Feeding and 8-OH-DPAT-related release of serotonin in the rat lateral hypothalamus

Based on the different effects of somatodendritic 5-HT1A agonist 8-OH-DPAT on food intake whether given to food-deprived rats or freely feeding rats, we hypothesized that the effects of 8-OH-DPAT on extracellular serotonin (5-HT) in the lateral hypothalamus (LH) will interfere with different feeding states, eventually resulting in different patterns of 5-HT release. In a microdialysis study we measured extracellular 5-HT in the LH after 8-OH-DPAT under four experimental conditions, i.e., in freely feeding rats with no food available, freely feeding rats with access to food, in food-deprived rats with no food available, and in food-deprived rats with good available after treatment. The results show a significant decrease of 5-HT release after 300 microg/kg 8-OH-DPAT (i.p.) in freely feeding rats. This effect is not seen when food is provided after drug treatment. In contrast, the same dose of 8-OH-DPAT has no effect on 5-HT release in food-deprived rats. In addition, providing food after drug treatment does not change the release pattern significantly in food-deprived rats, suggesting more complexity in the underlying mechanisms. The present study describes the effects of 8-OH-DPAT on 5-HT release in the LH, depending on feeding conditions and feeding-related behavioral states.     

A role for serotonin in lipopolysaccharide-induced anorexia in rats

Rats consistently reduce their food intake following injection of bacterial lipopolysaccharides (LPS). Because LPS increases CNS serotonin (5-HT) turnover, and because increases in CNS 5-HT turnover are associated with a decrease in food intake, we conducted a series of studies to examine 5-HT's potential role in LPS-induced anorexia. Chronic CNS 5-HT depletion by cisterna magna (CM) administration of 5,7-dihydroxytryptamine (5,7-DHT) failed to attenuate LPS-induced (100 microg/kg, ip) anorexia. In subsequent experiments, LPS was injected at lights out (hour 0) and [8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT)] or N-CBZ-[(8beta)-1,6-dimethylergolin-8-yl]methylamine (metergoline) was injected at hour 5 - the time when LPS-treated rats become anorectic. Food intake was measured during the subsequent 2 h. In LPS-treated rats, 8-OH-DPAT (62.5, 125, or 250 microg/kg, sc) injection increased food intake. In a 2 x 2 factorial arrangement of LPS and 8-OH-DPAT, 125 microg/kg 8-OH-DPAT increased food intake significantly more in LPS-treated rats than in non-LPS-treated rats (significant LPS x 8-OH-DPAT interaction). In LPS-treated rats, 1 and 5 mg/kg metergoline significantly enhanced food intake. However, in a 2 x 2 arrangement of LPS and metergoline, 1 mg/kg metergoline failed to increase food intake in LPS and non-LPS-treated rats in two separate trials. The ability of the 5-HT(1A) receptor agonist 8-OH-DPAT to attenuate LPS-induced anorexia in rats supports a role of 5-HT in LPS-induced anorexia.     

Hyperinsulinemia of the genetically obese (fa/fa) rat is decreased by a low dose of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

Changes in glycemia and insulinemia were determined in conscious lean (FA/?) and obese (fa/fa) rats after acute administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The intravenous injection of a low dose of 8-OH-DPAT (150 micrograms/kg) to lean rats rapidly promoted hyperglycemia. This modification was associated with a slight increase in insulinemia. The injection of 8-OH-DPAT markedly decreased basal hyperinsulinemia in obese rats while inducing hyperglycemia. Further evidence of the strong inhibitory effect of 8-OH-DPAT on insulin release was obtained in lean and obese rats during glucose tolerance tests. Intracerebroventricular injection of 8-OH-DPAT (45 micrograms/animal) triggered hyperglycemia and markedly decreased insulinemia in both lean and obese rats. This hypoinsulinemic effect of 8-OH-DPAT was more pronounced in the obese than in the lean animals. Measurement of the food intake elicited by 8-OH-DPAT (500 micrograms/kg s.c.) showed that the hyperphagic action of the 5-HT1A agonist was the same in FA/? and fa/fa rats. It is suggested that: (i) hyperinsulinemia of the genetically obese rat may be diminished by a low dose of 8-OH-DPAT; (ii) 5-HT1A autoreceptor-mediated regulation of serotonergic activity is not different in lean (FA/?) and obese (fa/fa) rats; (iii) 8-OH-DPAT could be of potential therapeutic use for some aspects of the pathology of type II diabetes.     

Cholecystokinin, amphetamine and diazepam and feeding in lean and obese Zucker rats.

The hyperphagia characteristic of some types of obesity may result from a deficiency in one or more components of the systems controlling satiety which in rats may include the gastrointestinal hormone cholecystokinin (CCK). Obesity may also influence responsivity to often used central nervous system (CNS)-acting drugs and combination of drugs. In these experiments it was shown that: (1) Zucker fatty rats were less sensitive than lean to intraperitoneal injections of 20 U/kg CCK after a 6-hr fast and when reduced were less sensitive than lean and less sensitive than when obese to injections of 5 U/kg CCK; (2) Although fatties were equally sensitive as leans to injections of 0.5 and 1.0 mg/kg d-amphetamine sulfate, when reduced, they were less sensitive; (3) Injections of 1.25 and 2.5 mg/kg diazepam produced smaller increases in food intake after a 6-hr fast in fatty and reduced fatty than lean rats; (4) Combination of diazepam with cholecystokinin in both fatty and lean rats produced feeding similar to that following injection of carrier; and (5) A similar additive effect was obtained in both fatty and lean rats when diazepam was combined with amphetamine; however, the fatty appeared to be more sensitive to the amphetamine than the diazepam effect. Thus the Zucker fatty rat appears to be less sensitive to these chemicals which affect food intake, which supports the contention that their CNS is generally less responsive.     

Effects of systemic 8-OH-DPAT on the feeding induced by hypothalamic NE infusion

Past research suggests that activating brain serotonin (5-hydroxytryptamine or 5-HT) systems can inhibit feeding induced by activating brain norepinephrine (NE) systems. To explore this interaction more fully, we tested the capacity of the endogenous 5-HT release inhibitor, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), to enhance feeding stimulated by infusing NE into the medial hypothalamus. All experiments were conducted using ad lib-fed adult male rats with indwelling cannulae aimed at the paraventricular nucleus (PVN). In the first study, proven PVN-NE responders were tested for 40-min food intake after receiving 20 nanomoles (nmol) 1-NE or saline in the PVN following subcutaneous (SC) pretreatment with 250 micrograms/kg 8-OH-DPAT or saline. Both drugs produced equivalent, reliable increments in feeding compared to PVN-saline. However, no additivity or synergy was seen when they were combined. Short-term water intake was unaffected by these treatments as was subsequent food or water intake over the next 22 hr. In a second study, additional proven PVN-NE responders were tested under two comparable conditions when 1) the 8-OH-DPAT dose was left at 250 micrograms/kg but the NE dose was lowered to 10 nmol, and 2) the 8-OH-DPAT dose was lowered to 120 micrograms/kg and the NE dose was increased to 40 nmol. In the first case, no reliable feeding was seen in response to either agent alone or combined. In the second case, NE alone enhanced feeding but 8-OH-DPAT did not. The combination of both produced the same enhanced feeding as seen with NE alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

8-Hydroxy-2-(di-n-propylamino)-tetralin inhibits food intake in fasted rats by an action at 5-HT1A receptors

The effects of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) on food intake were investigated in food-deprived rats. 8-OH-DPAT (25-100 microg/kg) administered subcutaneously immediately prior to the presentation of food produced a dose-related decrease in food intake in rats that had been fasted for 22 h. The hypophagic effect of 8-OH-DPAT (50 microg/kg) was abolished by pretreatment with the selective 5-HT1A receptor antagonist n-[2-(4-2-methoxyphenyl)-1-piperazinyl]-n-(2-pyridyl) cyclohexanecarboxamide (WAY 10063; 0.3 mg/kg). The results of this study show that the acute dose-dependent depressant effect of 8-OH-DPAT on food intake in fasted rats is mediated by an action at 5-HT1A receptors.     

Feeding responses to a high dose of 8-OH-DPAT in young and adult rats: influence of food texture

The present study was undertaken to investigate the hyperphagic responses to the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in young and adult rats fed either a powder diet or pellets. In the young rats, 8-OH-DPAT (500 micrograms/kg s.c.) increased the consumption of pellets--but not powder--during the 2 h following drug administration. On the other hand, 8-OH-DPAT did not promote hyperphagia in adult rats presented with either pellets or a powdered diet. The influence of the 5-HT1A agonist on midbrain serotonin (5-hydroxytryptamine, 5-HT) turnover was examined. Administration of 8-OH-DPAT (500 micrograms/kg s.c.) induced similar decreases in 5-HT turnover, as reflected by the ratio of 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT, in young and adult rats 1 h after administration. Nevertheless, some metabolic responses to 8-OH-DPAT were found to be influenced by age. Young and adult rats were injected with a low dose of 8-OH-DPAT (50 micrograms/kg s.c.) to specifically test the presynaptic regulation of 5-HT turnover. Again, midbrain 5-HIAA to 5-HT ratios were decreased to the same extent in both young and adult rats. The results suggest that (i) gnawing may be an important parameter in the food consumption that is triggered by a high dose of 8-OH-DPAT, (ii) analysis of the presynaptic effects of 8-OH-DPAT on 5-HT turnover cannot solely explain the influence of the agonist on feeding behavior.     

Effect of 5-HT1A receptor activation on hypothalamic glucose.

The somatodendritic 5-HT1A agonist 8-OH-DPAT reduces serotonergic activity and stimulates feeding in freely feeding rats. Interactions between circulating glucose and 5-HT1A receptor expression related to feeding have been described. The aim of the present microdialysis study was to (1) describe the relation between feeding and glucose in the LH, (2) to investigate if peripherally administered 8-OH-DPAT itself has an effect on extracellular glucose in the lateral hypothalamus (LH) of conscious rats. Baseline glucose concentrations were significantly different in microdialysis samples obtained from food deprived rats compared to freely feeding rats. After re-feeding, a significant rise in glucose levels by 45% was observed in the formerly food deprived rats. In freely feeding rats, 8-OH-DPAT (0.3 mg/kg, i.p.) reduced glucose level in the LH significantly. The effect of 8-OH-DPAT on brain glucose was antagonized by pre-treatment with the 5-HT1A antagonist WAY 100635 (3 mg/kg i.p.) which had no effect on its own. The data indicate, therefore, that the effect of 8-OH-DPAT on hypothalamic glucose is mediated by 5-HT1A receptors. In contrast, the same dose of 8-OH-DPAT proven effective in the brain had no effect on peripheral glucose. Only a very high dose of the 5-HT1A agonist (1.8 mg/kg i.p.) had a hyperglycaemic effect in the periphery. In conclusion, the present results show for the first time, that glucose in the lateral hypothalamus increases with a meal. The data demonstrate furthermore 8-OH-DPAT-induced changes of hypothalamic glucose level, implicating 5-HT1A receptors being involved not only in the control of hypothalamic 5-HT as shown before, but also in the control of hypothalamic glucose.     

Effect of acute and chronic treatment of rats with the putative anxiolytic drug ipsapirone on the turnover of monoamine transmitters in various brain regions. A comparison with the 5-HT1A agonist 8-OH-DPAT.

A fourteen-days treatment (twice a day) of male Wistar rats with the putative anxiolytic ipsapirone (10 mg/kg po) and the selective 5-HT1A agonist 8-OH-DPAT (1 mg/kg ip) induced changes in the turnover of serotonin and catecholamines in various regions of the brain. In contrast to 8-OH-DPAT, ipsapirone stimulated the development of tolerance in serotonin neurons in the hypothalamus, hippocampus, cortex and striatum. Nevertheless, adaptative changes were not produced by ipsapirone in dopamine neurons in the striatum or nucleus accumbens, or in noradrenaline neurons in the hypothalamus, hippocampus or cortex. The centrally active metabolite of ipsapirone 1-PP, which has adrenolytic properties, seems to be responsible for the effects on the dopamine and noradrenaline turnover.     

Antagonism by WAY-100635 of the effects of 8-OH-DPAT on performance on a free-operant timing schedule in intact and 5-HT-depleted rats

In this experiment we examined the effect of a serotonin receptor (5-HT1A) agonist and antagonist WAY-100635 (N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide) on temporal differentiation, in intact rats and rats whose serotonergic (5-HTergic) pathways had been destroyed by 5,7-dihydroxytryptamine (5,7-DHT). Thirteen rats received 5,7-DHT-induced lesions of the median and dorsal raphe nuclei; 14 rats received sham lesions. They were trained to press two levers (A and B) in 50-s trials, in which reinforcement was contingent upon responding on A in the first half, and B in the second half, of the trial. Logistic psychophysical curves were fitted to the relative response rate data (percent responding on B, %B), for derivation of timing indices [T50 (time corresponding to %B=50%), slope, Weber fraction] following WAY-100635, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], combinations of WAY-100635+8-OH-DPAT, and vehicle alone. WAY-100635 (30, 100 and 300 microg/kg, s.c.) did not affect the timing indices. 8-OH-DPAT (100, 200 microg/kg, s.c.) reduced T50 without affecting the Weber fraction. WAY-100635 (300 microg/kg) abolished the effect of 8-OH-DPAT on T50 in both the lesioned and sham-lesioned groups. 5-HT levels in the neocortex, hippocampus, amygdala, nucleus accumbens and hypothalamus of the lesioned group were <20% of those in the sham-lesioned group; catecholamine levels were unaffected. The results confirm that 8-OH-DPAT disrupts temporal differentiation in a free-operant psychophysical schedule, reducing T50, and indicate that this effect of 8-OH-DPAT is mediated by postsynaptic 5-HT1A receptors.     

Lesions of the posterior basolateral amygdala block feeding induced by systemic 8-OH-DPAT.

We have recently reported that bilateral electrolytic lesions of the posterodorsal amygdala (PDA) in female rats which induce protracted overeating and weight gain also attenuate short-term feeding stimulated by intraraphe infusions of the serotonin (5-HT) 1A agonist, (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin, (8-OH-DPAT). Bilateral lesions of the posterior basolateral amygdala (pBLA) in male rats have also been reported to enhance feeding and weight gain, but much less so than PDA lesions do in female rats. The present study was performed to determine if pBLA lesions in female rats might attenuate 8-OH-DPAT feeding and what, if any, relationship exists between 8-OH-DPAT-induced feeding and lesion-induced weight gain. Lesioned rats showed reliable increases in 24-h food intake and weight gain relative to shams during the days between surgery and acute drug-induced feeding tests. 8-OH-DPAT (0, 60, 120 or 240 microg/kg in saline) increased feeding of shams in a dose-dependent manner over 2 h. Feeding at the most effective dose (120 microg/kg) was reduced to vehicle levels in lesioned rats. The feeding induced by this dose correlated inversely (r=-.59, P<.01) with the magnitude of weight gained following lesions. Feeding at the highest dose (240 microg/kg) showed a biphasic effect of feeding inhibition over the first vs. second hour that was unaffected by lesions. These findings imply that either fibers of passage and/or cellular elements in both the PDA and pBLA normally inhibit overeating and weight gain via intact serotonergic mechanisms.     

Enhanced amphetamine anorexia, but not drinking suppression in obese Zucker rats

The effects of d-amphetamine on ad libitum consummatory behavior of genetically obese Zucker rats and their lean littermates were examined in two experiments. In Experiment 1 food intake was measured every two hours for six hours following intraperitoneal injections of 0.0, 0.5, and 1.0 mg/kg of d-amphetamine sulfate. Both lean and obese animals significantly suppressed food intake for the first two hours after injection of 0.5 and 1.0 mg/kg doses. Lean animals displayed no suppression of food intake at four or six hours after injection. In contrast to lean animals, obese rats continued to show a suppression of feeding at four hours after injection of 1.0 mg/kg. Total six-hour food intake of obese animals was significantly suppressed from baseline after 0.5 and 1.0 mg/kg of amphetamine, but only after the 1.0 mg/kg injection with lean animals. Experiment 2 examined the effects of these same doses on both food and water intake of different groups of obese and lean Zucker rats. The enhanced anorexia with the 1.0 mg/kg injection of amphetamine was replicated. Water intake, however, was suppressed only during the first two hours after both the 0.5 and 1.0 mg/kg injection in obese and lean rats. Results of the present experiments are discussed in light of previous studies of the effects of amphetamine on hypothalamically obese animals.     

Subchronic fluoxetine administration to rats: effects on 5-HT autoreceptor activity as measured by in vivo microdialysis.

Subchronic administration of fluoxetine to rats has been shown to induce subsensitivity of presynaptic 5-HT(1A) and 5-HT(1B) autoreceptors, and also postsynaptic 5-HT(1A) receptors in the hypothalamus. We investigated the effects of administration of fluoxetine (10 mg/kg i.p.) to rats for 6 days on presynaptic 5-HT(1A) receptor activity in the hypothalamus, postsynaptic 5-HT(1A) receptor activity in the hippocampus, and presynaptic 5-HT(1B) autoreceptor activity in both areas, using in vivo microdialysis. The effect of the 5-HT(1B/1D) antagonist (N-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-2'-methyl-4'-(5- methyl-1,2,4-oxadiazole-3-yl)[1,1'-biphenyl]-carboxamide (GR 127935) (5 mg/kg s.c.) to elevate 5-hydroxytryptamine (5-HT) levels was reduced in hippocampus but not hypothalamus of fluoxetine-treated rats. Fluoxetine did not alter either presynaptic 5-HT(1A) autoreceptor activity, as measured by the effect of injection of 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (0.2 mg/kg or 50 microg/kg s.c.) on 5-HT levels in the hypothalamus, or postsynaptic 5-HT(1A) receptor activity, as measured by the effect of 8-OH-DPAT (0.2 mg/kg s.c.) on cyclic AMP accumulation, in the hippocampus.     

Evidence for a role of the 5-HT2C receptor in central lipopolysaccharide-, interleukin-1 beta-, and leptin-induced anorexia

We examined the role of serotonin (5-HT) and the 5-HT(1A) and 5-HT(2C) receptors in the anorectic effects of centrally administered lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), and leptin. Food intake was measured in rats after intracerebroventricular (ICV) injections of LPS (20 ng), IL-1 beta (10 ng), or leptin (1 microg) at lights out, followed by intraperitoneal (IP) injections of either the 5-HT(1A) autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) (125 microg/kg) or the 5-HT(2C) receptor antagonist SB 242084 (0.3 mg/kg) at the onset of anorexia. SB 242084 significantly attenuated the food intake reduction caused by all compounds (all P<.01). IP 8-OH-DPAT attenuated ICV IL-1 beta-induced anorexia (P<.01). We also tested the involvement of the median raphe 5-HT(1A) receptors in peripheral LPS- and IL-1 beta-induced anorexia. Rats were injected intraperitoneally with either LPS (100 microg/kg) or IL-1 beta (2 microg/kg) at lights out, and 8-OH-DPAT (4 nmol) was administered directly into the median raphe nucleus at the onset of anorexia. Median raphe injections of 8-OH-DPAT significantly attenuated both IL-1 beta- and LPS-induced anorexia (both P<.01). These results implicate the 5-HT(2C) receptors in the mediation of central LPS-, IL-1 beta-, and leptin-induced anorexia. Our results also suggest that the midbrain raphe nuclei play a role in mediating the anorectic response to peripheral LPS and IL-1 beta.     

Influence of taste and food texture on the feeding responses induced by 8-OH-DPAT and gepirone

Previously it has been shown that 5-hydroxytryptamine (5-HT)_1A agonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and gepirone increase food intake in free-feeding rats. These experiments were conducted to examine the possible influence of taste and textural factors on the feeding responses induced by these two drugs. Separate groups of non-water-deprived rats were given access to one of a variety of different solutions of saccharin (0.02, 0.04, 0.20 and 2.0% w/v) or water for 2 h each day. Rats were then treated with different doses of 8-OH-DPAT (10, 60 or 100 µg/kg) or gepirone (1 or 2.5 mg/kg) in a repeated measures design. Under saline injection an inverted-U shaped concentration-response curve was obtained, with the highest level of intake occurring in rats drinking from the 0.20% saccharin solution. The highest doses of 8-OH-DPAT and gepirone suppressed drinking of saccharin, particularly over the first 30 min of the test period, leading to a flattening of the concentration response curve. At 2 h post-injection 60 µg/kg 8-OH-DPAT enhanced the consumption of the 0.04% saccharin solution only. In a second experiment, 8-OH-DPAT or gepirone was administered to rats eating either standard pelleted chow or the same food presented in powdered form. Both drugs stimulated feeding. However, interactions with food type were found. At 60 and 100 µg/kg 8-OH-DPAT increased eating of both food types equally, but with 500 µg/kg rats are significantly more of the pelleted food. Gepirone at 1 and 2.5 mg/kg also significantly increased pelleted food intake compared to powdered food intake. These results suggest that taste factors alone are unlikely to be a major determinant of 8-OH-DPAT's effects on food intake. On the other hand, food texture may play a significant role in the capacity to elicit feeding after high doses of both 8-OH-DPAT and gepirone.     

Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat

1. We examined the involvement of the frontal cortex in the 5-HT2A receptor-induced inhibition of 5-HT neurones in the dorsal raphe nucleus (DRN) of the anaesthetized rat using single-unit recordings complemented by Fos-immunocytochemistry. 2. Both transection of the frontal cortex as well as ablation of the medial region of the prefrontal cortex (mPFC) significantly attenuated the inhibition of 5-HT neurones induced by systemic administration of the 5-HT1A receptor agonist, 8-OH-DPAT (0.5-16 microg kg(-1), i.v.). In comparison, the response to 8-OH-DPAT was not altered by ablation of the parietal cortex. The inhibitory effect of 8-OH-DPAT was reversed by the 5-HT1A receptor antagonist, WAY 100635 (0.1 mg kg(-1), i.v.) in all neurones tested. 3. In contrast, cortical transection did not alter the sensitivity of 5-HT neurones to iontophoretic application of 8-OH-DPAT into the DRN. Similarly, cortical transection did not alter the sensitivity of 5-HT neurones to systemic administration of the selective 5-HT reuptake inhibitor, paroxetine (0.1-0.8 mg kg(-1) , i.v.). 4. 8-OH-DPAT evoked excitation of mPFC neurones at doses (0.5-32 microg kg(-1), i.v.) in the range of those which inhibited 5-HT cell firing. At higher doses (32-512 microg kg(-1), i.v.) 8-OH-DPAT inhibited mPFC neurones. 8-OH-DPAT (0.1 mg kg(-1), s.c.) also induced Fos expression in the mPFC. The neuronal excitation and inhibition, as well as the Fos expression, were antagonized by WAY 100635. 5. These data add further support to the view that the inhibitory effect of 5-HT1A receptor agonists on the firing activity of DRN 5-HT neurones involves, in part, activation of a 5-HT1A receptor-mediated postsynaptic feedback loop centred on the mPFC.     

Desensitization of 5-HT(1A) autoreceptors induced by neonatal DSP-4 treatment.

To examine the effect of noradrenergic lesion on the reactivity of central 5-HT(1A) receptors, DSP-4 (50 mg/kg) was administered neonatally 30 min after zimelidine (10 mg/kg) administration. 5-HT(1A) autoreceptors are involved in the regulation of serotonin (5-HT) synthesis. In HPLC assay R-(+)-8-OH-DPAT (0.03 mg/kg) significantly decreased 5-HT synthesis rate in striatum, hypothalamus and frontal cortex of control, whilst nonsignificantly in DSP-4-lesioned adult rats (10-12 weeks old). To determine which type of receptor, pre- or postsynaptically located, is involved in the attenuated response to 5-HT(1A) receptors' agonist, behavioral tests were conducted. R-(+)-8-OH-DPAT (0.015 mg/kg) caused hyperphagia of control rats, but did not change feeding of DSP-4 treated rats. R-(+)-8-OH-DPAT (0.1 mg/kg) induced hypothermia and "5-HT(1A) syndrome" in both control and DSP-4-lesioned animals. The nature of this phenomenon is attributable to the presynaptic adaptive mechanism and suggests the desensitization of 5-HT(1A) autoreceptors of rats with neonatal lesion of the central noradrenergic system.     

Different effects on the responses of functional pre- and postsynaptic 5-HT1A receptors by repeated treatment of rats with the 5-HT1A receptor agonist 8-OH-DPAT.

The effects of repeated treatment of rats with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 1.0 mg/kg, subcutaneously, twice daily for 7 days, on the stimulation of post- and presynaptic 5-HT1A receptors were examined. The postsynaptic responses, hypothermia and inhibition of the cage-leaving response, evoked by 0.05 mg/kg 8-OH-DPAT, were measured 48 hr after the final injection. Another postsynaptic response, the 5-HT syndrome (flat body posture and forepaw treading) was observed after the third injection of 8-OH-DPAT (1.0 mg/kg s.c.). One presynaptic response examined was the 8-OH-DPAT-induced decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA), that indicates a decrease in turnover of 5-HT, due to stimulation of 5-HT receptors on the cell bodies and measured as the ratio of 5-HIAA to 5-HT in the hippocampus, hypothalamus and medulla oblongata. Another presynaptic response was the 8-OH-DPAT-induced decrease in the accumulation of 5-hydroxytryptophan (5-HTP) in the hippocampus and hypothalamus, after inhibition of L-aromatic amino acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015), that is due to stimulation of autoreceptors on the 5-HT cell bodies. The kinetic properties of 5-HT1A receptors in the cerebral cortex and hippocampus, hippocampus alone, hypothalamus and medulla oblongata were determined with [3H]8-OH-DPAT. It was found that the postsynaptic effects were markedly attenuated after the treatment, the hypothermic effect already after a single dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurochemical and behavioural evidence for mediation of the hyperphagic action of 8-OH-DPAT by 5-HT cell body autoreceptors

Administration of 60 micrograms/kg s.c. of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a dose previously shown to cause hyperphagia in satiated rats (but not to cause the 5-HT behavioural syndrome) decreased 5-HIAA and 5-HIAA/5-HT ratio in several brain regions, the most marked effects being in pons + medulla oblongata, a region containing 5-HT cell bodies and ascending 5-HT axons. Micro-infusion of 8-OH-DPAT (250 and 500 ng) into the dorsal or medial raphe nuclei significantly increased food intake and feeding duration but did not produce the 5-HT behavioural syndrome. Results suggest that 8-OH-DPAT induced hyperphagia is mediated via a agonist action on somatodendritic 5-HT autoreceptors.     

The effect of naloxone on food-motivated behavior in the obese Zucker rat

 We assessed differences in food reinforced behavior between obese and lean Zucker rats with a progressive ratio schedule 3 (PR3) in which a subject emitted three additional lever-presses each time a reinforcer was delivered. The number of responses required for a reinforcer eventually exceeded its value, termed the ”break point”, a sensitive measure of food motivated behavior. Break points were higher in obese rats than lean controls for grain pellets (27.5 versus 9.5, P=0.01) but not for sweet pellets (51.6 versus 38.5, P=0.31). We determined if naloxone (0.01–3.0 mg/kg, SC), which reduces free food intake in obese Zucker rats, affects food motivated behavior in obese Zuckers and lean controls. Naloxone reduced break points in both obese and lean rats to a similar extent when working for either grain pellets or sweet pellets. Under free-access feeding conditions, naloxone again decreased pellet intake similarly in the obese and lean Zucker rats. Naloxone appeared to decrease free-access pellet consumption to a greater extent than break point in both groups. These results show that (1) obese rats exhibit higher levels of performance for food than lean rats only when working for the less valued grain pellet, (2) naloxone reduces both break points and free-access pellet consumption independent of genotype, and (3) naloxone appears to decrease food more effectively in rats given free access to food than in rats working for food. Received: 4 April 1998 / Final version: 19 August 1998