Centrally administered urocortin 2 decreases gorging on high-fat diet in both diet-induced obesity-prone and -resistant rats.

OBJECTIVE: Obesity is a costly, deadly public health problem for which new treatments are needed. Individual differences in meal pattern have been proposed to have a role in obesity risk. The present study tested the hypothesis that (i) the microstructure of chronic high-fat diet intake differs between genetically selected diet-induced obesity (DIO) and diet-resistant (DR) rats, and (ii) central administration of urocortin 2 (Ucn 2), a corticotropin-releasing factor type 2 agonist, decreases high-fat diet intake not only in lean DR rats, but also in obese DIO rats. DESIGN: Male, selectively bred DIO and DR rats (n=10/genotype) were chronically fed a high-fat diet. Food and water intake as well as ingestion microstructure were then compared under baseline conditions and following third intracerebroventricular injection of Ucn 2 (0, 0.1, 0.3, 1, 3 µg). RESULTS: Irrespective of genotype, Ucn 2 reduced nocturnal food intake with a minimum effective dose of 0.3 µg, suppressing high-fat diet intake by ∼40% at the 3 µg dose. Ucn 2 also made rats of both genotypes eat smaller and briefer meals, including at doses that did not reduce drinking. Obese DIO rats ate fewer but larger meals than DR rats, which they ate more quickly and consumed with two-third less water. CONCLUSIONS: Unlike leptin and insulin, Ucn 2 retains its full central anorectic efficacy to reduce high-fat diet intake even in obese, genetically prone DIO rats, which otherwise show a 'gorging' meal pattern. These results open new opportunities of investigation toward treating some forms of DIO.

Whole-body metabolism varies across the estrous cycle in Sprague-Dawley rats.

Food intake in rats and other mammals is lowest at estrus and highest at diestrus. While much is known about the effects of different estrous phases on energy intake, as well as some of the metabolic effects the associated hormones exert, little has been reported about changes in whole-body metabolism that accompany those phases. This study investigates how energy expenditure (EE) and respiratory quotient (RQ) vary in intact female Sprague-Dawley rats (n=12) tested mid-light cycle over 2 h on days associated with estrus vs. diestrus. Rats showed small but reliable decreases in body weight on days associated with estrus, but not diestrus. EE was significantly increased by approximately 21% on the day associated with estrus compared to diestrus. At the same time, RQ was significantly decreased by approximately 7% on the day associated with estrus, indicating a relative shift to fat over carbohydrate as the energy substrate to support energetic needs. Future investigations of ingestive processes can integrate the present findings to investigate how gender differences in feeding and metabolism contribute to regulatory behaviors.

Hypothalamic paraventricular nucleus injections of urocortin alter food intake and respiratory quotient.

Corticotropin releasing hormone (CRH) acts on the central nervous system to alter energy balance and influence both food intake and sympathetically-mediated thermogenesis. CRH is also reported to inhibit food intake in several models of hyperphagia including neuropeptide Y (NPY)-induced eating. The recently identified CRH-related peptide, urocortin (UCN), also binds with high affinity to CRH receptor subtypes and decreases food intake in food-deprived and non-deprived rats. The present experiment characterized further the feeding and metabolic effects of UCN by examining its impact after direct injections into the paraventricular nucleus (PVN) of the hypothalamus. In feeding tests (n=8), UCN (50-200 pmol) was injected into the PVN at the onset of the dark cycle and food intake was measured 1, 2 and 4 h postinjection. In separate rats (n=8), the metabolic effects of UCN were monitored using an open circuit calorimeter which measured oxygen consumption (V(O2)) and carbon dioxide production (V(CO2)). Respiratory quotient (RQ) was calculated as V(CO2)/V(O2). UCN suppressed feeding at all times studied and reliably decreased RQ within 30 min of infusion. Additional work examined the effect of UCN (50-100 pmol) pretreatment on the feeding and metabolic effects of NPY. NPY, injected at the start of the dark period, reliably increased 2 h food intake. This effect was blocked by PVN UCN administration. Similarly, UCN blocked the increase in RQ elicited by NPY alone. These results suggest that UCN-sensitive mechanisms within the PVN may modulate food intake and energy substrate utilization, possibly through an interaction with hypothalamic NPY.

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.

5-HT receptor blockade in the posterior amygdala elicits feeding in female rats.

Previous work suggests that feeding following intraventricular (i.v.t.) injections of the serotonin (5-HT)(1/2/7) antagonist metergoline (MET) is not localized to the hypothalamus. Since lesions of the posterior basolateral amygdala (pBLA) block feeding following systemic 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin, the ability of intra-pBLA MET to elicit feeding was investigated. In two separate experiments, feeding of female rats was measured over 2 h following 0, 3, 10 and 30 nmol and 0, 0.03, 0.3 and 3 nmol MET (mol. wt. 403.5) injected bilaterally into each pBLA. All three doses used in Experiment 1 increased feeding over 2 h. In Experiment 2, feeding over the first hour was enhanced after the two highest doses. Since intra-pBLA MET elicits feeding comparable to that seen using much higher doses administered i.v.t. these data implicate the pBLA as an extra-hypothalamic site mediating the effects of 5-HT in feeding control.

Posterodorsal amygdala lesions reduce feeding stimulated by 8-OH-DPAT.

Injections of the serotonin (5-HT)(1A) agonist, 8-hydroxy-2(di-n-propylamino)tetralin, (8-OH-DPAT), either systemically or into the midbrain raphe nuclei, elicit food intake in otherwise satiated rats. Lesions of the paraventricular nucleus of the hypothalamus are well known for producing long-term overeating, but past research has excluded this site as a potential locus for short-term 8-OH-DPAT feeding effects. More recent work shows that small lesions of the posterodorsal amygdala (PDA) elicit overeating in their own right. Since this and related regions of the amygdala receive 5-HT innervations from the dorsal raphe nucleus (DRN), we determined if PDA lesions might alter feeding after injecting 8-OH-DPAT into this midbrain region. Adult female rats received either bilateral electrolytic lesions of the PDA or sham lesions. After recording weight gains for over 1 month, all rats were implanted with DRN cannulae, then randomly tested every 3-4 days for 1 h intake of standard lab chow after 0, 0.4, 0.8 or 1.6 nmol injections of 8-OH-DPAT. Additional 90 min measures of intake were also made after 0 vs. 250 microg (760 nmol) 8-OH-DPAT s.c. At the two highest DRN doses tested, lesioned rats showed 50% less intake compared to shams. A similar profile emerged after the single s.c. dose. These results suggest that the PDA may be an important locus at which reduced release of endogenous 5-HT stimulates feeding. Alternatively, the PDA may represent part of a larger brain circuit whose integrity is necessary for eliciting intake in response to a variety of feeding stimuli.

The rewarding properties of neuropeptide Y in perifornical hypothalamus vs. nucleus accumbens.

There is a high coexistence of substance abuse in humans with eating disorders. One theory offered to account for this fact is that a common biochemical substrate may exist that mediates both processes. Brain neuropeptide Y (NPY) is one neurochemical system that might contribute to these separate, yet related, problems. To clarify the role of NPY in mediating reward processes and the possible interaction between reward and feeding, the present study examined the effects of injecting NPY bilaterally into the perifornical hypothalamus (PFH) vs. the nucleus accumbens (NAC) on intake of preferred vs. non-preferred food types, as well as on conditioned place preference (CPP) learning. NPY (24, 78, 156 and 235 pmol/side) stimulated intake of both regular powdered chow and sucrose when injected into the PFH, but not the NAC. A CPP that was negatively correlated with food intake occurred with the low (24 pmol/side) dose of NPY in the PFH, while a CPP that was not correlated with food intake was produced with the same dose in the NAC. The extent of the CPPs produced by NPY injection in both brain sites mirrored that produced by peripheral injection of amphetamine (2.5 mg/kg). These results indicate that NPY elicits reward-related behavior, but not feeding, from the NAC, and both behaviors from the PFH. However, the feeding effect derived from the PFH appears to overshadow a rewarding effect derived from this site. Considered together, these findings suggest that altered NPY functioning in both brain regions may contribute to some of the pathophysiological processes observed in eating disordered patients who have additional proclivities for substance abuse.

Effects of three neurochemical stimuli on delayed feeding and energy metabolism.

Infusions of norepinephrine (NE), the gamma-aminobutyric acid agonist, muscimol (MUS), or neuropeptide Y (NPY) into the paraventricular nucleus (PVN) of the hypothalamus all increase food intake. Such feeding may be due to direct activation of behavioral processes driving ingestion and/or to alterations in nutrient metabolism that feeding serves to normalize. To examine these possibilities, male Sprague-Dawley rats received PVN infusions of vehicle, 20 nmol NE, 1 nmol MUS or 100 pmol NPY at dark onset, then food intake was measured under three feeding conditions: (1) 1 and 2 h immediately after injections, (2) 1 h after a 1 h delay between injections and access to food, and (3) 1 h after a 1 h feeding delay, but with injections occurring just before presenting food. Measures of energy expenditure (EE) and respiratory quotients (RQs) in the absence of food were made over 2 h in parallel experiments. Results confirmed that NE, MUS and NPY all increased dark-onset feeding, but only NPY increased intake above control levels after a 1 h feeding delay. No neurochemically-induced changes in EE were observed, nor were there changes in RQs after NE or MUS. However, NPY reliably enhanced RQs from 30 to 120 min of testing. Our findings imply that NE and MUS initiate relatively immediate, short-term feeding that is not associated with changes in nutrient metabolism and does not summate with cues stimulated by delayed access to food. NPY initiates more protracted feeding temporally linked to enhanced carbohydrate metabolism. This may indicate that part of NPY's feeding stimulatory effects are secondary to physiological processes driving ingestion.

Paraventricular nucleus injections of naloxone methiodide inhibit NPY's effects on energy substrate utilization.

Microinjection of neuropeptide Y (NPY) into the paraventricular nucleus (PVN) of the hypothalamus stimulates eating and increases respiratory quotient. In contrast, administration of opioid receptor antagonists reduces food intake and suppresses NPY-induced feeding. The present study examined whether naloxone methiodide, an opioid antagonist, would suppress the potentiation of NPY on energy substrate utilization, when injected into the PVN. Naloxone methiodide was injected at doses of 0.1 and 1.0 g, 10 min prior to NPY treatment. NPY was administered immediately prior to the start of the nocturnal period and RQ was determined using an open-circuit calorimeter. Doses of 50 and 100 pmol NPY alone evoked reliable increases in RQ within 30min of treatment. Following naloxone methiodide pretreatment, the stimulatory action of NPY was significantly attenuated. These data indicate that opioid receptors in the PVN influence the action of NPY on energy substrate utilization.

5-Hydroxytryptaminergic receptor agonists: effects on neuropeptide Y potentiation of feeding and respiratory quotient.

The objective of the present report was to characterize further the potential interactive effects of NPY and 5-HT on feeding and whole-body calorimetry. Specifically, several experiments examined the impact of various 5-HT receptor agonists on NPY stimulated eating and alterations in respiratory quotient (RQ). This included the 5-HT1A/1B receptor agonist RU 24969, the 5-HT1B/2C agonist TFMPP and the 5-HT2A/2C agonist DOI. In feeding tests conducted at the onset of the dark cycle, RU 24969, TFMPP and DOI were administered 5 min prior to PVN injection of NPY and food intake was measured 1 h postinjection. The metabolic effects of NPY following similar pretreatment were monitored using an open-circuit calorimeter measuring the volume of oxygen consumed (VO2), carbon dioxide produced (VCO2) and RQ (VCO2/VO2). PVN injection of NPY (50-100 pmol) potentiated feeding and evoked reliable increases in RQ. DOI (5-20 nmol), but not RU 24969 (5-20 nmol) or TFMPP (10-40 nmol), antagonized NPY induced eating and blocked the peptide's effects on RQ. These findings suggest that 5-HT2A receptors within the PVN modulate NPY's effect on feeding and energy substrate utilization at the start of the nocturnal period.

Reversal of fenfluramine and fluoxetine anorexia by 8-OH-DPAT is attenuated following raphe injection of 5,7-dihydroxytryptamine.

Drugs that enhance serotonergic neurotransmission reduce food intake by directly or indirectly activating serotonergic receptors. In contrast drugs that inhibit serotonergic neurotransmission such as the 5-HT1A agonist 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) stimulate food intake. The present study examined the effects of 8-OH-DPAT on the feeding suppressant action of the indirect 5-HT agonists fenfluramine (FEN; 0.63-2.5 mg/kg) and fluoxetine (FLU; 2.5-10 mg/kg), as well as the 5-HT1B/2C agonist 1-(3-trifluoromethylphenyl)piperazine (TFMPP; 0.5-2 mg/kg). 8-OH-DPAT (62.5-250 microg/kg) was administered 5 min prior to FEN, FLU or TFMPP, injected 30 min before food access. While FEN, FLU and TFMPP dose-dependently reduced 2 h food intake, 8-OH-DPAT stimulated eating behavior. 8-OH-DPAT (62.5-250 microg/kg) pretreatment reversed the anorectic action of FEN (1.25 mg/kg) and FLU (5 mg/kg) but not TFMPP (1 mg/kg). Separate groups of rats were injected with 5,7-dihydroxytryptamine (5,7-DHT; 3 microg free base) into both the dorsal and median raphe, which resulted in extensive 5-HT depletion in hypothalamus (80%), striatum and hippocampus (90%). In both 5, 7-DHT and vehicle-injected rats, FEN (1.25 mg/kg) and FLU (5 mg/kg) suppressed feeding. In 5,7-DHT treated rats, however, the ability of 8-OH-DPAT (125 microg/kg) to block FEN and FLU induced anorexia was attenuated. That is, 8-OH-DPAT pretreatment did not reverse the feeding inhibitory effects of either FEN or FLU. Further, the ability of FEN and FLU to suppress food intake was not altered by the 5,7-DHT lesion. These findings suggest that the reversal of FEN and FLU anorexia by 8-OH-DPAT is partially dependent on the integrity of brain 5-HT systems since their disruption compromises the ability of this 5-HT1A agonist to antagonize the feeding suppressant action of either FEN or FLU. However, the ability of treatments which impair 5-HT neurotransmission to reverse FEN and FLU induced suppression of food intake may depend upon whether this impairment is acute and reversible (8-OH-DPAT), or chronic and irreversible (5,7-DHT).

Association of altered whole-body metabolism with locomotor sensitization induced by quinpirole.

Repeated exposure to drugs classed as psychostimulants can produce behavioral sensitization, defined as augmented motor responses to fixed doses of such compounds. For example, chronic treatment of rats with the dopamine D2/D3 agonist quinpirole increases the locomotor response to this drug to levels that are several times higher than after acute treatment. To determine if such enhanced activity is associated with changes in energy metabolism, one group of rats (n = 16) received 11 injections of quinpirole (0.5 mg/kg every second day) while a second received equal numbers of saline injections. Immediately after each injection, rats were placed in individual metabolic chambers where oxygen (O2) consumption, carbon dioxide (CO2) output, and motor activity were measured every 5 min for the next 2 h. Locomotor responses to quinpirole doubled during the course of treatment, thereby confirming the establishment of behavioral sensitization. The magnitude of energy metabolism and motor activity were positively correlated in control rats but not in quinpirole-treated rats. However, quinpirole reliably reduced respiratory quotient (CO2/O2). This suggests that enhanced utilization of body lipids could be a separate physiological consequence of quinpirole that might support in part the heightened locomotor activity characteristic of the behavioral sensitization it induces.

Acute amino acid loads that deplete brain serotonin fail to alter behavior.

Acute depletion of brain serotonin (5-HT) can be induced in both rats and humans by giving an amino acid load deficient in tryptophan (TRY). Because this treatment is relatively easy to administer and short-acting, it seems well suited for studying mood and/or behavioral changes linked to aberrant 5-HT functioning in humans. To investigate the ability of a TRY-deficient amino acid load to induce behavioral changes in animals, this study measured performance on an operant schedule of differential reinforcement of low rates of responding (DRL), locomotor activity in both novel and familiar environments, and paw-lick latencies on a hot-plate. All of these measures have been found previously to be altered by impairments of the brain 5-HT system. Adult male Sprague-Dawley rats were administered by gavage an amino acid load lacking TRY, an amino acid load containing TRY, or distilled water. Three hours later, behavioral tests were conducted. Although 5-HT levels were decreased in the hippocampus (-23.3%) and 5-hydroxyindoleacetic acid (5-HIAA) levels were decreased in the striatum (-35.1%) and hippocampus (-38.5%), there were no effects of the TRY-deficient load on any of the behavioral tests. Because reliable mood-altering effects have been reported in human subjects using this method, their behavioral counterparts may be too subtle to observe in animals. Alternatively, effects observed in humans may reflect nonserotonergically mediated consequences of such tryptophan deficient amino acid loads and/or preexisting abnormalities of 5-HT or other systems in such people.

Neuropeptide Y-induced operant responding for sucrose is not mediated by dopamine.

Neuropeptide Y (NPY) induces feeding in previously satiated animals after injection into the hypothalamus, especially the perifornical region (PFH). NPY also appears to have rewarding properties as evidenced by its ability to produce a conditioned place preference following injection into the nucleus accumbens (N.Acc), an effect ostensibly mediated by mesolimbic dopamine (DA). Since the progressive-ratio (PR) operant schedule has also been used to assess an organism's motivation to respond for rewarding stimuli, we tested the possibility that NPY increases PR responding for sucrose pellets. Adult male rats were injected with NPY (0-235 pmol) bilaterally through cannulae aimed to terminate in the PFH. This produced a dose-dependent increase in the total number of responses made and the number of reinforcers earned. The DA receptor blocker, alpha-flupenthixol (FLU)(0-0.2 mg/kg intraperitoneally), attenuated both NPY(156 pmol)-induced and drug-free PR responding while having no effect on NPY(156 pmol)-induced free-feeding. FLU injected directly into the N.Acc (0-5 microg) also failed to reduce sucrose free-feeding. These results suggest that distinct reward mechanisms are activated during PFH NPY-induced feeding vs. PR responding, since FLU disrupted the latter but not the former.

Stimulation of 5-HT(2A/2C) receptors within specific hypothalamic nuclei differentially antagonizes NPY-induced feeding.

The present study examined the impact of the 5-HT(2A/2C) agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on the feeding-stimulant action of neuropeptide Y (NPY) injected into three hypothalamic sites, the paraventricular nucleus (PVN), the perifornical hypothalamus (PFH) and the ventromedial nucleus (VMH). Injections of NPY (100-200 pmol) into each region potentiated food intake. Pretreatment with DOI (5-20 nmol) into the PVN effectively suppressed feeding elicited by PVN NPY (100 pmol). In contrast, DOI injections into the PFH and VMH failed to modify NPY-stimulated eating. This suggests that 5-HT(2A/2C) receptor modulation of NPY feeding within the hypothalamus is localized to the PVN.

Regional hypothalamic differences in neuropeptide Y-induced feeding and energy substrate utilization.

Previous research has shown that both the paraventricular nucleus (PVN) of the hypothalamus and the perifornical hypothalamus (PFH) are sites at which microinjection of neuropeptide Y (NPY) can induce eating. The PVN has also been shown to be responsive to the effects of exogenous NPY on energy substrate utilization. Therefore, the objective of the present study was to further characterize and compare the effects of NPY on whole-body calorimetry and feeding after microinjection into either the PVN or the PFH. The metabolic effects of NPY (19.5-78 pmol) were determined using an open-circuit calorimeter by measuring the volumes of oxygen consumed and carbon dioxide expired in order to compute respiratory quotients (RQs). Following NPY injection into the PVN (n = 10) or PFH (n = 10), RQs and locomotor activity were monitored over three hours. Additional groups of rats with PVN (n = 10) or PFH (n = 10) cannulae were tested for their feeding responses to these same doses of peptide. While NPY injections into the PVN evoked dose-dependent increases in RQ within 30-40 min of treatment, PFH NPY did not alter RQ at any of the doses tested. Locomotor activity was unaffected by NPY in either site. NPY administration into both the PVN and PFH stimulated eating, although the PFH was found to be the more sensitive in terms of absolute amount of food consumed. These findings support the hypothesis that the PVN may regulate metabolic processes that either produce or coincide with NPY-induced feeding. This contrasts with the PFH, which appears to mediate only the feeding-stimulatory actions of NPY.

Metergoline potentiates natural feeding and antagonizes the anorectic action of medical hypothalamic 5-hydroxytryptamine.

Medial hypothalamic injections of 5-hydroxytryptamine (5-HT) or its agonists have been reported to inhibit feeding elicited by norepinephrine (NE), suggesting that these two transmitter systems interact antagonistically in the control of ingestive behavior. The present study was designed to directly test the hypothesis that 5-HT inhibits adrenergic feeding, specifically at the onset of the rat's nocturnal eating cycle. Free-feeding animals were injected with 5-HT (5-20 nmol) immediately before NE (20 nmol) and food intake was measured 1.5 h postinjection. In separate groups of rats, the serotonergic antagonist metergoline (MET) (2.5-20nmol) was injected into the paraventricular nucleus (PVN) immediately before 5-HT, or before combined injections of 5-HT and NE. The feeding-stimulant action of MET alone, injected IP (0.25-2 mg/kg) or centrally (2.5-40 nmol), was also examined. Results indicated that administration of 5-HT into the PVN suppressed dark onset feeding and dose-dependently blocked NE-stimulated eating. Pretreatment with MET attenuated the inhibitory action of 5-HT on feeding, and reversed the serotonergic blockade of the adrenergic eating response. Further, systemically injected MET significantly increased dark onset feeding, whereas PVN injections failed to alter food intake reliably. These findings provide the first direct evidence that serotonergic and adrenergic systems within the PVN interact in a competitive manner to modulate the natural high rates of feeding displayed by rats during the early dark period. Although MET effectively blocked the anorectic effect of 5-HT, the feeding-stimulant action of this compound alone does not appear to be mediated within the PVN.

Effect of the CCKA antagonist devazepide on eating stimulated by raphe injection of 8-OH-DPAT.

Several recent studies have suggested that feeding suppression is mediated jointly by enhanced neurotransmission of cholecystokinin (CCK) and serotonergic (5-HT) systems. In the present study the CCKA receptor antagonist devazepide (50-200 micrograms kg-1, s.c.) was found reliably to potentiate the feeding response elicited by dorsal or median raphe injection of the 5-HT1A agonist 8-OH-DPAT (0.2-0.8 nmol). This effect was evident following co-administration of both feeding threshold and subthreshold doses of either compound, suggesting that the simultaneous suppression of CCK and 5-HT function may interact as joint effectors of overeating.

Ineffectiveness of hypothalamic serotonin to block neuropeptide Y-induced feeding.

A variety of recent research has suggested that the feeding associated with enhanced neuropeptide Y (NPY) activity within the hypothalamus may operate in part by interacting antagonistically with other neural processes responsive to serotonin (5-hydroxytryptamine or 5-HT). To test this possibility further, experiments were performed to determine if the magnitude of feeding produced by injecting NPY into the paraventricular nucleus (PVN) or the perifornical hypothalamus (PFH) was diminished by coinjections of 5-HT into these two sites or peripheral injections of the 5-HT agonist, d-fenfluramine. Adult male Sprague-Dawley rats were implanted unilaterally with stainless steel cannulae aimed to terminate either in the PVN or the PFH. In both studies, NPY (235 pmol) produced significant feeding in both sites either 1 or 2 h after injection when compared to saline. This enhanced feeding response was significantly greater in the PFH 2 h after injection (40% in the central study; 70% in the peripheral study). Coinjection of 5-HT (6.3, 12.5, or 25.0 nmol) into either site had no effect on the induction of this NPY-induced feeding response. However, peripherally injected d-fenfluramine (0.32, 0.63, or 1.25 mg/kg) produced strong dose-dependent attenuation both 1- and 2-h food intake elicited by 235 pmol NPY in either site, with the PFH being proportionately more sensitive to this effect. Viewed together, these results suggest that the feeding-suppressant effects of systemic fenfluramine on hypothalamic NPY-induced feeding may operate largely via peripheral mechanisms and/or central ones that have little to do with its 5-HT agonistic effects within the PVN or PFH.

Serotonin depletion by 5,7-dihydroxytryptamine does not affect G protein subunit levels in rat cortex.

To investigate the role of G proteins in denervation supersensitivity of the CNS serotonergic system, we examined the effect of lesioning serotonergic neurons on the abundance of cerebral cortical membrane G protein subunits in rats. Three weeks after intracisternal injection of 5,7-dihydroxytryptamine (5,7-DHT), which significantly reduced cortical 5-hydroxytryptamine (5-HT; -90%) and 5-hydroxyindoleacetic acid (approximately 98%) levels, no statistically significant differences were observed for G alpha s-1, G alpha s-s, G alpha i1, G alpha i2, G alpha q/11, G alpha 0, G beta 1 and G beta 2 immunoreactivity levels between sham-lesioned and 5,7-DHT lesioned rats. These data suggest that the functional supersensitivity of 5-HT neuronal system often observed following lesions of 5-HT fibers may not involve changes at the level of G proteins but may instead encompass other downstream elements of the 5-HT receptor signaling cascade.