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.     

Effects of the novel anxiolytics gepirone,buspirone and ipsapirone on free feeding and on feeding induced by 8-OH-DPAT

The effects of the novel anxiolytics gepirone, buspirone and ipsapirone on free feeding and on feeding induced by the 5-HT_1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), were examined. Gepirone dose-dependently increased feeding 2 and 4 h after injection, the magnitude of the response being larger than previously observed with any other 5-HT_1A receptor ligand. Previous studies have suggested that buspirone and ipsapirone can block some of the behavioural effects of 8-OH-DPAT. However, gepirone, buspirone and ipsapirone did not inhibit feeding induced by 8-OH-DPAT. These results indicate that gepirone is a very efficacious appetite stimulant in rats and suggest that gepirone, buspirone and ipsapirone act as 5-HT autoreceptor agonists in the feeding model.     

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.     

Effects of adrenalectomy on 8-OH-DPAT induced hypothermia in mice

Complex interactions exist between the hypothalamic-pituitary-adrenal (HPA) axis and the serotonergic system, and it has been suggested that these interactions may be fundamental to the pathophysiology and treatment of depressive illnesses. It has previously been found that chronic administration of corticosterone leads to adrenal suppression and an attenuation of somatodendritic 5-HT_1A receptor function. Adrenalectomy (ADX) has been shown to cause an increase in postsynaptic 5-HT_1A receptor numbers and possibly function. However, other reports have suggested that ADX does not alter somatodendritic 5-HT_1A receptor mRNA or binding, though little is known of the effect of ADX on the function of somatodendritic 5-HT_1A receptors. This study investigated the effect of markedly reducing corticosterone levels by ADX on 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)-induced hypothermia in mice, an in vivo model of somatodendritic 5-HT_1A receptor function. The degree of 8-OH-DPAT-induced hypothermia did not differ between control, sham, and ADX animals 14 days post operatively. Although repeated administration of corticosterone attenuates somatodendritic 5-HT_1A receptor function, these data demonstrate that lowering of corticosteroid levels by ADX have no effect. This suggests that the effects of repeated corticosterone administration is not mediated by a secondary adrenal suppression. The difference in the effects of ADX on somatodendritic as opposed to postsynaptic 5-HT_1A receptors may reflect the differential expression of corticosteroid receptor subtypes at postsynaptic and somatodendritic sites. Received: 30 March 1998/Final version: 23 July 1998     

Effects of hypothalamic knife cuts on feeding induced by paraventricular norepinephrine injections

The relationship between the fiber systems involved in the hypothalamic noradrenergic feeding response and the medial hypothalamic (MH) hyperphagia syndrome was appraised in male rats using knife cuts. Parasagittal knife cuts in the perifornical hypothalamus produced hyperphagia and excessive weight gain but failed to disrupt feeding in response to paraventricular hypothalamic injections of norepinephrine (NE). Coronal knife cuts in the posterior hypothalamus which extended from the midline to the lateral perifornical region also failed to disrupt NE feeding. These findings indicate that the output of the noradrenergic feeding system does not follow the feeding pathway implicated in the MH hyperphagia syndrome. They also suggest that the output of the noradrenergic feeding system is not directed laterally beyond the level of the fornix nor caudally into the lower brainstem over the medial forebrain bundle.     

Para-chlorophenylalanine prevents feeding induced by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)

The effects of para-chlorophenylalanine pre-treatment (PCPA, 150 mg/kg IP daily for 3 days) on feeding and stereotyped behaviour elicited by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in rats were investigated. PCPA depleted brain serotonin and 5-hydroxyindoleacetic acid concentrations by 90% and increased feding during a 2-h day-time test. 8-OH-DPAT (60–4000 μg/kg SC) increased food intake in control animals but decreased in in PCPA-treated animals during the 2-h test. PCPA treatment had no effect on 8-OH-DPAT-induced locomotion or serotonin-related stereotyped behaviour (i.e. forepaw treading, headweaving, wet dog shakes, etc). Since PCPA prevents the operation of pre-synaptic serotonergic mechanisms, the failure of 8-OH-DPAT to increase food intake in PCPA-treated rats suggests that 8-OH-DPAT-induced hyperphagia is autoreceptor mediated.     

Effects of histidine on working memory deficits induced by the 5-HT1A-receptor agonist 8-OH-DPAT

We investigated the effects of histidine on spatial memory deficits induced by the 5-HT1A-receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Working memory deficits were elicited by 8-OH-DPAT without affecting reference memory. Histidine improved the working memory deficit induced by 8-OH-DPAT at doses causing a significant increase in brain histamine content. This finding suggests that the histaminergic system regulates 8-OH-DPAT-induced working memory deficit.     

Effects of the putative 5-HT1A receptor antagonist NAN-190 on free feeding and on feeding induced by the 5-HT1A receptor agonist 8-OH-DPAT in the rat.

The effects of the putative 5-HT1A receptor antagonist NAN-190 on feeding and spontaneous locomotor activity in rats were examined. The drug elicited a robust, dose-dependent (0.01-10 mg/kg) increase in food consumption in free feeding animals. Microstructural analysis of feeding induced by NAN-190 (3 mg/kg) revealed that the drug increased the duration of feeding and number of feeding bouts but decreased the feeding rate. The increase in feeding induced by 3 mg/kg of NAN-190 was not apparent until 2-4 h after injection. This prolonged latency to onset of the feeding response appeared to be due to response competition. Thus, a 'neuroleptic-like' action of the drug on spontaneous motor activity was observed during the the initial 2 h following injection. A dopamine receptor antagonist action of NAN-190 was also indicated by the results of studies in which the drug was observed to block oral stereotypy induced by the dopamine receptor agonist apomorphine. In interaction studies, NAN-190 (0.1 and 10 mg/kg) failed to block the feeding response induced by the prototypical 5-HT1A receptor agonist 8-OH-DPAT (0.0625 and 1.0 mg/kg) and indeed, appeared to have an additive effect with 8-OH-DPAT on consummatory behaviour. These data suggest that NAN-190 may act as a partial agonist rather than an antagonist at the 5-HT1A receptor and also provide the first evidence that the drug has dopamine receptor antagonist properties in vivo.     

Effects of 8-OH-DPAT on motor activity in the rat

The administration of 8-OH-DPAT to rats produced a dose-dependent suppression of spontaneous locomotor activity in an open field arena. 8-OH-DPAT was administered in the dose range 12.5-1,600 micrograms.kg-1 SC. Vertical activity ("rearing") was more sensitive to the treatment than horizontal activity ("locomotion"), both in terms of potency and efficacy. The activity along the walls of the open field arena ("peripheral activity") was increased, and the rearing activity was decreased, relative to total horizontal activity and total activity, respectively. There were no effects by 8-OH-DPAT on treadmill locomotion. The rectal temperature was decreased by 8-OH-DPAT administration, not only in animals tested in the open field, but also in animals with an increased body temperature, produced by treadmill locomotion.     

Effects of lateral hypothalamic lesions on the anorexia induced by ethanolamine-O-sulfate

Intracisternal (IC) injection of the GABA-transaminase inhibitor, ethanolamine-O-sulfate (EOS), has been previously shown to induce dose-dependent anorexia in normal rats as well as to reverse overeating in several rodent models of acute and chronic hyperphagia. To determine if such anorexia might be mediated by cells within or fibers of passage which traverse the lateral hypothalamus (LH), adult female rats received bilateral radiofrequency heat lesions of the LH vs. anesthesia control injections and were allowed to recover normal feeding and drinking responses. Using a longitudinal design, all animals then received 100, 0, and 200 micrograms EOS in 20 microliters deionized water IC with 1 week separating each injection. In addition to daily measures of feeding, drinking and body weight, all animals were screened 24 hr after injections for sensorimotor competence and general health by testing open-field activity, catalepsy, paw-lick responses on a hot-plate and rectal temperature. As reported previously, IC EOS induced dose-dependent hypophagia and weight loss. However, the magnitude and duration of these effects were equivalent in lesioned and control rats. In addition, open-field activity and body temperature were reliably lowered as a function of dosage while catalepsy was increased. Again, this effect was equivalent in lesioned and control rats. Subsequent tests of drinking and feeding in response to hyperosmotic and hypoglycemic challenges, respectively, confirmed that lesioned rats were deficient compared to controls. These findings suggest that an intact LH axis is not required for the anorexigenic effects of IC EOS.     

Conditioned place preference induced by microinjection of 8-OH-DPAT into the dorsal or median raphe nucleus

Experiments were conducted to examine the ability of the selective 5-hydroxytryptamine (5-HT)_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to induce a conditioned place preference following peripheral injection, and direct microinjection into the dorsal or median raphe nuclei. An unbiased place preference paradigm was used in which control animals showed no preference for either of two compartments differing in terms of colour (white versus black), floor texture (rough versus smooth) and olfactory cues (no odour versus acetic acid odour). Drug treatments were paired with access to either of the two compartments, and saline injections were paired with access to the other compartment. Rats experiencing a low dose of 8-OH-DPAT (125 µg/kg) with a specific compartment demonstrated a significant preference for that compartment over one paired with saline injections. The magnitude of this effect was similar to that observed in rats treated with 1.5 mg/kgd-amphetamine. A significant place preference was found in animals receiving injections of 8-OH-DPAT in the dorsal raphe at 0.1 µg but not 1 µg. Animals also displayed a preference for the compartment paired with 1 µg 8-OH-DPAT injected into the median raphe; lower doses were not effective. These results indicate that the mechanism by which 8-OH-DPAT induces a conditioned place preference involves activation of raphe somatodendritic 5-HT_1A autoreceptors, leading to a reduction in 5-HT neurotransmission. This demonstration of the rewarding properties of 8-OH-DPAT, together with previous results showing increased feeding and sexual behaviour following 8-OH-DPAT treatment, strongly suggests an important role for brain 5-HT systems in reward and reinforcement processes.     

Estradiol modulation of the hyperphagia induced by the 5-HT1A agonist, 8-OH-DPAT.

Ovariectomized rats were primed with sesame oil or estradiol benzoate followed 48 h later by either sesame oil or progesterone. Four hours later, rats were treated with either saline or 0.25 mg/kg 8-hydroxy-2-9(di-n-propylamino)tetralin (8-OH-DPAT). Rats were allowed to eat for 4 h after this final treatment. Animals in all hormonal conditions showed hyperphagia following 8-OH-DPAT. However, the hyperphagia was significantly attenuated by pretreatment with estradiol benzoate. There was no effect of progesterone on the hyperphagic response. These results suggest that previous findings of an estrous cycle modulation of the hyperphagic response to 8-OH-DPAT arise from the modulatory effects of estradiol, and not progesterone, during the female reproductive cycle.     

Effects of serotonin antagonists on motion sickness and its suppression by 8-OH-DPAT in cats

This investigation evaluated the antagonist properties of (-)propranolol, (+)propranolol, metergoline and BMY 7378 on the known effect of 8-OH-DPAT (DPAT) to decrease motion sickness in cats. (-)Propranolol produced a greater decrease in the antiemetic effect of DPAT than did (+)propranolol. Although metergoline produced a decrease in the antiemetic effect of DPAT, the decrease could not be clearly attributed to interactions with 5-HT1A receptors because metergoline alone slightly enhanced motion sickness. Depletion of 5-HT with PCPA produced a weaker, nonsignificant enhancement of motion sickness, while mesulergine had no effect. As neither nonspecific 5-HT receptor blockade with metergoline nor depletion of 5-HT mimicked the antiemetic effect of DPAT, it was concluded that DPAT acts on postsynaptic 5-HT1A receptors to prevent emesis. BMY 7378 alone decreased the incidence of motion sickness. A dose just below this agonist range did not decrease the effects of DPAT.     

Ventromedial hypothalamic mediation of sucrose feeding induced pain modulation

Electrophysiological and behavioural studies suggest a modulatory role of ventromedial nucleus of the hypothalamus (VMH) in nociceptive behaviour. Lesion of the VMH produces hyperalgesia and a greater preference for sucrose solution. Hyperalgesia is also produced by sucrose feeding. To explore specifically the contribution of glucoreceptor neurons of the VMH in the mediation of sucrose-fed hyperalgesia, 2-deoxy-D-glucose (2-DG, antimetabolite of glucose) was slowly albeit continuously infused (1 microl/h for 7 days by microinfusion pumps) into the VMH of adult male rats. Simultaneously, the rats underwent tests for their nociceptive responses in control and sucrose-fed states. The tests for nociception, namely, tail flick latency (TFL), thresholds of tail flick (TF), vocalization during stimulus (SV), vocalization after discharge (VA) were recorded at 0500 h. The tests were repeated after 6, 12, and 48 h in 1 M saline (control group) and 2-DG (experimental group) microinfused rats. Rats were presented with sucrose (20%) solution for 48 h at 0500 h ad libitum in addition to food pellets and tap water. Infusion of 2-DG per se in the VMH led to hypoalgesia (in threshold of TF, SV, VA) while feeding sucrose for 6-12 h per se led to hyperalgesia (in TFL, threshold of SV and VA). Sucrose feeding to 2-DG rats, however, attenuated the hypoalgesia of 2-DG as well as the hyperalgesia of sucrose feeding. The results suggest that the VMH glucoreceptor neurons probably modulate sucrose mediated phasic pain responses.     

8-OH-DPAT specifically enhances feeding behaviour in mice: evidence from behavioural competition

The behavioural specificity of the hyperphagic effects of 8-OH-DPAT is a controversial issue. The present study addressed this question through the introduction of behavioural competition. Feeding behaviour in male mice was assessed under both basal (free-feeding) and social conflict conditions. Since, in the latter condition, defence and escape are prepotent responses, elicitation of feeding would be indicative of a specific treatment effect on mechanisms controlling food intake. Results showed that 8-OH-DPAT enhanced basal feeding duration (at doses of 0.05–0.50 mg/kg) and also elicited feeding in intruder mice during encounters with aggressive resident conspecifics (at doses of 0.10–0.50 mg/kg). As the 5-HT₃ antagonist GR 38032F (1.0–2.0 mg/kg) enhanced feeding only under basal conditions, the effect of 8-OH-DPAT cannot readily be attributed to anxiety reduction. Finally, diazepam (1.0–2.0 mg/kg) produced a similar profile to that of 8-OH-DPAT, suggesting that the hyperphagic effects of the 5-HT_1A agonist are not pharmacologically specific.     

Quinpirole, 8-OH-DPAT and ketanserin modulate catalepsy induced by high doses of atypical antipsychotics

The effect of the selective dopamine D2 receptor agonist quinpirole, the selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT2A receptor antagonist ketanserin on catalepsy induced by atypical antipsychotics clozapine, risperidone, olanzapine and sertindole at higher doses was studied in rats. Haloperidol (0.5, 1 and 2 mg/kg), clozapine (50 and 75 mg/kg) and olanzapine (15 and 30 mg/kg) produced catalepsy dose-dependently while sertindole at doses up to 40 mg/kg failed to produce catalepsy in rats. However, sertindole (15, 30 and 45 mg/kg) produced a cataleptic effect in mice in a dose-dependent manner. At a high dose (5 mg/kg), risperidone produced catalepsy in rats. Quinpirole (0.05 and 0.1 mg/kg) reversed the cataleptic effect of haloperidol (2 mg/kg), risperidone (5 mg/kg), olanzapine (30 mg/kg) and sertindole (45 mg/kg). Quinpirole (0.05 and 0.1 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15 and 0.3 mg/kg) dose-dependently reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg) without affecting the cataleptic effect of olanzapine. However, the higher dose (0.45 mg/kg) of 8-OH-DPAT reversed it significantly. 8-OH-DPAT (0.3 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15, 0.3 and 0.45 mg/kg) failed to reverse sertindole-induced catalepsy. Ketanserin (0.75 and 1.5 mg/kg) completely reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg). Ketanserin (0.75 and 1.5 mg/kg) dose-dependently reversed olanzapine (30 mg/kg) and sertindole (45 mg/kg)-induced catalepsy without any effect on clozapine (75 mg/kg)-induced catalepsy. A higher dose (3 mg/kg) of ketanserin reversed clozapine-induced catalepsy. The present study suggests that atypical antipsychotics show fewer extrapyramidal symptoms (EPS) due to greater modulation of the serotonergic system. Therefore, an antipsychotic with dopamine D2/5-HT2A antagonistic action and 5-HT1A agonistic action may prove to be superior to the existing antipsychotics.     

Effects of 8-OH-DPAT and fluoxetine on activity and attack by female mice towards lactating intruders

1. The impact of the serotoninergic receptor on the attack directed by female mice towards lactating intruders was assessed by studying the effects of 8-OH-DPAT (a serotoninergic agonist) and fluoxetine (an inhibitor of serotonin reuptake) on this paradigm at a range of doses and post-injection durations. 2. The specificity of these drug actions behaviour were examined by studying their effects on wheel running activity and performance in the open field. Non-sedative doses of 200 and 250 micrograms/kg of 8-OH-DPAT reduced attack by resident females on lactating intruders. 3. Higher doses (12-16 mg/kg) of fluoxetine reduced activity measures whereas lower non-sedative doses (up to 8 mg/kg) were without action on this aggression paradigm. 4. Additional studies with specific serotoninergic drugs are needed to clarify the role of this transmitter in attack by female mice on lactating intruders.     

A nitric oxide synthase inhibitor reduces hyperphagia induced in rats by the 5-HT(1A) receptor agonist, 8-OH-DPAT, independently of hypothalamic serotonin metabolism

In rats, a nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) inhibited the hyperphagia induced by the 5-hydroxytryptamine (5-HT)(1A) autoreceptor agonist, 8-hydroxy-2-di-n-(propylamino)tetralin (8-OH-DPAT). 8-OH-DPAT reduced 5-HT metabolism in the hypothalamus, and this was not blocked by pretreatment with L-NAME. L-NAME also did not affect basal hypothalamic 5-HT metabolism or reverse the decreases in 5-HT synthesis in hypothalamus. These results suggest that the hypophagic effects of L-NAME, which inhibits NO formation, are independent of 5-HT metabolism in the hypothalamus.     

Effects of 8-OH-DPAT and WAY-100635 on performance on a time-constrained progressive-ratio schedule

Rationale. Performance on progressive-ratio schedules has been proposed as a means of assessing the effects of drugs on motivation. We have adopted a mathematical model proposed by Killeen to analyse the effects of drugs acting at 5-HT_1A receptors on progressive-ratio performance. According to this model, the relationship between response rate and ratio size is described by a bitonic (inverted-U) function. One parameter of the function, a, expresses the motivational or "activating" effect of the reinforcer (duration of activation of responding produced by the reinforcer), whereas another parameter, δ, expresses the minimum time needed to execute a response and is regarded as an index of "motor capacity". Objective. To examine the effect of the selective 5-HT_1A receptor agonist 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] and the antagonist WAY-100635 [N-[2-(4-[2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclo-hexanecarboxamide] on progressive-ratio schedule performance. Methods. Sixteen rats responded for a food-pellet reinforcer on a time-constrained progressive-ratio schedule (55-min sessions). In phase 1, they received single doses (s.c.) of 8-OH-DPAT (25, 50, 100, 200 μg kg⁻¹, four treatments at each dose) or the vehicle (0.9% saline solution). In phase 2, they received WAY-100635 (30, 100, 300 μg kg⁻¹) according to the same regimen. In phase 3, they received 8-OH-DPAT (100 μg kg⁻¹) alone or in combination with WAY-100635 (30 μg kg⁻¹). 8-OH-DPAT dose dependently increased the value of a, significant increases being seen with the 50, 100 and 200 μg kg⁻¹ doses. The highest dose also increased δ. WAY-100635 did not significantly alter either a or δ. WAY-100635 significantly attenuated the effect of 8-OH-DPAT on both a and δ. Conclusions. The results suggest that 8-OH-DPAT enhanced the activating effect of the reinforcer (the highest dose may also have induced motor debilitation). The finding that the effect of 8-OH-DPAT on a was attenuated by WAY-100635 implicates 5-HT_1A receptors in this effect. The results are consistent with previous reports that 8-OH-DPAT facilitates feeding and food-reinforced operant responding in rats and suggest that these effects may be brought about by an increase in food motivation. Electronic Publication