François Jenck

Antidepressant treatment prevents chronic unpredictable mild stress-induced anhedonia as assessed by ventral tegmentum self-stimulation behavior in rats

The effect of chronic unpredictable mild stress on sensitivity to reward was evaluated using the brain self-stimulation procedure. Rats were allowed to electrically self-stimulate the ventral tegmental area, one of the main cerebral structures subserving positive reinforcement. Stimulation thresholds (frequency of stimuli) for self-stimulation responses were determined prior to, during, and following a 19-day period of exposure to a variety of mild unpredictable stressors. Stimulation threshold was increased in stressed rats, suggesting a decrease in the rewarding properties of brain stimulation. This deficit became evident after about 1 week of mild stress, lasted throughout the stress period, and progressively diminished following termination of the stress regime. In stressed rats concomitantly treated with the tricyclic antidepressant desipramine (5 mg/kg b.i.d.), no stress-induced increase in self-stimulation threshold was observed. However, desipramine did not modify self-stimulation threshold in non-stressed animals. Thus, the increased threshold for brain self-stimulation produced by a period of chronic unpredictable mild stress can be completely prevented by concomitant antidepressant treatment and may provide an heuristic animal model of depression.

Dorsal periaqueductal gray-induced aversion as a simulation of panic anxiety: elements of face and predictive validity.

Neurosurgical stimulation of the dorsal periaqueductal gray (dPAG) matter in man induces acute signs of autonomic arousal and feelings of subjective anxiety; those signs have phenomenological similarity with the symptom profile characterizing a panic attack. Animals undergoing dPAG stimulation show comparable physical signs of autonomic activation and sudden fear-suggestive behavioral reactions that can be shaped into operant self-interruption behavior. Drugs known to acutely reduce (alprazolam, clonazepam) or precipitate (yohimbine, caffeine) panic attacks in patients were found to acutely and dose-dependently reduce or enhance, respectively, aversion induced by dPAG stimulation in rats. When considered as an animal model of panic anxiety, the dPAG model simultaneously meets criteria of face validity (symptomatic homology) and predictive validity (pharmacological homology under short-term treatment); aspects of its construct validity (theoretical rationale supporting the model) are discussed. It is suggested that dPAG stimulation-induced aversion may represent a model of some aspects of panic disorders.

Urocortin, a novel neuropeptide with anxiogenic-like properties

POTENTIAL anxiogenic-like properties of urocortin, a corticotropin-releasing factor (CRF)-related neuropeptide, were investigated in models of anxiety in rodents. In the elevated plus-maze, CRF- and urocortin-treated rats (0.1 nmol, i.c.v.) spent less time and made fewer entries into open arms. In the light-dark test in mice, urocortin (0.006–0.06 nmol, i.c.v.) dose-dependently reduced time and number of transitions into the lit area. Urocortin also dose-dependently (0.02–0.2 nmol, i.c.v.) reduced mice exploratory behaviour in an open field. This effect was reversed by diazepam (0.1–1 mg/kg, i.p) and by the CRF receptor antagonist α-helical CRF (0.8–8 nmole, i.c.v.). These data show that urocortin produces anxiety-like effects in several behavioural paradigms in rodents.

A non peptidic corticotropin releasing factor receptor antagonist attenuates fever and exhibits anxiolytic-like activity.

The multiple actions of corticotropin-releasing factor (CRF) on neuroendocrine and behavioural functions can now be examined using new, high affinity, non peptidic antagonists which exhibit central activity upon systemic application. We have shown that compound CP 154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine) displaces [125I][Tyr0]CRF from rat hippocampal CRF receptors (IC50 = 0.5 nM) and from pituitary CRF receptors (IC50 = 0.04 nM). The same compound inhibits in a concentration-dependent manner the ovine CRF (0.1 microM)-stimulated adenylate cyclase activity in membranes of a mouse pituitary adenoma cell line, AtT20, with an IC50 value of 50 nM. Systemic application of the CRF receptor antagonist (0.16 mg/kg i.p.) blocked recombinant human interleukin-1 beta 5 micrograms/kg i.p.) induced fever in rats. The CRF receptor antagonist CP 154,526 (1 mg/kg i.p.) also exhibited signs of anxiolytic-like activity in the elevated plus-maze test in rats.

Some critical determinants of the behaviour of rats in the elevated plus-maze

The effects of daytime testing periods, repeated test exposures, and level of illumination were tested on the behavior of rats in an elevated plus-maze consisting of two open and two enclosed arms. Rats made significantly more entries into the open arms and spent significantly more time in the open arms when testing was carried out between 8 h and 12 h than when performed between 14 h and 17 h. Repeated exposure to the test apparatus tended to reduce time spent by rats in the open arms, number of entries into the open arms and total locomotor activity. Finally, it was found that an increase of the level of illuminance was followed by a decrease of all behavioural parameters. Since conflicting results have been reported for drug treatments evaluated in the elevated plus-maze (e.g., for compounds acting at the 5-HT1A receptor), the present results, based on the experimental conditions used, provide one possible explanation for these discrepancies.

Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate emotional responses in anxiety models in rodents

This study investigated behavioural effects of very potent 5-HT reuptake inhibitors after acute treatment (cianopramine and citalopram), as well as after chronic treatment (cianopramine), in two behavioural models of anxiety: 1) the light/dark choice procedure in mice and 2) the elevated plus-maze test in rats. In addition, the responses of mice to novelty in a free exploration paradigm were assessed after acute administration of both drugs. A single injection of cianopramine or citalopram increased neophobic reactions in the free exploration test. Furthermore, these drugs increased the avoidance reaction to a brightly illuminated chamber in the light/dark choice procedure as well as to open arms in the elevated plus-maze test. In contrast, after chronic treatment (10 mg/kg IP, once daily for 21 days) of cianopramine, anxiogenic-like effects were no longer produced in the light/dark choice paradigm whereas in the elevated plus-maze test, anxiolytic-like effects appeared. These results shed more light on the 5-HT hypothesis of anxiety, insofar as the increased availability of 5-HT resulting here from reuptake inhibition seems to initially result in an increased emotional reactivity which, however, subsequently disappears during chronic treatment.

Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs

A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HT1C receptors in the brain. Conventional tricyclic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine) as well as mianserin and trazodone were found to display high to low nanomolar affinity for 5-HT1C receptors. Antidepressants of other chemical classes and with other mechanisms of action (affecting amine uptake systems: fluoxetine, citalopram, sertraline, fluvoxamine, nomifensine, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had negligible affinities (micromolar range) for 5-HT1C receptors, except fluoxetine. When tested in an in vivo rat model thought to reveal functional agonistic or antagonistic properties at 5-HT1C receptors, all antidepressants displaying high affinity for this receptor type (except clomipramine and trimipramine) were antagonists at 5-HT1C receptors. Antidepressants with a lower affinity for 5-HT1C receptors (except nomifensine) were inactive in this functional in vivo model. Taken together, these results suggest that antagonism at brain 5-HT1C receptors is a component of the antiserotonergic properties of a number of established antidepressants. In addition, the study confirmed that 5-HT1A receptors functionally interact with 5-HT1C receptors, which suggests that some degree of activity at 5-HT1A receptors may also be an important property for antidepressant activity.

5HT2C receptor agonists exhibit antidepressant-like properties in the anhedonia model of depression in rats

Potential antidepressant properties of preferential 5HT2C receptor agonists were investigated in stress-induced anhedonia, a validated simulation of depression. This simulation evaluates the hedonic state of stressed rats by recording variations in self-stimulation threshold measured before, during, and after exposure to intermittent, unpredictable, mild stressors. This stress regimen gradually elevates self-stimulation threshold, suggesting the development of an anhedonic state. In stressed animals, chronic treatment with the preferential 5HT2C receptor agonists Ro 60-0175 and Ro 60-0332 (3 mg/kg i.p. b.i.d.) prevented the loss of sensitivity to reward. Similarly, when stressed anhedonic animals were curatively treated with Ro 60-0175 (3 mg/kg i.p. b.i.d.), the stress-induced anhedonia was gradually reversed. These results suggest a role for 5HT2C receptors in some aspects of depression, and potential antidepressant properties for selective 5HT2C receptor agonists. Such compounds may offer an innovative approach to the treatment of mood disorders.

ANTIAVERSIVE EFFECTS OF 5HT2C RECEPTOR AGONISTS AND FLUOXETINE IN A MODEL OF PANIC-LIKE ANXIETY IN RATS

Dose-dependent increases in threshold for operant fear/escape responses of rats submitted to aversive stimulation of the dorsolateral periaqueductal gray (dPAG) were recorded following intraperitoneal injection of three chemically unrelated but selective 5HT2C receptor agonists (Ro 60-0175, Org 12962 and Ro 60-0332) and fluoxetine. The decreased sensitivity of rats to the acute panic-like aversion elicited by stimulation of this limbic periventricular region was detected at dosages devoid of impairing effects on the latencies needed for operant brain stimulation interruption. In this paradigm which has been validated as a simulation of acute anxiety with relevance to panic disorder, the selective activation of 5HT2C receptors by Ro 60-0175, Org 12962 or Ro 60-0332 induces effects analogous to those observed following benzodiazepine receptor activation by antipanic agents such as clonazepam or alprazolam or following non-selective and indirect 5HT receptor activation by fluoxetine. Potency and efficacy of 5HT2C receptor agonists were intermediate between those of clonazepam and fluoxetine, indicating authentic antiaversive properties and suggesting antipanic potential for these 5HT2C receptor agonists. In addition, these data suggest that the 5HT2C receptor subtype may play a major role in the therapeutic properties of selective serotonin reuptake inhibitors. It is also speculated that serotonin/benzodiazepine interactions existing in the brain may functionally involve the 5HT2C receptor subtypes and that the anxiogenic action reported under certain circumstances for 5HT mimetics are not mediated by 5HT2C receptor subtypes.

Synthesis of (1S, 3aS)-8-(2,3,3a, 4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro [4.5]decan-4-one, a potent and selective orphanin FQ (OFQ) receptor agonist with anxiolytic-like properties

The development of 8-(2,3,3a,4,5, 6-hexahydro-1H-phenalen1-yl)-1-phenyl-1,3,8-triaza-spiro[4. 5]decan-4-ones 3 starting from (RS)-8-acenaphten-1-yl-1-phenyl-1,3, 8-triazaspiro[4.5]decan-4-one 1 is reported. The synthesis and the binding affinities at human OFQ and opioid (micro, kappa, delta) receptors of the stereoisomers 3a-f are described. In vitro the most selective compound, (1S,3aS)-8-(2,3,3a,4,5, 6-hexahydro-1H-phenalen1-yl)-1-phenyl-1,3,8-triaza-spiro[4. 5]decan-4-one 3c, was found to act as a full agonist at the OFQ receptor in the GTPgamma(35)S binding test. It turned out to be selective versus a variety of other neurotransmitter systems. When tested in vivo following intraperitoneal injection, compound 3c was found to decrease neophobia in a novel environment and to exhibit dose-dependent anxiolytic-like effects in the elevated plus-maze procedure, thus confirming the effects observed following intracerebroventricular infusion of the OFQ peptide in rat.