Helen C. Jackson

The effects of idazoxan and other α2‐adrenoceptor antagonists on food and water intake in the rat

1 Idazoxan (1, 3, 10 mg kg−1, i.p.) produced a significant increase in food and water intake in freely feeding rats during the daylight phase. 2 The more selective and specific α2‐adrenoceptor antagonists, RX811059 (0.3, 1, 3 mg kg−1, i.p.) and RX821002 (0.3, 1, 3 mg kg−1, i.p.), did not produce hyperphagia in rats, however, the highest dose produced a significant increase in water intake. 3 The peripherally acting α2‐adrenoceptor antagonist, L‐659,066 (1, 3, 10 mg kg−1, i.p.), did not affect food intake in the 4 h following injection, but the highest dose (10 mg kg−1), produced a large increase in water intake. 4 These results indicate that α2‐adrenoceptor antagonists may increase water intake by a peripherally mediated mechanism. 5 The lack of effect of RX811059 and RX821002 on food intake contrasts with the large dose‐related increases induced by idazoxan and suggests that the hyperphagic effects of idazoxan are not due to α2‐adrenoceptor blockade but may instead reflect its affinity for a non‐adrenoceptor site, a property not shared by the other α2‐antagonists.

Are δ-opioid receptors involved in the regulation of food and water intake?

The effect of the δ-opioid antagonists ICI 154,129 (1–100 μg, i.c.v.) and ICI 174,864 (1–100 μg, i.c.v.) and of the δ-agonist d-Ala2-d-Leu5- enkephalin (DADL; 1–10 μg, i.c.v.) on the intake of food and water of non-deprived rats was investigated. Animals treated with either ICI 154,129 or ICI 174,864 ate and drank significantly less than vehicle-treated controls over a 3hr test period. The suppressant effects of these peptides on appetite were similar to those observed with the more commonly-used opioid antagonists, naltrexone and Mr 2266. In contrast, the δ-agonist DADL produced an increase in both the consumption of food and water in the 3 hr following administration of drug. The findings presented in this study lend further support to the hypothesis that an endogenous enkephalin/δ -receptor system may play a role in the tonic induction of ingestive behaviour.

Exploring δ-receptor function using the selective opioid antagonist naltrindole

Abstract Until recently the only pharmacological probes for δ-receptors have been peptide enkephalin analogues. These suffer from a number of limitations including high cost, partial agonist effects and a propensity for neurotoxicity. A stable non-peptide antagonist, naltrindole, has recently become available. We have explored its intrinsic actions and found that it attenuated swim stress-induced antinociception, a model for endogenous δ-receptor activation. Naltrindole may therefore be a useful alternative to presently available δ-receptor antagonists.

Body temperature discriminates between full and partial benzodiazepine receptor agonists

The benzodiazepine full agonist loprazolam and the beta-carboline ZK 93423 produced hypothermia in mice (1-30 mg/kg i.p.). Maximal effects were seen at relatively low doses of these compounds. In contrast, the partial agonists Ro 17-1812 (a benzodiazepine) and ZK 91296 (a beta-carboline), did not modify rectal temperature at doses up to 30 mg/kg i.p. (which would be receptor saturating). Body temperature may therefore be a useful test for discriminating between full and partial agonists at the benzodiazepine receptor.

Effects of benzodiazepine receptor inverse agonists on locomotor activity and exploration in mice

This study investigates the effects of benzodiazepine receptor inverse agonists on the locomotor and exploratory behaviour of mice when tested in a familiar environment. The weak partial inverse agonist Ro 15-3505 (0.3, 1, 3 mg/kg i.p.) significantly increased locomotion and hole-dipping in habituated mice. However, the more efficacious partial inverse agonists Ro 15-4513 (0.3, 1, 3 mg/kg i.p.) and Ro 19-4603 (0.03, 0.1, 0.3 mg/kg i.p.) had no effect on these parameters. The benzodiazepine receptor antagonist flumazenil (3, 10, 20 mg/kg i.p.) also increased locomotion and hole-dipping in habituated mice, although like Ro 15-3505, these effects were of short duration occurring largely in the first 15 min following injection. Opposite effects were obtained with the partial benzodiazepine agonist Ro 17-1812 (1, 3, 10 mg/kg i.p.) which produced a longer-lasting significant decrease in hole-dipping behaviour in habituated mice without altering locomotion. Finally, in contrast to its effects in habituated animals, Ro 15-3505 (0.3, 1, 3 mg/kg i.p.) did not modify either locomotion or exploration in mice which were tested in a novel environment, showing that the effects of the inverse agonist were state-dependent. This demonstration that, under certain conditions, the weak benzodiazepine receptor inverse agonist Ro 15-3505 and the antagonist flumazenil, produce behavioural activation is in accordance with the work of others suggesting that these classes of compound may increase arousal and may therefore be of some value in treatment of memory disorders.

Inhibition of baolofen-induced hypothermia in mice by the novel GABAB antagonist CGP 35348

This study shows that the selective GABAB antagonist CGP 35348 had no effect on body temperature in mice in doses up to 300 mg/kg i.p. However, the highest dose abolished the hypothermia induced by the GABAB agonist baclofen (10 mg/kg i.p.) but not that produced by the GABA-mimetic progabide (200 mg/kg i.p.); the benzodiazepine agonist loprazolam (3 mg/kg i.p.); the alpha 2-agonist UK 14,304 (1 mg/kg i.p.) nor the mu-opioid agonist morphine (30 mg/kg i.p.). These findings, showing selective antagonism of GABAB receptors by CGP 35348, confirm that this compound may be a valuable tool for exploration of GABAB receptor function in vivo.

The role of opioid receptor sub-types in tifluadom-induced feeding.

There is now considerable evidence that opioid agonists and benzodiazepines increase food and water intake in a variety of animal species. The appetitive effects of the novel opioid‐benzodiazepine tifluadom have been investigated. (±)‐Tifluadom significantly increased food intake in freely‐feeding rats. This stimulation of appetite was attributable principally to the activity of the (+)‐isomer. Furthermore tifluadom‐induced feeding was blocked by the opioid antagonists naloxone, naltrexone, Mr 1452 and Mr 2266 but not by the δ‐opioid receptor antagonist ICI 154, 129, or by the benzodiazepine antagonist Ro 15–1788. These results suggest that tifluadom exerts its effect on food intake by interaction with opioid as opposed to benzodiazepine receptors and that this activity is mediated by κ and/or μ‐ rather than δ‐opioid receptor sub‐types.

Hyperphagia induced by 2-deoxy-D-glucose in the presence of the δ-opioid antagonist ICI 174, 864

The effect of the selective δ-opioid antagonist ICI 174, 864 (N, N-bisallyl-Tyr-Aib-Aib-Phe-Leu-OH: Aib = α-aminoisobutyric acid) on the hyperphagia induced by 2-deoxy-D-glucose (2-DG) was investigated in non-deprived rats. The increase in food intake produced by 2-DG (500mg/kg i.p.) was not reduced by ICI 174, 864 at a dose (3μg/rat i.c.v.) which totally abolished the feeding response to the δ-agonist D-Ala2-D-Leu5-enkephalin (10μg/rat i.c.v.). These findings suggest that the appetitive effects of 2-DG are not mediated by an enkephalinergic/δ-receptor system. They do not, however, preclude the possible involvement of endogenous opioids acting at other sub-types of opioid receptor in this glucoprivic ingestional response, which is suppressed by less specific opioid antagonists such as naloxone.

The involvement of μ- and κ- but not δ-opioid receptors in the body weight gain of suckling rats

The effects of the benzomorphan antagonist Mr 2266 and the selective δ-antagonist ICI 154,129 on the body weight gain of 6-day-old suckling rat pups was observed. Mr 2266 significantly reduced body weight gain in these animals, though ICI 154,129 had no affect on this variable. These findings suggest that μ- and κ- but probably not δ-opioic receptors are involved in the regulation of ingestive behaviours in infant rats. The results are discussed in relation to the development of opioid-receptor subtypes in the neonatal rat brain.

Anxiety and Panic Disorders

Anxiety is one of the major causes of distress and is often overlooked or minimized by doctors and the general public. Moreover, there is accumulating evidence that patients with panic disorder have a high risk of suicide attempts. The classification of anxiety has become progressively refined over the past decade, with a number of discrete syndromes being characterized. The major division is between those disorders characterized by sudden surges of anxiety (panic attacks) and those without. The syndrome of repeated panic attacks is called panic disorder. Often, panic disorder leads to avoidance behavior—agoraphobia. Current drug treatments for panic disorder are antidepressants (tricyclics or monoamine oxidase inhibitors) or potent benzodiazepines such as alprazolam. The state characterized by morbid worrying is called generalized anxiety disorder, and is treated either with benzodiazepines or buspirone. At present, these two conditions are the main targets for new drug development. However, there is growing interest in phobic conditions (especially social phobia) and stress-related anxiety—posttraumatic stress disorder, both of which may respond to the newer antidepressants or monoamine oxidase inhibitors.