Effect of memantine on the alpha 7 neuronal nicotinic receptors, synaptophysin- and low molecular weight MAP-2 levels in the brain of transgenic mice over-expressing human acetylcholinesterase.

Transgenic mice over-expressing human acetylcholinesterase (hAChE-Tg) display memory impairments, cholinergic deficits and reduced dendritic branching. In this study, we found a reduced number of N-Methyl-D-Aspartate (NMDA) binding sites and reduced levels of low molecular weight (LMW) microtubule associated protein 2 (MAP-2), in addition to an increased number of alpha4 and alpha7 nicotinic receptor (nAChR) binding sites in the brain of hAChE-Tg mice. Treatment with memantine, 20 mg/kg/day during 14 days, significantly increased the number of [(125)I]alphabungarotoxin (alpha7 nAChR) binding sites in the frontal- and retrosplenial cortex of hAChE-Tg mice and synaptophysin- and LMW MAP-2 levels in the cortex of both hAChE-Tg and FVB/N controls. The findings reveal an alteration of the glutamatergic system in hAChE-Tg mice. Whether the effect of memantine on alpha7 nAChRs, synaptophysin- and LMW MAP-2 levels is a direct effect, or an indirect effect via the NMDA receptors, has to be further evaluated.

Expression of nicotinic acetylcholine receptors in human and rat adrenal medulla.

Neuronal nicotinic receptors (nAChRs) are expressed in the brain but also in the peripheral tissues including the adrenal medulla. However, it is unclear which nAChRs are present in the human adrenal medulla. In the study, receptor binding assay, Western blot and RT-PCR have been performed to investigate the expression of nAChRs in adrenal medulla from human, rat and mouse. The results showed that in human adult adrenal medulla, mRNAs for nAChR alpha3, alpha4, alpha5, alpha7, beta2, beta3, and beta4 subunits but not beta2 in the fetal human adrenal medulla were expressed. Saturation binding of [3H]epibatidine showed two binding sites in human aged adrenal medulla. The specific binding of [3H]epibatidine (0.1 nM) was significantly higher in human fetal compared to human aged adrenal medulla. mRNAs for the alpha3, alpha4, alpha5, alpha7, beta2, and beta4 subunits but not the beta3 were detectable in adult rat and mouse adrenal medulla. No differences in gene-expression of the nAChRs were observed between new born, adult and aged rat adrenal medulla. Saturation binding of [3H]epibatidine showed only one binding site in rat adrenal medulla. Lower protein levels for the nAChR subunits were observed in the rat adrenal medulla compared to rat brain. There was lower protein levels of the nAChRs in aged rat adrenal medulla compared to the young rats. Sub-chronic treatment of nicotine to rats did not influence level of the nAChRs in the adrenal medulla. In conclusion, the expression of nAChRs in adrenal medulla is age- related and species dependent.

The neurochemical markers in cerebrospinal fluid to differentiate between aseptic and tuberculous meningitis.

In this study, the use of neurochemical markers in patients with aseptic and tuberculous meningitis has been investigated. The cerebrospinal fluid levels of amino acids, nitrite (a metabolite of nitric oxide), vitamin B12 and homocysteine were quantitated in both groups of patients. Among the amino acids, aspartic acid and glutamic acid both excitatory amino acid, GABA, glycine and tryptophan were all significantly increased in both patient groups whereas decreased level of taurine and increased level of phenylalanine were only found in patients with tuberculous meningitis. The levels of nitrite and its precursor arginine were significantly higher in patients with tuberculous meningitis whereas unchanged levels were found in patients with aseptic meningitis. A significantly increased homocysteine level and a decreased level of vitamin B12 were found only in patients with tuberculous meningitis whereas unchanged levels were found in patients with aseptic meningitis. This indicates that patients with tuberculous meningitis are particularly prone to vitamin B12 deficiency resulting into increased level of HC, and involvement of free radical showing the importance of these biological markers for promoting the possibility for the design of therapeutic approach.

Differential changes of nicotinic receptors in the rat brain following ibotenic acid and 192-IgG saporin lesions of the nucleus basalis magnocellularis.

The basal forebrain cholinergic neurons are implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). The nicotinic acetylcholine receptors (nAChRs) have been found to be significantly afflicted in AD. To study the underlying mechanisms for dysfunction of the basal forebrain cholinergic neurons development of suitable animal models is warranted. In this study we investigated the effects of bilateral lesions of the nucleus basalis magnocellularis on nAChRs in the rat brain using the cholinergic system selective immunotoxin 192-IgG saporin and non-selective excitotoxin ibotenic acid. Changes in nAChRs were measured by 3H-cytisine and 3H-epibatidine, two ligands with different selectivity for nAChRs subtypes. In the parietal cortex of ibotenic acid lesioned rates, the choline acetyltransferase activity (ChAT) was decreased by 24% while no changes were detected in the frontal cortex or hippocampus. Similarly, a 40% decrease was observed in the number of nAChRs labelled by 3H-cytisine, but not by 3H-epibatidine, in the parietal cortex, while no changes were found in the frontal cortex or hippocampus. Although the 192-IgG saporin induced lesions reduced the ChAT activity in the frontal cortex, parietal cortex and hippocampus by 77, 50 and 21%, respectively, no changes were observed in the number of nAChRs as studied by 3H-cytisine or 3H-epibatidine. The results indicate a difference in vulnerability of the cortical nAChR subtypes to experimental lesions of the nucleus basalis magnocellularis. The findings in this study suggest that a major portion of the nAChRs might be located on non-cholinergic neurons in the brain.

Dopamine D1 or D2 antagonists enhance inhibition of consummatory ingestive behavior by CCK-8.

A dopamine D1 (SKF-38393, 1 mg)- or D2 (LY-171555, 0.1 mg)-receptor agonist inhibited intake of an intraorally infused solution of sucrose by male rats, a test of consummatory ingestive behavior. Treatment with a D1 (SCH-39166, 0.1 mg) or D2 (raclopride, 0.6 mg) antagonist reversed inhibition by the respective agonist but enhanced the inhibitory effect of cholecystokinin octapeptide (CCK-8; 1.8 micrograms). It was not possible to demonstrate specific effects of D1 and D2 agonists on intake of pellets, a test that does not discriminate consummatory ingestive behavior from appetitive ingestive behavior, i.e., behavior used to obtain food. The results demonstrate specific involvement of dopamine D1 and D2 receptors in inhibition of consummatory ingestive behavior.

Increased cerebrospinal fluid concentration of nitrite in Parkinson's disease.

The concentration of nitrite, a metabolite of nitric oxide (NO), was increased in the cerebrospinal fluid (CSF) of untreated patients with Parkinson's disease and in patients treated with L-DOPA in comparison with a group of patients without dopaminergic dysfunction. There was no difference in the concentration of L-arginine (ARG), a precursor of NO, between the groups. There was a highly significant, linear relationship between the concentration of nitrite and ARG in the CSF suggesting that the production of NO is dependent on the availability of ARG. The results support the possibility that production of NO is increased in the brain in Parkinson's disease.

Inhibition of serotonin synthesis attenuates inhibition of ingestive behavior by CCK-8.

Ingestive behavior was activated in male rats by intraoral infusion of a 1-M solution of sucrose. Injection of cholecystokinin octapeptide (CCK-8; 1.6 or 5.0 micrograms) inhibited ingestion of the sucrose solution and increased the concentration of 5-hydroxytryptamine (5-HT) in the paraventricular hypothalamic nuclei. The inhibitory effect of the low, but not the high, dose of CCK-8 was attenuated by depleting 5-HT in the brain with p-chlorophenylalanine (PCPA; 100 mg/kg for 3 days). Treatment with 5-hydroxytryptophan (20 mg/kg) increased the concentration of 5-HT in the brain of rats pretreated with either NaCl or PCPA and enhanced the inhibitory effect of CCK-8 on ingestive behavior in the PCPA-, but not NaCl-, treated rats. 5-HT may play a role in the mechanism of action of CCK-8 but additional factors must be involved.

Glutamate inhibits ingestive behaviour.

Male rats treated with reserpine were motionless and ingested only a few of ten consecutive intraoral injections of a 1 M solution of sucrose. While injection of apomorphine, a dopamine agonist, stimulated locomotion and stereotyped sniffing in reserpinized rats, it did not reactivate ingestive responses. The non-competitive N-methyl-D-aspartate receptor antagonist MK801, however, stimulated locomotion as well as ingestion suggesting involvement of glutamate in the suppressive effect of resperpine on ingestive responses. A series of experiments was therefore undertaken to investigate the possible physiological role of glutamate in feeding. For this purpose, we used Grill's intraoral intake test, in which the rat is infused intraorally with a sucrose solution and the amount ingested measured. In untreated rats, MK801 dose-dependently facilitated ingestion of the sucrose solution and antagonized inhibition of ingestion by cholecystokinin octapeptide. Administration of cholecystokinin octapeptide or ingestion of sucrose increased the concentration of glutamate in the nucleus of the solitary tract, a brain stem relay transmitting sensory information from the gastrointestinal tract to the forebrain. MK801 was found to bind specifically to this brain area and block the elevation of glutamate and dopamine levels which occurred after treatment with cholecystokinin octapeptide in this neural site. Together these data suggest that dopamine and glutamate may interact within the nucleus of the solitary tract in controlling ingestive behaviour.

Brain cholecystokinin tetrapeptide levels are increased in a rat model of anxiety.

Rats exposed to the smell of a predator adopted the freezing posture indicative of anxiety. Correlatively, the concentration of cholecystokinin tetrapeptide (CCK-4) was increased in the olfactory bulb, frontal and central cortex, dorsal and ventral striatum, central amygdala and the nucleus of the solitary tract. The concentration of CCK-8 was increased only in the ventral striatum. Glutamate was increased in the cortex and the striatum and dopamine was increased in the cortex. Intraperitoneal injection of CCK-4 increased brain levels of CCK-4 and replicated, in part, the behavioural effect of the smell of the predator. Injection of a CCK-B-receptor antagonist had the opposite behavioural effect. The results support a role for CCK-4 in anxiety.

Quantitation and identification of two cholecystokinin peptides, CCK-4 and CCK-8s, in rat brain by HPLC and fast atom bombardment mass spectrometry.

A sensitive HPLC method has been described for quantitation of two cholecystokinin (CCK) peptides in discrete rat brain regions. Separation and quantitation was performed by the reversed-phase HPLC combined with electrochemical detection. Analytical recoveries of the tetrapeptide (CCK-4) and octapeptide-sulphate (CCK-8s) were 96% and 94%, respectively. The between assay coefficient of variation (CV) was less than 3% for both peptides. The within-assay CV was 4% and 6% for CCK-4 and CCK-8s and the detection limit was 2 and 10 pmol/mL, respectively. For identification of structures, the peptides were fractionated by semi-preparative HPLC using a novel SMART system for micropurification. The fractions were analysed by fast atom bombardment mass spectrometry (FAB MS) which confirmed the presence of both CCK-4 and CCK-8s in the rat brain tissue.

Simultaneous display of sexual and ingestive behaviour by rats.

Intraoral infusion of sucrose activates consummatory ingestive behaviour in rats selectively, i.e. the rat only emits the responses used to ingest food. Activation of consummatory ingestive behaviour in this way had no effect on the subsequent display of sexual behaviour by male or female rats and vice versa. Rats infused intraorally with sucrose and presented with a sexual partner showed ingestive and sexual behaviour simultaneously. Pretreatment with cholecystokinin octapeptide inhibited the ingestion of sucrose in both males and females but had no effect on the simultaneous display of sexual behaviour. Ingestion of sucrose from a drinking spout, a test in which the rat has to emit responses to obtain food, i.e. show appetitive ingestive behaviour, was inhibited by the presentation of a sexual partner in rats of both sexes. These results show that the mechanisms controlling consummatory sexual and ingestive behaviour operate independently and that the presentation of a sexual partner inhibits appetitive ingestive behaviour. Daily intraoral infusion of sucrose reduced pellet intake in ovariectomized rats while the rats maintained their body weight. Implantation of an oestradiol-filled implant reduced body weight and inhibited daily intake of pellets but had no effect on the intake of intraorally administered sucrose. Subsequent removal of the oestradiol implant increased sucrose intake and body weight but did not have a marked effect on pellet intake. Thus, rats respond to a lowering of the set point for body weight by decreasing their intake of the least preferable kind of food and increase their intake of the most preferable kind of food in response to an elevation of the set point for body weight. Ovariectomized rats infused intraorally once daily with a highly nutritive milk diet in the absence of food pellets ingested very large amounts and reduced their intake in response to oestradiol implantation. Thus, although oestradiol can inhibit consummatory ingestive behaviour, its suppressive effect on ingestion cannot be described in terms of selective effects on appetitive and/or consummatory aspects of the behaviour nor in terms of an alteration in the preference for a sweet solution. Inhibition of ingestive behaviour occurred within 24 h after oestrogen treatment as opposed to stimulation of sexual behaviour which had a longer latency, suggesting that oestradiol affects ingestive and sexual behaviour via different mechanisms. While the mechanisms controlling consummatory ingestive and sexual behaviour must be different, there is evidence for a common mechanism mediating the incentive motivation and reward aspects of these behaviours. The mechanisms which enable rats to select between two, possibly equally rewarding courses of action, i.e. display of sexual or ingestive responses, however, are unknown.

A comparison between the effect of cholecystokinin octapeptide and apomorphine on ingestion of intraorally administered sucrose in male rats.

The involvement of dopamine receptors in the inhibitory effect of Cholecystokinin octapeptide on ingestive behaviour was investigated. Male rats were infused intraorally with a 1 M solution of sucrose and the amount ingested after treatment with the dopamine receptor agonist apomorphine was compared with that after treatment with Cholecystokinin octapeptide. The test allows a distinction between the consummatory aspects of ingestive behaviour, i.e. responses used to ingest food, from the appetitive aspects, i.e. responses used to obtain food, because it ignores the latter aspects. Comparisons were also made between the effects of apomorphine and Cholecystokinin octapeptide on pellet intake, a test in which the rat has to display appetitive ingestive behaviour. Injection of apomorphine (400 µg) increased the concentration of plasma apomorphine within 0.3 min and the concentration of dopamine in the cerebrospinal fluid within 1 min of injection and induced behavioural stereotypes within 10 min in food-deprived male rats. Plasma apomorphine and cerebrospinal fluid dopamine levels had decreased by 30 min and the behavioural stereotypies had decreased by 40 min after the injection. Injection of apomorphine also inhibited the consumption of food pellets and the ingestion of sucrose. Inhibition of pellet and sucrose ingestion paralleled the effect of apomorphine on Stereotypie behaviour. Thus, injection of a dopamine receptor agonist is followed by alterations in plasma levels of the agonist, cerebrospinal fluid dopamine levels and in Stereotypie and ingestive behaviour which occur in parallel, in an inverted U-shaped manner and with a temporal delay between each event. These results show a close correlation between dopamine receptor stimulation and inhibition of ingestive behaviour. However, reversal of the inhibitory effect of apomorphine on ingestive behaviour required pretreatment with a lower dose of a dopamine receptor antagonist (cis-flupentixol) (0.1 mg) than reversal of Stereotypie behaviour (0.8 mg). The effect of dopamine receptor stimulation on consummatory ingestive behaviour is thus relatively weak and not secondary to the induction of Stereotypic behaviour. Treatment with a high dose of cis-flupentixol (0.8 mg) caused a prolonged period of immobility but had no effect on the ingestion of sucrose. Dopamine receptor blockade, therefore, interferes with appetitive, but not consummatory ingestive behaviour. Injection of Cholecystokinin octapeptide (5 µg) suppressed pellet and sucrose intake in a manner comparable to that of apomorphine, but induced no behavioural stereotypes and caused a gradual, rather than inverted U-shaped, increase in the concentration of dopamine in the cerebrospinal fluid that did not correlate with the effect on ingestive behaviour. Furthermore, while the inhibitory effect of apomorphine on the ingestion of sucrose was reversed by pretreatment with a low dose of cis-flupentixol (0.1 mg), the inhibitory effect of Cholecystokinin octapeptide was only partially reversed by cis-flupentixol and a higher dose (0.8 mg) was required. Blockade of cholecystokinin-A receptors, by treatment with L-364,718, but not cholecystokinin-B receptors, by treatment with L-365,260, blocked the inhibitory effect of Cholecystokinin octapeptide and, by itself, L-364,718 increased the amount of ingested sucrose. The inhibitory effect of Cholecystokinin octapeptide on consummatory ingestive behaviour, which is mediated by cholecystokinin-A receptors, is likely to involve mechanisms in addition to dopaminergic ones.

Evidence that Release of Dopamine in the Brain is Involved in the Inhibitory Effect of Cholecystokinin Octapeptide on Ingestion of Intraorally Administered Sucrose in Male Rats.

To study the possibility that release of dopamine in the brain mediates the inhibitory effect of Cholecystokinin octapeptide on ingestive behaviour, the effect of amphetamine on intake of pellets or an intraorally administered sucrose solution was compared with that of Cholecystokinin octapeptide. Additionally, comparisons were made between the effect of Cholecystokinin octapeptide and pargyline, a monoamine oxidase inhibitor, and α-methyl-ρ-tyrosine, a tyrosine hydroxylase inhibitor. While amphetamine dose-dependently inhibited pellet intake it failed to inhibit sucrose intake in doses which caused behavioural stereotypies (<800 µg). Cholecystokinin octapeptide (5 µg) inhibited ingestive behaviour in both tests. A very high dose of amphetamine (2 mg) was required to inhibit sucrose intake to a level comparable to that of Cholecystokinin octapeptide. Pargyline (5 to 25 mg) or α-methyl-p-tyrosine (25 to 100 mg) dose-dependently inhibited pellet intake but had only weak effects on the intake of sucrose. Pargyline increased the concentration of dopamine and 3-methoxytyramine in the dorsal striatum and decreased the concentration of 3,4-dihydroxyphenylacetic acid. α-Methyl-ρ-tyrosine decreased the concentration of dopamine and 3,4-dihydroxyphenylacetic acid, but not that of 3-methoxytyramine. Injection of amphetamine (2 mg), but not Cholecystokinin octapeptide, in rats pretreated with pargyline increased the concentration of 3-methoxytyramine in the dorsal striatum and this effect was blocked by pretreatment with α-methyl-ρ-tyrosine. Pretreatment with α-methyl-ρ-tyrosine partially reversed the inhibitory effect of Cholecystokinin octapeptide on sucrose ingestion, enhanced the effect of amphetamine but did not affect that of apomorphine, a dopamine agonist. The results support the possibility that the inhibitory effect of Cholecystokinin octapeptide on consummatory ingestive behaviour, in part, is mediated via release of dopamine in the brain.

Determination of Enkephalins in Rat Cerebrospinal Fluid with High-Performance Liquid Chromatography-Electrochemical Detection: Increased Concentrations During Lactation are Controlled by Sucking.

Abstract Methionine- and leucine-enkephalin were measured in the cerebrospinal fluid of lactating rats by high-performance liquid chromatography and electrochemical detection. The concentration of both peptides was high while the rats were nursing their litter. The concentration of methionine-enkephalin decreased rapidly when the mother left her litter and increased equally rapidly after mother-young reunion, provided the pups were allowed direct contact with the nipples of the mother. The level of leucine-enkephalin did not change during the period of time the lactating rat normally stayed away from its litter but decreased after prolonged (12 h) mother-pup separation. These results show that the concentration of methionine-, but not leucine-enkephalin in the cerebrospinal fluid fluctuates as the lactating rat interacts with its litter and is directly dependent upon the suckling stimulus. Although methionine-enkephalin may contribute to the inhibition of sexual behaviour which occurs during lactation, the role of the enkephalins in the other behavioural and endocrine adaptations of lactation is unknown.

Involvement of dopamine in inhibition of food intake by cholecystokinin octapeptide in male rats.

Abstract Deprivation of food reduced the level of dopamine in the cerebrospinal fluid of male rats and subsequent ingestion of food or intraperitoneal injection of Cholecystokinin octapeptide restored the level. Injection of a dopamine receptor agonist (apomorphine) or Cholecystokinin octapeptide inhibited food intake and these effects were reversed by pretreatment with a dopamine receptor antagonist (cis-flupentixol). Blockade of cholecystokinin-A receptors, by treatment with L-364,718, but not cholecystokinin-B receptors, by treatment with L-365,260, blocked the inhibitory effect of Cholecystokinin octapeptide on food intake but did not affect the inhibitory effect of apomorphine. It is suggested that Cholecystokinin interacts with dopamine in the control of food intake.

beta-Endorphin acts on the reproductive tract of female rats to suppress sexual receptivity.

Sexual receptivity was suppressed in female rats immediately after the male had ejaculated. The inhibition was prevented by intravaginal injection of naloxone (100 micrograms) before testing and intravaginal injection of beta-endorphin (1.0 micrograms) inhibited sexual behavior in female rats in a manner comparable to that of ejaculation by the male. beta-Endorphin was present in ejaculatory plugs collected from the vagina of female rats (8.2 +/- 0.6 pM) and in seminal fluid collected from male rats (7.7 +/- 0.2 pM). The results suggest that beta-endorphin in the ejaculate of the male rat can act on the reproductive tract of the female rat to suppress her sexual behavior.

Involvement of cholecystokinin in food intake: I. Concentrations of cholecystokinin-like immunoreactivity in the cerebrospinal fluid of male rats.

Abstract To investigate the role of central neural cholecystokinin in food intake the concentration of cholecystokinin-like immunoreactivity was measured by radioimmunoassay in the cerebrospinal fluid of male rats. Characterization of the molecular forms of Cholecystokinin was made by high-performance liquid chromatography before radioimmunoassay. Four molecular forms of cholecystokinin corresponding to standards of the tetra-, penta- and sulphated octapeptide and a late eluting peak probably corresponding to cholecystokinin-58 were found. The concentration of cholecystokinin-like immunoreactivity in the cerebrospinal fluid decreased in response to 48 h of food deprivation and was restored after 1 h of food intake, the main increase occurring within 30 min after the onset of feeding. Cholecystokinin-like immunoreactivity increased in the cerebrospinal fluid 10 min after an intraperitoneal injection of 5 mug cholecystokinin octapeptide, a dose which also suppressed the amount of food consumed during 1 h in rats deprived of food for 48 h. Intraperitoneal injection of the peripheral, cholecystokinin A receptor antagonists lorglumide (450 mug) or L-364. 718 (20 mug) reversed the inhibitory effect of cholecystokinin octapeptide on food intake and prevented the increase of cholecystokinin-like immunoreactivity in the cerebrospinal fluid. It is suggested that central neural cholecystokinin is involved in the control of food intake and that this is reflected in the alterations in cholecystokinin-like immunoreactivity in the cerebrospinal fluid which occur in response to food deprivation and food intake. However, a variety of ways of intracerebral administration of Cholecystokinin octapeptide failed to affect food intake in food-deprived rats. The possibility is raised that Cholecystokinin octapeptide acts in concert with another transmitter in the brain to affect food intake.

Involvement of Cholecystokinin in Food Intake: II. Lactational Hyperphagia in the Rat.

Abstract The role of Cholecystokinin in the hyperphagia of lactation was studied by measuring the concentration of this hormone in plasma and cerebrospinal fluid in relation to food intake in lactating rats. Cholecystokinin was measured by high-performance liquid chromatography and radioimmunoassay in plasma and by radioimmunoassay in cerebrospinal fluid. Plasma concentrations of Cholecystokinin were increased in freely-fed lactating rats compared with non-lactating, regularly cycling rats. However, after 24 h of food deprivation the concentration of plasma Cholecystokinin was markedly decreased in the lactating rats to levels which were lower than those of non-lactating animals. Furthermore, plasma levels of Cholecystokinin did not increase in response to 1 h of feeding in lactating rats, whereas in non-lactating rats they did. In contrast, the concentration of cholecystokinin-like immunoreactivity in the cerebrospinal fluid was the same in freely-fed lactating and non-lactating rats. As in plasma, food deprivation markedly decreased the levels of cholecystokinin-like immunoreactivity in the cerebrospinal fluid of lactating rats but unlike in plasma, the levels were restored by feeding. The levels of cholecystokinin-like immunoreactivity were not changed under these conditions in the non-lactating rats. These results show that there is no correlation between the concentration of Cholecystokinin in plasma and cerebrospinal fluid, which supports the suggestion that the cholecystokinin-like immunoreactivity in the cerebrospinal fluid is derived from the brain. Removal of the litter from lactating rats deprived of food for 24 h reduced food intake and increased the concentration of cholecystokinin-like immunoreactivity in the cerebrospinal fluid, but not in plasma. The inhibition of food intake caused by an intraperitoneal injection of Cholecystokinin octapeptide increased after litter removal. It is suggested that hunger in the lactating rat is reflected by a decrease in the levels of cholecystokinin-like immunoreactivity in the cerebrospinal fluid and satiety by the restoration of these levels.

Involvement of Cholecystokinin in Food Intake: III. Oestradiol Potentiates the Inhibitory Effect of Cholecystokinin Octapeptide on Food Intake in Ovariectomized Rats.

Abstract The role of Cholecystokinin in a model of hypophagia, oestradiol-treated Ovariectomized rats, was investigated. Implantation of oestradiol-filled constant-release implants in rats made obese by ovariectomy potentiated the inhibitory effect of intraperitoneal injection of Cholecystokinin octapeptide on food intake after 24 h of food deprivation. The alterations in the concentration of Cholecystokinin in pjasma and of cholecystokinin-like immunoreactivity in cerebrospinal fluid produced by deprivation of food for 24 h and subsequent food intake for 1 h were unaffected by the oestradiol treatment as was the amount of food consumed during 1 h. Oestradiol-treated rats deprived of food for 6 h, however, consumed less food during a 15-min test than controls. Treatment with oestradiol blunted the decrease in the concentration of cholecystokinin-like immunoreactivity in the cerebrospinal fluid in response to 6 h of food deprivation. No alterations in the concentration of Cholecystokinin in plasma occurred after this period of food deprivation and subsequent feeding during 15 min in either oestradiol-treated or control rats. Thus, treatment with oestradiol enhances responsivity to exogenous Cholecystokinin octapeptide and changes the response of endogenous levels of cholecystokinin-like immunoreactivity in the cerebrospinal fluid to a short period of food deprivation. It is suggested that these effects are caused by an action of oestradiol on Cholecystokinin pathways in the brain. The results support the suggestion that hunger in the rat is inversely related to the decrease in the concentration of cholecystokinin-like immunoreactivity in the cerebrospinal fluid.