Paul J. Fletcher

Increased food intake in satiated rats induced by the 5-HT antagonists methysergide, metergoline and ritanserin

Two series of experiments examined whether 5-hydroxytryptamine (5-HT) antagonists induce feeding in rats. In the first series of experiments separate groups of rats were injected with various doses of methysergide, cyproheptadine, metergoline or ritanserin prior to a 2 h period of access to a wet mash diet which induced vigorous feeding under control conditions. None of the antagonists increased food intake in this paradigm. Rather, at certain doses, methysergide, cyproheptadine and ritanserin induced slight decreases in food intake. Since 5-HT may be involved in controlling satiety, it may be that a more appropriate test of the efficacy of these compounds involves administering them to maximally satiated rats. Consequently, the effects of these drugs were investigated in groups of rats which had fed to satiety immediately prior to drug treatment. In this paradigm methysergide, metergoline and ritanserin, but not cyproheptadine, induced definite increases in food intake. It is suggested that this effect occurs via a dissipation of satiety signals, and that these results further support the hypothesis that 5-HT is involved in controlling satiety. The possibility that these antagonists act on peripheral 5-HT systems is discussed.

The involvement of 5-hydroxytryptaminergic and dopaminergic mechanisms in the eating induced by buspirone, gepirone and ipsapirone

1 The roles of 5‐hydroxytryptamine (5‐HT) and dopamine systems in mediating the increased feeding induced by buspirone, gepirone and ipsapirone were investigated. 2 All three compounds induced dose‐dependent increases in food intake when administered subcutaneously to free feeding rats. Buspirone was effective over a narrower dose range than either gepirone or ipsapirone, and the maximal effect observed was smaller than the effects elicited by gepirone and ipsapirone. 3 Depletion of brain 5‐HT with parachlorophenylalanine (PCPA) prevented the effects of equi‐effective doses of gepirone (2.5 mg kg−1) and ipsapirone (2.5 mg kg−1), but failed to prevent buspirone (1 mg kg−1)‐induced eating. Thus buspirone does not appear to interact with 5‐HT systems to elicit feeding. 4 Gepirone (0.2 μg) and ipsapirone (0.04 and 0.2 μg) increased food intake when injected into the dorsal raphé nucleus (DRN), presumably by inhibiting the activity of DRN 5‐hydroxytryptaminergic afferents. Buspirone (0.04–5 μg) was ineffective when injected into the DRN. 5 Pretreatment with haloperidol (0.1 mg kg−1, 30 min) significantly attenuated the effects of equi‐effective doses of buspirone, gepirone and ipsapirone, indicating that these drugs interact with dopaminergic systems to increase feeding. 6 Previously it has been shown that each of these drugs increases striatal dopamine activity. Increased dopaminergic neurotransmission in the striatum induces a general behavioural activation, which under certain conditions facilitates feeding. It is possible that this mechanism underlies the behavioural effects of buspirone, gepirone and ipsapirone. The effects of gepirone and ipsapirone probably involve an indirect action to inhibit the activity of DRN 5‐hydroxytryptaminergic afferents, whereas buspirone interacts directly with dopaminergic systems.

8-OH-DPAT elicits gnawing, and eating of solid but not liquid foods

The behavioural specificity of the eating elicited by the serotonergic agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was investigated. In non-deprived rats 8-OH-DPAT (60–240 μg/kg) increased the consumption of solid food pellets. The consumption of an 18% glucose solution was unaffected by 60 μg/kg 8-OH-DPAT, and markedly reduced by 120 μg/kg 8-OH-DPAT. When rats were pre-fed glucose, to reduce glucose intake under control conditions, 60 μg/kg 8-OH-DPAT significantly decreased subsequent glucose consumption. The failure of 8-OH-DPAT to induce a hyperphagic response to glucose suggests that this compound does not elicit eating by an action upon feeding motivation. Observational analyses showed that 8-OH-DPAT-treated rats exhibited several oro-facial motor responses, including gnawing, which were attenuated by pretreatment with haloperidol. It is likely, therefore, that the increase in solid food intake elicited by 8-OH-DPAT is incidental to drug-induced gnawing. Possible mechanisms of this action are discussed.

A comparison of the effects of tryptamine and 5-hydroxytryptamine on feeding following injection into the paraventricular nucleus of the hypothalamus

The effects of 5-hydroxytryptamine (5-HT) and tryptamine injected into the paraventricular nucleus of the hypothalamus (PVN) on food intake, and on noradrenaline- (NA) induced feeding were examined. In nondeprived rats, 12.5-100 nmol 5-HT reduced the intake of palatable wet mash diet over a 30-minute period. Tryptamine (50 and 100 nmol) was without effect in this paradigm. However, when tryptamine was injected into the PVN of rats pretreated with the monoamine oxidase inhibitor, pargyline, a strong anorectic effect was observed. The action of tryptamine in pargyline-treated rats was not affected by depletion of 5-HT levels in the PVN with PCPA. This indicates that the effect of tryptamine is not mediated by a release of endogenous 5-HT. Tryptamine injected into the PVN potentiated the effect of a low dose of 5-HT on food intake. This effect may be due to a prolongation of the activity of 5-HT resulting from tryptamine competing with 5-HT for the same reuptake system. Tryptamine and 5-HT attenuated the feeding response elicited by injection of 25 nmol NA into the PVN. Both tryptamine and 5-HT were more potent at attenuating the effects of NA than in reducing the intake of the palatable wet mash diet. Overall, the results suggest that tryptamine may act via the serotonergic system in the PVN to affect food intake, but it is a weaker compound than 5-HT in this respect.

A pharmacological analysis of the eating response induced by 8-OH-DPAT injected into the dorsal raphé nucleus reveals the involvement of a dopaminergic mechanism

Direct injection of the 5-hydroxytryptamine (5-HT) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the dorsal raphé nucleus (DRN) dose dependently increased food intake in free feeding rats. The hypothesis that this effect is mediated by 5-HT1A receptors was tested by investigating the abilities of the putative 5-HT1A antagonists metergoline, propanolol and spiperone to prevent 8-OH-DPAT-induced eating. Metergoline failed to affect 8-OH-DPAT-induced eating when injected either peripherally or into the DRN. Peripherally injected propranolol and spiperone prevented 8-OH-DPAT-induced eating, but these drugs were ineffective when injected into the DRN. These results indicate that 8-OH-DPAT-induced eating may not involve 5-HT1A receptors within the DRN. The ability of peripherally injected spiperone to prevent the eating response to 8-OH-DPAT reflects its dopamine blocking activity since haloperidol was an effective antagonist of 8-OH-DPAT-eating. This result may indicate that 8-OH-DPAT produces a general behavioural activation by reducing the inhibitory influence which 5-HT normally exerts over the nigrostriatal dopamine pathway, and that this behavioural activation is expressed as eating when food is the most salient goal object present.

Dorsal raphe microinjection of 5-HT and indirect 5-HT agonists induces feeding in rats

Previous work has shown that 5-hydroxytryptamine (5-HT) receptor agonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reduce 5-HT neurotransmission and induce feeding in rats. The effects of 8-OH-DPAT appear to be mediated in part in the dorsal raphe nucleus by serotonergic somatodendritic autoreceptors which normally regulate impulse flow in 5-HT dorsal raphe neurons. The present experiments sought to examine whether suppression of dorsal raphe serotonergic neural activity induced by exogenously applied, or endogenously released 5-HT would increase feeding. Free-feeding rats were microinjected in the dorsal raphe with 5-HT, the 5-HT releasing compound d-fenfluramine, the 5-HT re-uptake inhibitor zimelidine, or the type-A monoamine oxidase inhibitor brofaromine. Dose dependent increases in food intake over a 1 h period were found following treatment with 5-HT and the three indirectly acting compounds. Thus, increased serotonergic activity within the dorsal raphe increases feeding, presumably by inhibiting the activity of dorsal raphe 5-HT neurons. In addition the effects of 5-HT were blocked by pretreatment with haloperidol, indicating the involvement of a dopaminergic mechanism in mediating the effects of feeding of a suppression in dorsal raphe 5-HT neural activity. The results are discussed in terms of the general role which serotonergic neurons arising from the dorsal raphe may play in behavioural inhibition.

Effects of 8-OH-DPAT, buspirone and ICS 205-930 on feeding in a novel environment: comparisons with chlordiazepoxide and FG 7142

Previously, the 5-hydroxytryptamine (5-HT)1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone and the 5-HT3 receptor antagonist ICS 205-930 have been shown to exert anxiolytic-like effects in several animal models. In the experiments reported here the effects of these compounds on feeding behaviour and food preference in a novel environment were examined, and compared with the effects of the anxiolytic drug chlordiazepoxide and the anxiogenic compound FG 7142. Chlordiazepoxide significantly reduced the latency to begin eating and prolonged the total time spent eating; chlordiazepoxide also abolished food neophobia, by significantly increasing the time spent eating novel food items. In contrast, FG 7142 significantly increased eating latency and reduced eating duration. Both 8-OH-DPAT and buspirone significantly enhanced eating duration, but unlike chlordiazepoxide eating was directed only towards the familiar food. In addition buspirone, but not 8-OH-DPAT, reduced eating latency. ICS 205-930 significantly increased eating latency and reduced eating duration; however, these effects were observed only at the lowest dose tested. All of these behavioural effects were observed only when animals were unfamiliar with the testing situation, and cannot be accounted for in terms of changes in mechanisms controlling hunger. The behavioural paradigm used in these experiments may induce a competition between the drives to explore a novel environment and to eat. It is suggested that the tendency of buspirone and 8-OH-DPAT to suppress exploratory activity may thus result in enhanced feeding duration. Similarly enhanced exploratory activity induced by ICS 205-930 may result in animals taking longer to contact food, and spending less time eating. These results serve to illustrate that compounds which have different pharmacological actions, but which have been shown in other tests to have anxiolytic-like activity, can induce different behavioural effects. The suitability of this behavioural test for assessing anxiolytic effects of drugs is discussed.

M-octopamine injected into the paraventricular nucleus induces eating in rats: a comparison with noradrenaline-induced eating.

1 The effects on food intake in rats of injection of m ‐and p‐octopamine into the paraventricular nucleus (PVN) of the hypothalamus were examined, and compared to the effects of noradrenaline (NA). 2 m‐Octopamine injected into the PVN induced a dose‐dependent increase in food intake, with the maximal effect occurring at a dose of 25 nmol. p‐Octopamine did not elicit eating unless it was administered to animals pretreated with the monoamine oxidase inhibitor, pargyline. 3 The effects of pretreatment with various adrenoceptor antagonists, injected into the PVN, on the eating responses induced by 25 nmol m‐octopamine and NA were examined. The α1‐adrenoceptor antagonist, corynanthine, and the β‐adrenoceptor antagonist, propranolol, failed to alter the eating induced by m‐octopamine or NA. The effects of these two amines were susceptible to blockade of α2‐adrenoceptors. Idazoxan reversed the eating induced by m‐octopamine and noradrenaline. However, yohimbine was effective only against the eating induced by m‐octopamine. Thus, both m‐octopamine and NA appear to act via α2, but not α1 or β‐adrenoceptors. 4 Injection of α‐methyl‐p‐tyrosine into the PVN attenuated the effect of m‐octopamine, but not of NA. This result suggests that m‐octopamine elicits eating, at least in part, by releasing endogenous NA. 5 The NA and octopamine uptake inhibitor, desipramine, significantly potentiated the eating induced by a low dose of m‐octopamine. This effect may occur because desipramine would prolong the synaptic activity of released NA. 6 The results indicate that m‐octopamine elicits a marked and reliable eating response which is mediated largely by a release of endogenous NA, which acts at α2‐receptors. These results are consistent with the view that octopamine may function as a modulator of NA activity in the central nervous system.

The effects of d-fenfluramine on saccharin intake and preference, and on food and water intake

The effects of d-fenfluramine on saccharin intake and preference were examined to investigate whether the reduced rate of eating induced by this compound reflects a reduction in the palatability of foods. In two separate experiments, water deprived rats were offered a choice between a 0.05% solution of saccharin and water, or a 0.2% saccharin solution and water. Injection of d-fenfluramine at doses which reliably decreased food intake resulted in dose dependent reductions in total fluid intake and saccharin intake. A trend towards reduced water intake was observed also, and this together with the reduced saccharin intake resulted in no overall change in saccharin preference. In a further experiment, d-fenfluramine reduced the water intake of water deprived rats to the same extent as it reduced total fluid intake in the choice tests. Since d-fenfluramine failed to alter saccharin preference, it is unlikely that the slowed eating rate induced by this compound indicates a reduction in food palatability. Instead, it is likely that this behaviour results from a subtle motor deficit, such that fenfluramine treated animals are unable to maintain ingestion at the same rate as non-drugged animals. This explanation could account for the reduction in the consumption of non-nutritive saccharin solutions and water in water deprived animals. The relevance of this action to the anorectic effect of fenfluramine is discussed.

Tryptamine impairs the acquisition of a one-way active avoidance task

The effects of intraperitoneal administration of tryptamine to rats pretreated with iproniazid, on the acquisition of an unsignalled one-way active avoidance task, were examined. Tryptamine at 2.5 and 5 mg/kg significantly increased the number of trials required to perform this task to a 9/10 consecutive avoidances criterion, without affecting escape performance. The iproniazid pretreatment had no affect on acquisition, or any other performance variable, of the task. Tryptamine did not significantly affect the avoidance response, or escape response latencies; further tryptamine did not alter gross locomotor activity measured as photocell counts. These results suggest that the acquisition deficit was not the result of nonassociative effects such as changes in response capability, general activity level or nociception. The acquisition deficit induced by tryptamine may involve a direct stimulation of central 5-HT receptors since it was not induced by systemically administered 5-HT, was reversed by the 5-HT antagonists methysergide and metergoline, but was not affected by depletion of brain 5-HT, with PCPA, or by the dopamine antagonist haloperidol. Possible behavioural mechanisms for the action of tryptamine are discussed.