Patrick Martin

Reversal of helpless behavior in rats by putative 5-HT1A agonists.

This study is designed to measure effects of serotonin 1A (5-HT1A) agonists on escape deficits produced by inescapable shock in rats--a model of learned helplessness. Rats were first exposed to 60 inescapable shocks (15-sec duration, 0.8 mA, every 1 min +/- 15 sec), and 48 hr later, they were subjected to daily 15-min shuttle-box sessions (30 trials/day) on 3 consecutive days. Twice daily intraperitoneal injection of buspirone (total daily dose of 0.5 and 1 mg/kg), gepirone (0.06 and 0.125 mg/kg), 8-OH dipropylamino-tetralin (8-OH-DPAT) (0.03, 0.06, 0.125, and 0.25 mg/kg), and ipsapirone (TVXQ 7821) (0.03 and 0.06 mg/kg) eliminated escape failures. This indicates that an antidepressant-like effect--reversal of helpless behavior--can be obtained with drugs assumed to stimulate serotonin 1A receptors.

Shuttle-box deficits induced by inescapable shocks in rats: Reversal by the beta-adrenoreceptor stimulants clenbuterol and salbutamol

Beta-adrenoreceptor stimulants such as salbutamol and clenbuterol have been reported to be effective in depressive states and to share many actions with classical antidepressants in animals. To further explore the antidepressant activity of these drugs, we investigated their effects in rats subjected to helplessness training. Rats were first exposed to inescapable shock pre-treatment (60 shocks, 15 sec duration, 1 mA every minute +/- 15 sec) and 48 hr later, shuttle-box training (30 trials/day, ITI: 30 sec) was initiated in order to evaluate escape and avoidance deficits. Rats pretreated with inescapable shocks exhibited escape and avoidance deficits when tested for subsequent responding in a shuttle-box. The deficits are particularly marked at the third training session. Daily IP injections of clenbuterol (total daily dose: 0.5 and 0.75 mg/kg) and salbutamol (16 and 24 mg/kg) prevented escape deficits as did daily injections of classical antidepressants such as desipramine (16 and 24 mg/kg/day) and clomipramine (16 and 24 mg/kg/day). These data extend previous results bearing on the similarity of action of beta receptor stimulants and tricyclic antidepressants and further support the notion of a close relationship between noradrenergic function, more especially beta-adrenoreceptors, and helpless behavior.

Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle

Significance In tissues such as bone marrow, intestinal mucosa, or regenerating liver, the daily rhythm of cell division is controlled by the cell’s circadian clock. Determining how this clock organizes important processes such as cell division, apoptosis, and DNA damage repair is key to understanding the links between circadian dysfunction and malignant cell proliferation. We show that in proliferating mouse fibroblasts there is more than one way in which the clock and cell cycle synchronize their oscillations and that one of them is the biological equivalent of the phase locking first discovered by Huygens in the 17th century when he coupled two clocks together. When phase-locked two coupled oscillators have a fixed relative phase and oscillate with a common frequency. Daily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle progression, and hence its biological relevance, is not understood. In particular, we do not know how the temporal organization of cell division at the single-cell level produces this daily rhythm at the tissue level. Here we use multispectral imaging of single live cells, computational methods, and mathematical modeling to address this question in proliferating mouse fibroblasts. We show that in unsynchronized cells the cell cycle and circadian clock robustly phase lock each other in a 1:1 fashion so that in an expanding cell population the two oscillators oscillate in a synchronized way with a common frequency. Dexamethasone-induced synchronization reveals additional clock states. As well as the low-period phase-locked state there are distinct coexisting states with a significantly higher period clock. Cells transition to these states after dexamethasone synchronization. The temporal coordination of cell division by phase locking to the clock at a single-cell level has significant implications because disordered circadian function is increasingly being linked to the pathogenesis of many diseases, including cancer.

Effects of an extract of Ginkgo Biloba (EGB 761) on “learned helplessness” and other models of stress in rodents

The effects of repeated oral administration of an extract of Ginkgo Biloba (EGB 761) on various behavioral models of stress in rodents were investigated. The models in rats included learned helplessness, shock-suppressed licking (Vogel conflict test) and forced swimming-induced immobility (behavioral despair). The models in mice included shock-suppressed exploration (four plates test), spontaneous exploration (staircase test) and food consumption in a novel situation (emotional hypophagia). Further tests in rats examined the effects of EGB 761 on memory (passive avoidance test) and responsiveness to shock to determine whether the preventive effects observed with EGB 761 in the learned helplessness procedure were due either to drug-induced impairment of memory or to reduced shock sensitivity. In all experiments EGB 761 was administered over 5 days at daily doses of 50 and 100 mg/kg PO. In some experiments (Vogel test, four plates test, staircase test, emotional hypophagia) the effects of acute administration were also investigated. The results showed that repeated administration of EGB 761 (50 and 100 mg/kg/day) before exposure to unavoidable shock (preventive treatment) clearly reduced the subsequent avoidance deficits in the learned helplessness procedure but was less effective when first administered after helplessness induction (curative treatment). EGB 761 did not affect performance in the passive avoidance task or alter the animals response to electric shock, suggesting that the effects observed in the learned helplessness procedure were not due to impaired memory or reduced shock sensitivity. Anxiolytic-like activity was also seen in the emotional hypophagia test in mice where repeated administration of EGB 761 increased the amount of food consumed.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of monoamine oxidase inhibitors compared with classical tricyclic antidepressants on learned helplessness paradigm

The present study investigated the effect of monoamine oxidase inhibitors, nialamide which is a non specific monoamine oxidase inhibitor (MAOI), toloxatone which is a A type MAOI and L-deprenyl which is a B type MAOI compared with classical tricyclic antidepressants (clomipramine, desipramine and imipramine), on the escape deficit induced by inescapable shocks (learned helplessness paradigm). Rats were first exposed to inescapable shock pretreatment (60 shocks, 15 sec duration, 0.8 mA, every minute + 15 sec) and 48 h later, shuttle box training (30 trials/day, 15 min.) was initiated in order to evaluate interference effect. Rats with inescapable shocks exhibited escape and avoidance deficits when tested for subsequent responding in a shuttle-box. Daily i.p. injections of nialamide (8 and 16 mg/kg), toloxatone (16 and 32 mg/kg), L-deprenyl (32 and 64 mg/kg) and tricyclic antidepressants (clomipramine: 16 and 32 mg/kg, desipramine: 16 and 24 mg/kg, imipramine: 16 and 32 mg/kg) eliminated escape deficits. In rat exposed to inescapable shocks and treated with L-deprenyl (16 mg/kg/day), nialamide (32 mg/kg/day) or toloxatone (64 mg/kg/day), avoidance responses are significantly increased as compared with non drugged rats preexposed to inescapable shocks. These data extend previous results bearing on the similarity of action of MAOI and tricyclic antidepressants in learned helplessness paradigm (Sherman et al., 1982) and are in agreement with data obtained in other animal models of depression.

Noradrenergic and opioid mediation of tricyclic-induced reversal of escape deficits caused by inescapable shock pretreatment in rats

The present study was undertaken to investigate the possible involvement of a noradrenergic and opioid mediation of the reversal by tricyclic antidepressants of escape deficits produced by inescapable shock pretreatment. Rats were first exposed to 60 inescapable shocks (15 s duration, 0.8 mA, every min±15 s) and 48 h later subjected, to daily shuttle-box sessions (30 trials/day, ITI: 30 s) during 3 consecutive days. Twice-daily IP injection of desipramine or clomipramine (total daily dose: 32 mg/kg) prevented escape deficits. Penbutolol (0.125; 0.25; 0.5 mg/kg), prazosin (1; 2 mg/kg) and naloxone (0.5; 1 mg/kg) given once a day dose-dependently attenuated the beneficial effect of tricyclic antidepressants in reducing the number of escape failures in rats exposed to shock pretreatment. In agreement with data obtained in the forced-swimming model, these findings support the notion that activation of noradrenergic and opioid receptors is an important factor in the mediation of the effects of tricyclic antidepressants in animal models of depression.

Noradrenergic rather than GABAergic processes as the common mediation of the antidepressant profile of GABA agonists and imipramine-like drugs in animals

The present study was aimed at investigating in rats whether a common mechanism might underlie the reversal of depressive-like behaviors by classical antidepressants and by GABA agonists such as muscimol. Blockade of GABA transmission with picrotoxin (1 mg/kg IP) abolished the muscimol (0.5-1 mg/kg)-induced reduction of immobility in the swimming test and the reversal of escape failures in the learned helplessness paradigm. Conversely, picrotoxin was found not to reduce the efficacy of imipramine-like drugs in these same animal models. The combination of muscimol and tricyclics given at subeffective doses resulted in behavioral changes that can be accounted for by an additive interaction between these two classes of drugs. These data confirm the antidepressant-like profile of GABA agonists but suggest that it is unlikely that the primary antidepressant mechanism of conventional antidepressants involves GABA-A receptors. In the swimming test, prazosin (2 mg/kg), an alpha adrenoceptor blocker, antagonized the reduction of immobility produced by both muscimol and imipramine-like drugs. In the learned helplessness paradigm, penbutolol (0.25-0.5 mg/kg) and, though to a lesser extent prazosin, counter-acted the reversal of escape failures caused by muscimol and imipramine. On the basis of these data, it is tempting to speculate that increased transmitter outflow at noradrenergic receptors may be an essential component in the mechanism of action of imipramine-like drugs but also of GABA agonists.

Decreased GABA B Receptors in Helpless Rats: Reversal by Tricyclic Antidepressants

Recently, sufficient evidence has accumulated to suggest that a central GABAergic dysfunction may be primarily related to the physiopathology of affective disorders and that antidepressant mechanisms have an intrinsic GABAergic component. In depressed patients GABA levels are reported to be low in the cerebral spinal fluid and plasma, and GABA synthesis is decreased in some brain areas, including the frontal cortex. GABA mimetics exhibit antidepressant-like actions in behavioral models in the olfactory bulbectomized rat and in the learned helplessness paradigm. In the olfactory bulbectomized rat, GABA B receptors are down regulated in the frontal cortex and in the learned helplessness paradigm, GABA release is diminished in the hippocampus. These decreases are reversed by antidepressants in parallel with their behavioral activities. In this study, data obtained indicate that in the learned helplessness paradigm, GABA B receptors are decreased in the frontal cortex and this decrease is reversed by imipramine and desipramine (16 mg/kg/day) in animals which are considered to be responders to antidepressant treatments.

Gonadotropin-releasing hormone (GnRH) as antidepressant: a psychopharmacological animal study

Because the secretion of gonadotrophic hormones is disturbed in some depressive states, it has been hypothesized that gonadotropin-releasing hormone (GnRH) has antidepressant properties in humans, but no clear information has emerged from clinical trials. The lack of experimental psychopharmacological data prompted us to investigate the effects of GnRH on the learned helplessness behavioral model of depression in rats. GnRH was injected i.p. at doses of 0.06, 0.25, 0.50, 1 and 2 mg/kg per day. GnRH significantly reduced the number of escape failures at doses of 1 mg/kg per day or higher during the first shuttle-box session and at doses of 0.25 mg/kg per day onwards during the third shuttle-box session. These antidepressant-like effects of GnRH were similar to those observed with the tricyclic antidepressants imipramine (32 mg/kg per day) or clomipramine (32 mg/kg per day) in the same model. Moreover, while the induction of learned helplessness behaviour resulted in a fall in the plasma levels of FSH and LH, normal values of these hormones could be restored by a behaviorally effective GnRH regimen. From these data it can be suggested that GnRH exhibits an interesting antidepressant-like activity in rats.

Involvement of angiotensin-converting enzyme inhibition in reversal of helpless behavior evoked by perindopril in rats.

Several clinical investigations have suggested that captopril, an angiotensin-converting enzyme inhibitor (ACEI) currently used as an anti-hypertensive agent, exhibits antidepressant properties in humans. In the present study we evaluated the action of perindopril, another ACEI, and two of its metabolites, the di-acide form perindoprilat, which possesses ACE inhibitory properties, and BDM-4, an inactive metabolite, in the learned helplessness paradigm. In order to confirm a possible action of these drugs via dipeptidyl carboxypeptidase inhibition, we also investigated two inactive analogues of perindopril and perindoprilat. Perindopril (0.06-8 mg/kg per day) and perindoprilat (0.25-8 mg/kg per day) induced a reversal of escape deficits. BMD-4 and two analogues failed to reverse helpless behavior. These results support the hypothesis that ACE inhibition is a key factor in the behavioral antidepressant-like activity of perindopril and perindoprilat.