cholecystokinin and Seizures

Topics: Animals; Cholecystokinin; Dynorphins; Endorphins; Enkephalins; Hippocampus; Neuropeptides; Protein Precursors; RNA, Messenger; Seizures

Topics: Animals; Anticonvulsants; Cholecystokinin; Epilepsy; Humans; Seizures

A significant proportion of temporal lobe epilepsy (TLE) patients experience drug-resistant seizures associated with mesial temporal sclerosis, in which there is extensive cell loss in the hippocampal CA1 and CA3 subfields, with a relative sparing of dentate gyrus granule cells and CA2 pyramidal neurons (PNs). A role for CA2 in seizure generation was suggested based on findings of a reduction in CA2 synaptic inhibition (Williamson and Spencer, 1994) and the presence of interictal-like spike activity in CA2 in resected hippocampal tissue from TLE patients (Wittner et al., 2009). We recently found that in the pilocarpine-induced status epilepticus (PILO-SE) mouse model of TLE there was an increase in CA2 intrinsic excitability associated with a loss of CA2 synaptic inhibition. Furthermore, chemogenetic silencing of CA2 significantly reduced seizure frequency, consistent with a role of CA2 in promoting seizure generation and/or propagation (Whitebirch et al., 2022). In the present study, we explored the cellular basis of this inhibitory deficit using immunohistochemical and electrophysiological approaches in PILO-SE male and female mice. We report a widespread decrease in the density of pro-cholecystokinin-immunopositive (CCK

Topics: Animals; CA2 Region, Hippocampal; Cholecystokinin; Disease Models, Animal; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; Interneurons; Male; Mice; Pilocarpine; Seizures; Status Epilepticus

To evaluate the changes in serum CCK-8 and leptin levels in patients with refractory epilepsy treated with the ketogenic diet (KD).. In this prospective study, patients aged between one and 40 years with refractory epilepsy were included. CCK-8 and leptin were measured in serum at baseline and after three and 12 months of treatment with the KD using an enzyme-linked Immunoabsorbant Assay. Seizure frequency and responsiveness were calculated.. Fifty-four patients were included; 26 patients (48%) were still on the KD at 12 months. After three and 12 months, respectively, 39% and 26% were responders. CCK-8 values were statistically significantly increased at three months (p=0.005) and 12 months (p=0.012). In responders, at three months follow-up, this increase of CCK-8 was significant (p=0.020), whereas in the non-responders it was not (p=0.34). Leptin values were decreased at three and 12 months, the decrease at three months being statistically significant in post-pubertal men (p=0.028) and post-pubertal women (p=0.007).. In responders to the KD, serum CCK-8 increased statistically significantly during treatment at three months. Serum leptin decreased statistically significantly at three months in men and in post-pubertal women. It is plausible that the increase of CCK-8 and the decrease of leptin contribute to the anti-convulsive effect of the KD.

Topics: Adolescent; Adult; Biomarkers; Child; Child, Preschool; Cholecystokinin; Diet, Ketogenic; Drug Resistant Epilepsy; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Humans; Infant; Leptin; Male; Peptide Fragments; Prospective Studies; Seizures; Time Factors; Treatment Outcome; Young Adult

Structures within the piriform cortex (PC) including the endopiriform nucleus (DEN) and pre-endopiriform nucleus (pEn) have been implicated to be involved in seizure genesis in models of temporal lobe epilepsy. We used stereological methods to examine the specificity and extent of neuron loss in the PC of pilocarpine-treated rats. Both 7 days and 2 months post-status epilepticus rats showed significant neuron loss in the pEn and DEN, layer III of the intermediate PC, and layers II and III of the caudal PC. Total losses in the PC were 40 and 46% in 7 days and 2 months post-status epilepticus rats, respectively (p<0.01). The numbers of parvalbumin (PV)- and cholecystokinin (CCK)-immunopositive neuron profiles significantly decreased, and somatostatin (SS)-immunopositive neuron profiles tended to decrease. A large decrease in the number of PV-immunopositive neuron profiles occurred in the pEn, adjoining parts of the DEN and deep layer III of the PC, portions of the DEN bordering the claustrum and agranular insular cortex, and layer III of the caudal PC. The regions with decreased numbers of PV-, CCK-, and SS-immunopositive neuron profiles overlapped with those where many Nissl-stained neurons were lost and many degenerating cell bodies were detected. These results suggest that the decreases in the numbers of PV/SS/CCK-immunopositive neurons are related to neuron loss rather than to a low rate of synthesis of their peptides or proteins.

Topics: Animals; Cell Death; Cerebral Cortex; Cholecystokinin; Disease Models, Animal; Immunohistochemistry; Male; Neurons; Nissl Bodies; Parvalbumins; Pilocarpine; Rats; Rats, Sprague-Dawley; Seizures; Somatostatin; Status Epilepticus

Repeated brief seizures evoked by kindling progressively increase seizure susceptibility and eventually induce spontaneous seizures. Previous studies have demonstrated that the initial seizures evoked by kindling increase paired-pulse inhibition at 15-25 msec interpulse intervals in the dentate gyrus and also induce apoptosis, progressive neuronal loss, mossy fiber sprouting, and neurogenesis, which could potentially alter the balance of excitation and/or inhibition and modify functional properties of hippocampal circuits. In these experiments, paired-pulse inhibition in the dentate gyrus was reduced or lost after approximately 90-100 evoked seizures in association with emergence of spontaneous seizures. Evoked IPSCs examined by single electrode voltage-clamp methods in granule cells from kindled rats experiencing spontaneous seizures demonstrated altered kinetics (reductions of approximately 48% in 10-90% decay time, approximately 40% in tau, and approximately 65% in charge transfer) and confirmed that decreased inhibition contributed to the reduced paired-pulse inhibition. The loss of inhibition was accompanied by loss of subclasses of inhibitory interneurons labeled by cholecystokinin and the neuronal GABA transporter GAT-1, which project axo-somatic and axo-axonic GABAergic inhibitory terminals to granule cells and axon initial segments. Seizure-induced loss of interneurons providing axo-somatic and axo-axonic inhibition may regulate spike output to pyramidal neurons in CA3 and could play an important role in generation of spontaneous seizures. The sequence of progressive cellular alterations induced by repeated seizures, particularly loss of GABAergic interneurons providing axo-somatic and axo-axonic inhibition, may be important in the development of intractable epilepsy.

Topics: Animals; Axons; Carrier Proteins; Cells, Cultured; Cholecystokinin; Dentate Gyrus; Epilepsy; Evoked Potentials; GABA Plasma Membrane Transport Proteins; Humans; Interneurons; Kindling, Neurologic; Kinetics; Male; Membrane Proteins; Membrane Transport Proteins; Neural Inhibition; Organic Anion Transporters; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Seizures

Generalized tonic-clonic seizures of brain stem origin in rats are associated with acute induction of neuronal Fos in several discrete regions of the brain. One particular site in the dorsal pons shows remarkable Fos induction following generalized tonic seizures induced by maximal electroshock in normal rats or by audiogenic stimulation in genetically epilepsy-prone rats (GEPRs). Although this area shows the most intense Fos induction of any brain area following generalized tonic seizures, its identity has been uncertain. Based on its general location, we hypothesized that this nucleus was either 1) a component of the pedunculopontine tegmentum nucleus-pars compacta (PPTn-pc) or 2) the superior lateral subnucleus of lateral parabrachial area (LPBsl). The present study used Fos-protein immunocytochemistry in combination with the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry, cholecystokinin (CCK) immunocytochemistry, and neuronal tract-tracing to determine the identity of this cluster of Fos-immunoreactive neurons in the dorsal pons. Following maximal electroshock seizure (MES), Fos labeling was compared to NADPH diaphorase staining (a marker for cholinergic neurons of the PPTn-pc); retrograde transport of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) injected into the ventromedial nucleus of the hypothalamus (VMH; to identify the LPBsl) or CCK immunoreactivity (also a marker for LPBsl neurons). Results showed this cluster of Fos immunoreactive (FI) neurons to be closely associated, but not overlapping, with the lateral and most caudal aspect of the PPTn-pc. Alternatively, WGA-HRP retrograde-labeled neurons corresponded precisely with the seizure-induced FI neurons. Additionally, the location of CCK immunoreactive neurons directly overlapped with the FI neurons, although they were not nearly as prevalent. These results demonstrate that the seizure-induced FI neurons in this area are neurons of the LPBsl and not cholinergic neurons of the PPTn-pc. This is the first report of seizure-induced Fos expression specifically localized to the superior lateral subnucleus of the lateral parabrachial area.

Topics: Animals; Cholecystokinin; Electroshock; Female; Histocytochemistry; Immunohistochemistry; Molecular Probes; NADPH Dehydrogenase; Neurons; Pons; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Seizures; Wheat Germ Agglutinin-Horseradish Peroxidase Conjugate

Using the P77PMC strain of rat, which is genetically prone to audiogenic seizures, and also has decreased levels of cholecystokinin (CCK), we examined the analgesic response to peripheral electrical stimulation, which is, in part, opiate-mediated. A number of studies have suggested that CCK may function as an antagonist to endogenous opiate effects. Therefore, we hypothesized that the P77PMC animals would show an enhanced analgesic response based on their decreased CCK levels producing a diminished endogenous opiate antagonism. We found that the analgesic effect on tail flick latency produced by 100 Hz peripheral electrical stimulation was more potent and longer lasting in P77PMC rats than in control rats. Moreover, the potency of the stimulation-produced analgesia correlated with the vulnerability to audiogenic seizures in these rats. We were able to block the peripheral electrical stimulation-induced analgesia (PSIA) using a cholecystokinin octapeptide (CCK-8) administered parenterally. Radioimmunoassay showed that the content of CCK-8 in cerebral cortex, hippocampus and periaqueductal gray was much lower in P77PMC rat than in controls. These results suggest that low CCK-8 content in the central nervous system of the P77PMC rats may be related to the high analgesic response to peripheral electrical stimulation, and further support the notion that CCK may be endogenous opiate antagonist.

Topics: Acoustic Stimulation; Acupuncture Analgesia; Animals; Brain Chemistry; Cholecystokinin; Electric Stimulation; Female; Male; Pain Measurement; Peripheral Nerves; Radioimmunoassay; Rats; Rats, Inbred Strains; Rats, Wistar; Seizures

Kindling, a model of temporal lobe epilepsy, induces a number of neuropeptides including corticotropin-releasing factor (CRF). CRF itself can produce limbic seizures which resemble kindling in some aspects. However, tolerance to the convulsant effects of CRF develops rapidly. Hypothetically, this could be explained should seizures also induce the CRF-binding protein (CRF-BP), which has been postulated to restrict the actions of CRF. Therefore, in the present study, we used in situ hybridization to examine the effects of amygdala-kindled seizures on the mRNA levels of CRF and CRF-BP. Kindled seizures markedly elevated CRF and CRF-BP in the dentate gyrus of rats. CRF and CRF-BP were induced almost exclusively in GABAergic interneurons of the dentate hilus. The CRF and CRF-BP interneurons also expressed neuropeptide Y but not cholecystokinin. CRF appeared to have an excitatory role in the dentate gyrus as it decreased the afterhyperpolarization of dentate granule neurons. These results suggest that CRF may contribute to the development of amygdala kindling. However, the compensatory induction of CRF-BP may serve to limit the excitatory effects of CRF in the dentate gyrus.

Topics: Amygdala; Animals; Carrier Proteins; Cholecystokinin; Corticotropin-Releasing Hormone; Electrophysiology; gamma-Aminobutyric Acid; Hippocampus; In Situ Hybridization; In Vitro Techniques; Interneurons; Kindling, Neurologic; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Seizures; Sheep

Cholecystokinin (CCK) can be a potent anticonvulsant neuropeptide in certain seizure models. Therefore, we examined whether seizures produced by electrical kindling of the amygdala or electroconvulsive seizures (ECS) would affect the expression of CCK mRNA in rat brain. Following a single kindled seizure, CCK mRNA expression was decreased about 20-58% in the amygdala. In contrast, after multiple consecutive kindled seizures, CCK mRNA expression was increased in the amygdala, cerebral cortex, CA1 pyramidal cell layer of the hippocampus and dentate hilus. A single ECS produced no effect on CCK mRNA expression, but multiple ECS increased expression in the interneurons of the hippocampus 24 h after the last seizure. Since seizures produced by ECS can be anticonvulsant to further ECS or kindled seizures, the CCK increases in the hippocampus may represent a compensatory anticonvulsant adaptation observed in both models. Overall, the kindling-induced alterations in CCK expression appear to be more complex involving multiple brain regions and distinct temporal properties.

Topics: Amygdala; Animals; Autoradiography; Cerebral Cortex; Cholecystokinin; Electroshock; Gene Expression; Hippocampus; In Situ Hybridization; Kindling, Neurologic; Kinetics; Male; Organ Specificity; Pyramidal Cells; Rats; Rats, Sprague-Dawley; RNA Probes; RNA, Messenger; Seizures; Sulfur Radioisotopes; Time Factors

Cholecystokinin-octapeptide (CCK-8S) is widely distributed in neurones of the central nervous system, where it is thought to act as a transmitter or modulator. CCK-8S has been shown to exert anti-convulsant activity in animal seizure models and changes in cortical and hippocampal CCK-immunoreactivity and preproCCK messenger RNA (mRNA) have been reported following electrically- and chemically-induced seizures. In the present study, the spatiotemporal effect of amygdaloid-kindled seizures on levels of preproCCK messenger RNA in rat brain were determined using quantitative in situ hybridization histochemistry. Stimulation-evoked seizures produced bilateral increases (45-70%) in preproCCK mRNA throughout layers II-III of the cerebral cortex. These increases were rapidly induced, occurring 30-60 min after the last stage 5 seizure, but transient, as no significant changes were detected after 2 h, or subsequently at 24 or 72 h, or 2-8 weeks, post-stimulation. Rapid changes in the relative levels of preproCCK mRNA, post-seizure, suggest a possible stabilization of preproCCK transcripts and increased production of CCK-8S peptide, which may be involved in anticonvulsant mechanisms in response to the acute seizures.

Topics: Amygdala; Animals; Brain; Cerebral Cortex; Cholecystokinin; Kindling, Neurologic; Kinetics; Male; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures; Sincalide; Time Factors; Transcription, Genetic

Recent studies have suggested that cholecystokinin may have a role in modulating the effects of the endogenous opioid system in physiological functions such as thermoregulation and pain control. However, the possible interaction of cholecystokinin and morphine in epileptogenesis is unknown. We studied the effect of subcutaneous morphine and intracerebroventricularly administered cholecystokinin octapeptide sulphate ester and receptor antagonists CCK-A (MK 329) and CCK-B (L 365,260) on seizures provoked by maximal electroshock in male Sprague-Dawley rats. Seizures were induced through electrode-gel-coated ear clip electrodes by a high voltage, high internal resistance constant current generator, 30 minutes after morphine administration and 10 minutes after cholecystokinin-8-SE, CCK-A and CCK-B infusion. Morphine decreased the length of the tonic component of the seizure and cholecystokinin potentiated this decrease. Cholecystokinin antagonists blocked the effects of both cholecystokinin and morphine. The results suggest that cholecystokinin acts as an endogenous agonist with opioids in the regulation of seizure susceptibility through both CCK-A and B receptors and may be responsible for part of the anticonvulsant action of morphine.

Topics: Animals; Benzodiazepinones; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Injections, Spinal; Male; Morphine; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Seizures; Shock

The release of cholecystokinin (CCK) in vitro has been shown to be influenced by NMDA receptors. In this study we have investigated whether excitotoxin-induced seizure activity affects the release and tissue content of CCK. Excitotoxin injection caused a significant decrease in CCK in ipsilateral frontal, parietal and temporal cortex by (30-54%) at 8 h compared to contralateral cortex and sham-operated controls and the effect was reversed by 24 h. No change was detected in occipital cortex, hippocampus and nucleus accumbens. The effect in frontal and temporal cortex was maximal at 8 h and could be completely prevented by treatment with MK-801(3 mg/kg i.p.). Anaesthesia (pentobarbital) alone or in combination with MK-801 did not affect peptide levels at 8 h. CCK mRNA levels were also studied quantitatively by slot-blot analysis but were unaffected at 6, 8 and 24 h after excitotoxin injection. The decrease in CCK tissue levels indicated that seizure activity stimulated CCK release which was confirmed in ex vivo experiments where K(+)-evoked (34 mM) CCK release was significantly enhanced in ipsilateral cerebral cortex at 6 h compared to contralateral cortex.

Topics: Animals; Cerebral Cortex; Cholecystokinin; Dizocilpine Maleate; Frontal Lobe; Hippocampus; Immunoblotting; Kainic Acid; Male; Nucleus Accumbens; Potassium; Radioimmunoassay; Rats; RNA, Messenger; Seizures; Temporal Bone

Topics: Animals; Anti-Anxiety Agents; Benzodiazepinones; Body Temperature; Cholecystokinin; Devazepide; Eating; Female; Hexachlorocyclohexane; Male; Rats; Receptors, Cholecystokinin; Seizures

A selective loss of somatostatin- and neuropeptide Y-immunoreactive neurons has been reported in the dentate gyrus of rats with cerebral ischemia, following sustained electric stimulation, and in patients with non-tumor-related temporal lobe epilepsy. Three theoretical possibilities were tested that may explain why these neurons are more vulnerable than others, such as the cholecystokinin- and calcium-binding protein-containing cells: (1) the seizure-sensitive neurons are more involved in specific excitatory circuitry than are the seizure-resistant cells; (2) the somatostatin- and neuropeptide Y-immunoreactive neurons are less protected by inhibitory GABAergic inputs than cells immunoreactive for cholecystokinin; and (3) the seizure-sensitive neurons do not contain calcium-binding proteins. The present results of light and electron microscopic, single and double, immunostaining experiments and co-localization studies performed on the hippocampal formations of rats and non-human primates, support the idea that the calcium-binding protein content of a neuron defines its seizure sensitivity.

Topics: Animals; Brain Mapping; Calcium-Binding Proteins; Chlorocebus aethiops; Cholecystokinin; Cytoplasmic Granules; Epilepsy, Temporal Lobe; Female; gamma-Aminobutyric Acid; Hippocampus; Male; Microscopy, Electron; Neural Inhibition; Neurons; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Rats, Wistar; Seizures; Somatostatin; Synapses; Synaptic Transmission

P77PMC rat is a breed of rat with congenital audiogenic seizure (AS). AS attacks could be suppressed by cholecystokinin octapeptide (CCK-8) injected intracerebroventricularly (i.c.v.). In the present study we made i.c.v. injection of plasmid pSV2-beta Gal or pSV2-CCK encapsulated with lipofectin. Expression of pSV2-beta Gal in brain occurred from d 1 to d 14, with maximal expression at d 3 and d 4. After i.c.v. injection of pSV2-CCK plasmid, the AS of the P77PMC rats was markedly reduced, which was most obvious at d 3 and d 4. The time course of the AS repression was almost identical with that of pSV2-beta Gal expression. The results suggest that the repression of the AS in P77PMC rats is accounted for by the expression of foreign CCK gene in brain tissue.

Topics: Acoustic Stimulation; Animals; beta-Galactosidase; Cerebral Ventricles; Cholecystokinin; DNA; Epilepsy; Genetic Therapy; Genetic Vectors; Plasmids; Rats; Rats, Mutant Strains; Recombinant Fusion Proteins; Seizures

Concentrations of preprosomatostatin-mRNA and preprocholecystokinin-mRNA were determined by Northern blot analysis in rats 2, 10, and 30 days after strong seizures induced by a single intraperitoneal injection of kainic acid. At all time intervals examined, levels of preprosomatostatin-mRNA were increased in the frontal cortex; so were levels of preprocholecystokinin-mRNA in the striatum. Transient increases, i.e., 2 days after kainic acid, of preprocholecystokinin-mRNA were observed in the frontal cortex and the substantia nigra. Preprocholecystokinin-mRNA was reduced in the hippocampus 2 and 10 days after kainic acid. Both preprosomatostatin- and preprocholecystokinin-mRNA levels showed a tendency to be reduced in the amygdala/pyriform cortex at all three time intervals. The increases in mRNA levels suggest enhanced rates of synthesis of the respective neuropeptides subsequent to kainic acid-induced seizures. They may also reflect a prolonged increase in the activity of the respective peptide-containing neurons. This is of special interest in the frontal cortex, since in this area both neuropeptides are found in interneurons and are widely colocalized with gamma-aminobutyric acid.

Topics: Animals; Cholecystokinin; Kainic Acid; Male; Protein Precursors; Rats; Rats, Inbred Strains; RNA, Messenger; Seizures; Somatostatin

Electrolytic lesions of the dentate gyrus hilus have been demonstrated to induce behavioral seizure activity and to result in perturbations in the amount of enkephalin, cholecystokinin, and dynorphin immunoreactivity in the hippocampal mossy fiber system. In the present study, electroencephalographic (EEG) recordings, made from hippocampus contralateral to a hilus lesion in mouse, demonstrate the presence of recurrent hippocampal seizure activity which begins approximately one hour postlesion and continues for several hours thereafter. Behavioral seizures were found to correspond to periods of epileptiform hippocampal EEG. Immunocytochemical analyses of enkephalin-(ENK-I) and cholecystokinin-immunoreactivity (CCK-I) in contralateral hippocampus of animals sacrificed at various postlesion intervals revealed that both ENK-I and CCK-I were depleted from the mossy fibers at 6 and 12 hr postlesion, and that ENK-I rebounded to supranormal levels by 27 hr. In two animals sacrificed 60 days following lesions which induced extreme behavioral seizure activity, ENK-I was still elevated while CCK-I was completely absent from the mossy fiber system. These data suggest that heightened physiological activity, in the form of recurrent limbic seizures, induces long-lasting but quite different alterations in enkephalin and CCK concentration in the hippocampal mossy fiber system.

Topics: Afferent Pathways; Animals; Cholecystokinin; Electroencephalography; Enkephalins; Hippocampus; Immunohistochemistry; Male; Mice; Motor Activity; Nerve Fibers; Seizures; Time Factors

Light microscopic immunocytochemical techniques were used to evaluate the influence of recurrent limbic seizure activity on the immunoreactivity for 3 neuropeptides--enkephalin, dynorphin, and cholecystokinin (CCK)--contained within the mouse hippocampal mossy fiber axonal system. Seizures were induced either by the placement of a small unilateral electrolytic lesion in the dentate gyrus hilus or by intraventricular injection of kainic acid. Both treatments induce epileptiform activity in hippocampus lasting several hours. Four days after either lesion placement or injection of 0.05-0.1 microgram kainic acid, immunoreactivity for all 3 peptides was altered throughout the intact mossy fiber system, bilaterally, but in distinctly different ways: enkephalin immunoreactivity (ENK-I) was dramatically elevated, dynorphin immunoreactivity was reduced, and CCK immunoreactivity (CCK-I) was either severely reduced or completely absent in the mossy fiber system. ENK-I was also clearly increased in other areas, including the lateral septum, the entorhinal cortex, and within the entorhinal (perforant path) efferents to temporal hippocampus. In contrast, the loss of CCK seemed restricted to the mossy fiber system in that immunostaining appeared normal in scattered hippocampal perikarya, within the dentate gyrus commissural system, as well as within other limbic structures. Four days after injections of 0.2 or 0.25 microgram kainic acid, mossy fiber ENK-I was greatly elevated, dynorphin immunoreactivity was reduced, but, unlike the situation with lower kainic acid doses, CCK-I was only modestly reduced in the mossy fibers and was clearly reduced in other hippocampal systems as well. These data indicate that epileptiform physiological activity differentially affects the regulation of 3 neuroactive peptides contained within the hippocampal mossy fiber system and suggest a mechanism through which seizurelike episodes can have a lasting influence on the operation of specific hippocampal circuitries.

Topics: Animals; Cholecystokinin; Dynorphins; Enkephalins; Hippocampus; Immunochemistry; Kainic Acid; Mice; Nerve Fibers; Seizures

In an attempt to understand the neurochemical basis of kindling, this study investigated the effects on brain cholecystokinin (CCK) of amygdaloid kindled and non-kindled seizures. Thirteen brain regions were examined in rats sacrificed either 24 hr or 3 weeks after the last kindled seizure, or 24 hr after a suprathreshold stimulation-induced (non-kindled) seizure; and in sham kindled rats. There were no significant differences in CCK immunoreactivity between any of these groups. These results do not confirm a previous report of an increase in CCK in the hippocampus following amygdaloid kindling in the rat.

Topics: Animals; Brain; Brain Chemistry; Cholecystokinin; Kindling, Neurologic; Male; Organ Size; Radioimmunoassay; Rats; Rats, Inbred Strains; Seizures

Dose responses were evaluated for the effects of diazepam alone or together with the cholecystokinin receptor antagonist CR 1409 on pentetrazole-induced convulsions, motor performance and spontaneous motor activity. The results obtained showed that the cholecytokinin antagonist potentiated the effects of diazepam on motor performance and the anticonvulsant activity of diazepam, while it did not affect spontaneous motor activity. The data presented are consistent with a role for cholecystokinin in some effects of diazepam.

Topics: Animals; Cholecystokinin; Diazepam; Dose-Response Relationship, Drug; Drug Synergism; Glutamine; Male; Mice; Mice, Inbred Strains; Motor Activity; Pentylenetetrazole; Proglumide; Seizures

Intraperitoneal administration of cholecystokinin octapeptide sulphate ester (CCK-8-SE) and nonsulphated cholecystokinin octapeptide (CCK-8-NS) enhanced the latency of seizures induced by picrotoxin in mice. Experiments with N- and C-terminal fragments revealed that the C-terminal tetrapeptide (CCK-5-8) was the active centre of the CCK octapeptide molecule. The analogues CCK-8-SE and CCK-8-NS (dose range 0.2-6.4 mumol/kg) and caerulein dose range 0.1-0.8 mumol/kg) showed bell-shaped dose-effect curves, with the greatest maximum inhibition for CCK-8-NS. The peptide CCK-5-8 had weak anticonvulsant activity in comparison to the octapeptides, 3.2 mumol/kg and larger doses of the reference drug, diazepam, totally prevented picrotoxin-induced seizures and mortality. The maximum effect of the peptides tested was less than that of diazepam. Experiments with analogues and derivatives of CCK-5-8 demonstrated that the effectiveness of the beta-alanyl derivatives of CCK-5-8 were enhanced and that they were equipotent with CCK-8-SE. Of the CCK-2-8 analogues, Ser(SO3H)7-Ac-CCK-2-8-SE and Thr(SO3H)7-Ac-CCK-2-8-SE and Hyp(SO3H)-Ac-CCK-2-8-SE were slightly more active than CCK-8-SE.

Topics: Animals; Cholecystokinin; Dose-Response Relationship, Drug; Male; Mice; Peptide Fragments; Picrotoxin; Seizures; Sincalide; Structure-Activity Relationship

Cholecystokinin octapeptide (CCK-8), caerulein and diazepam inhibited exploratory rearing activity and harman-induced convulsions in mice. Pretreatment with the selective benzodiazepine receptor antagonist Ro 15-1788, reduced or abolished the sedative and anticonvulsive effects of diazepam, but left the same effects of both peptides unaffected. The peptide-induced ptosis was even increased by Ro 15-1788. The results suggest that the CCK-like peptides do not directly interact with the benzodiazepine receptor.

Topics: Animals; Anticonvulsants; Benzodiazepinones; Blepharoptosis; Body Temperature; Ceruletide; Cholecystokinin; Diazepam; Flumazenil; Harmine; Hypnotics and Sedatives; Male; Mice; Peptide Fragments; Seizures; Sincalide

Caerulein, cholecystokinin octapeptide (CCK-8) and diazepam delayed the onset of seizures produced by harman and thiosemicarbazide (TSC). Caerulein had the potency of diazepam, whereas CCK-8 was less active by a factor of four. The convulsions induced by isoniazid (INH) were very resistant to both caerulein and diazepam; CCK-8 was not tested against isoniazid. Haloperidol did not influence the effect of TSC; it enhanced isoniazid-induced seizures, and antagonized the convulsant effect of harman.

Topics: Animals; Anticonvulsants; Ceruletide; Cholecystokinin; Diazepam; Haloperidol; Harmine; Isoniazid; Male; Mice; Mice, Inbred Strains; Seizures; Semicarbazides; Sincalide

Caerulein and the C-terminal octapeptide of cholecystokinin (CCK-8), after subcutaneous administration to mice, both delayed the onset and retarded the development of toxic effects of convulsants such as strychnine, pentetrazol, bicuculline, and picrotoxin. They also increased the seizure threshold doses of intravenously infused pentetrazol and picrotoxin. In this regard, both peptides were at least equipotent with diazepam.

Topics: Animals; Anticonvulsants; Bicuculline; Ceruletide; Cholecystokinin; Diazepam; Kinetics; Male; Mice; Pentylenetetrazole; Seizures; Sincalide; Strychnine; Time Factors