamine Agents; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar; Sincalide; Tetragastrin

This study investigated the interplay of cholecystokinin (CCK) and endogenous opioid peptides in the regulation of anxiety. The acute administration of non-selective CCK agonist caerulein (1 and 5 microg/kg) and a selective CCK(B) receptor agonist BOC-CCK-4 (1, 10 and 50 microg/kg) induced a dose-dependent anxiogenic-like action in the plus-maze model of anxiety. BOC-CCK-4 displayed a similar efficacy with caerulein, indicating that the described effect was mediated via CCK(B) receptor subtype. The opioid antagonist naloxone itself (0.5 mg/kg) did not change the exploratory activity of rats in the plus-maze. However, the combination of naloxone with the sub-effective doses of caerulein (1 microg/kg) and BOC-CCK-4 (1 microg/kg) induced a significant inhibition of exploratory behaviour in rats. Accordingly, CCK and endogenous opioid peptides have an antagonistic role in the exploratory model of anxiety in rats.

Topics: Animals; Anxiety; Ceruletide; Cholecystokinin; Disease Models, Animal; Drug Synergism; Exploratory Behavior; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Tetragastrin

Praomys (Mastomys) natalensis, an African rodent ranging in size between a mouse and a rat, is more susceptible to the induction of duodenal ulcers by constant infusion of exogenous histamine through an osmotic minipump implanted subcutaneously than other rodent species tested such as mouse, rat, or guinea-pig. By increasing the doses of infused histamine, there were increases in the incidence, intensity, and perforation rate of duodenal ulcers in Mastomys. The induction of duodenal ulcers in Mastomys by tetra- and pentagastrins was unsuccessful, probably because of the limited releasing capacity of the present minipump for use of these two peptides which were sparingly soluble in water. More soluble human synthetic gastrin I was approximately three to four times as potent as histamine for inducing duodenal ulcers in Mastomys. The susceptibility of Mastomys to the induction of duodenal ulcer by cysteamine appears to be comparable to that of rat. The complete suppression of histamine-induced duodenal ulcers of Mastomys was possible by repeated subcutaneous injections of cimetidine.

Topics: Animals; Cimetidine; Cysteamine; Disease Models, Animal; Duodenal Ulcer; Female; Gastrins; Guinea Pigs; Histamine; Male; Mice; Mice, Inbred DBA; Pentagastrin; Rats; Rodentia; Species Specificity; Tetragastrin