Masahiro Nankai

Antidepressantlike effects of chronic nicotine on learned helplessness paradigm in rats

BACKGROUND The association between smoking and depression has been widely investigated. Smoking cessation is known to induce depression to a variable extent, and patients with a history of depression are more likely to experience depressive symptoms. To investigate the hypothesis that nicotine may have an antidepressantlike effect, we used learned helpless rats as an animal model of depression. METHODS Learned helplessness was produced according to our previous method. Learned helpless rats were implanted with nicotine and escape test was performed at 7 and 14 days after the implantation. RESULTS The number of escape failure in the rats receiving 1.5 mg/kg/day of nicotine was significantly reduced (p < .05) compared to control at day 14. Furthermore, this effect was blocked when the nicotinic receptor antagonist mecamylamine was coadministered. CONCLUSIONS These results suggest that chronic nicotine may act as an antidepressant, probably via nicotinic receptors.

The pharmacology of native N-methtl-D-aspartate receptor subtypes: Different receptors control the release of different striatal and spinal transmitters

1. N-methyl-D-aspartate (NMDA) increases the release of radiolabelled dopamine, GABA, acetylcholine and spermidine from rat striatal slices and of noradrenaline from the dorsal cervical spinal cord. 2. These five responses show differing sensitivities to NMDA and also to a variety of competitive antagonists, NMDA channel blockers, glycine antagonists and polyamine site antagonists. 3. Inhibitory activity profiles for 20 different antagonists are presented. All compounds tested showed some degree of selectivity with regard to the different responses and each response showed particular characteristics that suggested mediation by a particular native NMDA receptor subtype. 4. Receptors controlling dopamine, GABA and noradrenaline release were generally more sensitive to most antagonists compared to those controlling acetylcholine and spermidine release. 5. Receptors controlling spermidine release were furthermore insensitive to magnesium, argiotoxin, ifenprodil and eliprodil and displayed low sensitivity to memantine, dextrorphan and dextromethorphan. 6. Receptors controlling noradrenaline release could be further discriminated from those controlling dopamine and GABA release by very high sensitivity to magnesium and MK-801 and to the glycine antagonist L-689,560 but not to other glycine antagonists (CNQX, DNQX, 7-Chlorokynurenate, HA-966). 7. Many other individual drug or receptor differences were noted. The different profiles observed suggest a wide diversity of native NMDA receptors with different properties and an unexpectedly rich pharmacopeia of subtype selective antagonists of native NMDA receptors. 8. Matching subtype selectivity to particular behavioural effects may be possible and the design of subtype selective NMDA antagonists for particular clinical applications while avoiding side effect generation seems to be feasible.

Platelet 3H-paroxetine binding in control subjects and depressed patients: Relationship to serotonin uptake and age

3H-paroxetine is regarded as a better ligand for the serotonin (5-hydroxytryptamine; 5-HT) uptake site than 3H-imipramine. In the present study, platelet 14C-5-HT uptake and 3H-paroxetine binding were simultaneously measured in 12 control subjects. There was a significant positive correlation between the individual Bmax value for 3H-paroxetine binding and the Vmax value for 14C-5-HT uptake. Platelet 3H-paroxetine binding was also determined in 21 drug-free patients who satisfied DSM-III-R criteria for major depression and 21 control subjects. A negative correlation was found between the Bmax values for 3H-paroxetine binding with age in control subjects. There was no change in 3H-paroxetine binding in depressed patients compared with control subjects. Our results indicated that 3H-paroxetine was a good ligand for evaluating 5-HT uptake sites, and the influence of age ought to be taken into consideration in the study of 3H-paroxetine binding. The present study indicated that there was no change in 5-HT uptake sites in platelets from depressed patients.

Increased 5-HT2 receptor-mediated behavior 11 days after shock in learned helplessness rats.

In the learned helplessness procedure, rats can be differentiated into two distinct groups. Learned helplessness (LH) rats do not learn to escape a controllable shock while non-learned helplessness (NLH) rats learn this response. This deficit in performance in LH rats lasted for 11 days. In LH rats, pretreatment with acute desipramine (15 mg/kg i.p.) or chronic diazepam (0.95 mg/kg/day p.o. for 7 days) did not produce recovery from this deficit of performance, but pretreatment with chronic desipramine (17.7 mg/kg/day p.o. for 7 days) or chronic mianserin (6.1 mg/kg/day p.o. for 7 days) led to recovery. Before presentation of uncontrollable shock, there was no difference between LH and NLH rats, but 11 days after the shock, head shakes induced by (+/-)-1-(2,5-demethoxy-4-iodophenyl)-2-aminopropane (DOI) in LH rats was significantly more frequent than those in NLH and naive rats without change of [3H]ketanserin binding. The basal corticosterone level was higher in LH rats than in NLH rats. These findings suggest that the learned helplessness model is a reliable animal model of depression accompanied by 5-HT2 receptor hypersensitivity.

Platelet [3H]imipramine binding in depressed patients and its circadian variations in healthy controls

Platelet [3H]imipramine binding was determined in 28 patients with major depression, 11 with bipolar disorders, and 28 healthy controls. The mean maximum number of binding sites (Bmax) in depressed patients was significantly lower than in healthy controls. A significant negative correlation was found between the Bmax values and the total scores of the 17-item Hamilton depression rating scale in major depression. Our results suggest that the Bmax values in major depression may be related to severity of depression. There were significant circadian variations in the Bmax values of [3H]imipramine binding on human platelets from six healthy controls. The mean Bmax values were significantly low in the dark phase and high in the light phase.

Acute immobilization stress reduces (±DOI)-induced 5-HT2A receptor-mediated head shakes in rats

Acute immobilization stress induced by taping four limbs, applying tail pinch stress and electric foot shock stress immediately reduced the frequency of head shakes induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((±)DOI), a 5-HT2A/C agonist in rats. Immobilization stress due to the use of cylinder restraint and forced swimming did not affect 5-HT2A-mediated behavior. Acute immobilization stress did not affect [3H]ketanserin binding to the 5HT2A receptor in the prefrontal cortex and hippocampus. Presynaptic serotonergic lesions with 5,7-dihydroxytryptamine (5,7-DHT) did not affect the reduction in 5-HT2A-mediated behavior after acute immobilization stress. The decreases in head shake frequency after acute immobilization stress by taping were attenuated by pretreatment with diazepam (2.5 mg/kg IP): This attenuation was reversed by pretreatment with flumazenil (10 mg/kg IP). The reduction in (±)DOI- induced 5-HT2A-mediated behavior caused by stress may be related to a change in agonist affinity to the receptor or changes in other neurotransmitter systems or the effect of PI turnover.

Striatal NMDA receptor subtypes: the pharmacology of N-methyl-d-aspartate-evoked dopamine, γ-aminobutyric acid, acetylcholine and spermidine release

We have examined the inhibitory potencies of MK 801, memantine, dextromethorphan, Mg2+ and of strychnine-insensitive glycine site antagonists on the N-methyl-D-aspartate (NMDA)-evoked (300 microM) release of [14C]acetylcholine and [3H]spermidine or [14C] gamma-aminobutyric acid [14C]GABA and [3H]dopamine from rat striatal slices. MK 801, dextromethorphan and all glycine antagonists examined (7-chlorokynurenate, L-689,560 ((+/-)-trans-2-carboxy-5,7-dichlorotetrahydroquinoline-4-phenylure a), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 6,7-dichloroquinoxaline-2,3-dione (DNQX), and (+)-HA966 ((3-amino-1-hydroxypyrrolidin-2-one) more potently inhibited NMDA-evoked dopamine and GABA release than acetylcholine and spermidine release by a factor of 3-21. MgCl2, which does not inhibit NMDA-evoked spermidine release, and memantine which only weakly antagonised NMDA-evoked spermidine release, inhibited NMDA-evoked dopamine, acetylcholine and GABA release with similar potencies. No pharmacological differences were observed between NMDA-evoked dopamine and GABA release. These findings extend those suggesting that NMDA-evoked acetylcholine and spermidine release are mediated by different NMDA receptor subtypes in the striatum and suggest a third native subtype with a distinct pharmacology that regulates striatal dopamine and GABA release.

Evidence for native NMDA receptor subtype pharmacology as revealed by differential effects on the NMDA-evoked release of striatal neuromodulators: Eliprodil, ifenprodil and other native NMDA receptor subtype selective compounds☆

NMDA increases the release of [14C]acetylcholine and [3H]spermidine or of [14C]GABA and [3H]dopamine from rat striatal slices. The pharmacology of these responses suggests that release of dopamine and GABA, acetylcholine, and spermidine is mediated, respectively, by three distinct NMDA receptor subtypes. IC50 values of compounds for the inhibition of dopamine and GABA release were closely matched, suggesting mediation by the same subtype. This receptor was generally more sensitive to all NMDA antagonists tested relative to that controlling acetylcholine or spermidine release (channel blockers, glycine antagonists, competitive antagonists and polyamine antagonists). The receptors controlling acetylcholine and spermidine release were characterised by lower antagonist sensitivity in general, and that controlling spermidine release was further defined by a marked insensitivity to ifenprodil, eliprodil, magnesium, dextromethorphan, dextrorphan, memantine, desipramine and polyamine spider toxins. In binding studies in which the displacement of 2 nM [3H]MK801 was studied in membranes prepared from a number of brain regions (in the presence of saturating concentrations of glutamate, glycine and spermidine) small regional differences in IC50 values were observed for a number of channel blockers, but no compound generated biphasic displacement curves that would allow masking of a particular subtype and it was not possible to detect binding components that were insensitive to memantine, dextrorphan dextromethorphan or desipramine. Ifenprodil produced biphasic displacement curves in the 1-day-old rat cortex and midbrain (with IC50 values of approximately 2 and 70 microM) and both ifenprodil and eliprodil displaced a small proportion (18%) of [3H]MK-801 with high affinity in the adult rat spinal cord. Displacement of [3H]MK801 by these compounds in all other adult brain regions (cortex, striatum, hippocampus, thalamus, pons, medulla, cerebellum) was monophasic and of low affinity. In general the subtype selectivity suggested by the release studies was not mirrored in the binding experiments, probably because of excessive heterogeneity of sites in the membrane preparations and to the subtype selectivity of [3H]MK801 itself.

Acute immobilization stress reduces (+/-) DOI induced 5-HT2-mediated head shakes in rats.

A number of investigators have reported that acute stress increases the concentration of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the brain. In the present study we sought to examine the effects of acute immobilization stress on 5-HT2 receptors. After acute immobilization stress, head shakes induced by selective 5HT, agonist (&)DO1 [ 1-(2,5-dimethoxy-4iodophenyl)-2-aminopropane] and r3H] ketanserin labeled 5-HT, receptor in the prefrontal cortex were examined. The effects of pretreatment with diazepam before the stress sessions were also determined.

Neuroendocrinological Effects of L‐Threo‐3, 4‐Dihydroxyphenylserine (DOPS), a Putative Norepinephrine Precursor, on Healthy Volunteers

Abstract: The effect of L‐threo‐3, 4‐dihydroxyphenylserine (DOPS) on plasma Cortisol, prolactin, thyrotropin‐stimulating hormone (TSH) and growth hormone concentrations was studied in nine healthy male volunteers. The drug was administered orally (300 mg or 600 mg DOPS) using a multiple crossover placebo‐controlled study design. Plasma hormone concentrations were measured at 30 minute intervals for 3 hours after dosing. Plasma DOPS peak concentrations were observed between 2 and 3 hours after dosing. DOPS, however, had no effect on plasma hormone concentrations and this may be attributed to the known low brain permeability of DOPS in healthy subjects.