Antidepressant effects of nicotine in an animal model of depression

Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats, selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg SC) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [³H]cytisine binding (selective for the α₄β₂ nicotinic receptor subtype) but not [¹²⁵I]alpha-bungarotoxin binding (selective for the α₇ subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists may have therapeutic benefits in depressive disorders. Received: 9 June 1998/Final version: 6 August 1998     

Activation of 5-HT1B receptors in the nucleus accumbens reduces amphetamine-induced enhancement of responding for conditioned reward

Previously, we have demonstrated that 5-hydroxytryptamine (5-HT) injected into the nucleus accumbens attenuates the potentiating effects of d-amphetamine on responding for conditioned reward (CR). The present studies examined the 5-HT receptor involved in this effect by investigating the effects of 5-HT agonists with differing affinities for 5-HT₁ and 5-HT₂ receptors on d-amphetamine-induced potentiation of responding for CR. Rats were trained to associate a light/tone stimulus (subsequently the CR) with water delivery. In a test phase, they were allowed access to a lever delivering the CR, and an inactive (NCR) lever. Responding on the CR lever was greater than responding on the NCR lever, indicating that the light/tone stimulus functioned as a CR. Responding for the CR was selectively potentiated by injections of d-amphetamine (10 μg) into the nucleus accumbens. This effect was reduced by injections into the nucleus accumbens of 5-CT (0.5 and 1 μg), RU24969 (10 μg), CP93,129 (1.25 and 2.5 μg) but not by DOI (10 μg) or 8-OH-DPAT (5 μg). The lower doses of 5-CT and CP93,129 did not reduce baseline responding for CR, or responding for water in a separate group of animals, indicating that the effects of these drugs were behaviourally selective. The higher doses abolished the CR effect, and in the case of 5-CT and RU24969 also reduced responding for water. All of the effective drugs share in common the ability to stimulate 5-HT_1B receptors, albeit with differing selectivities. The effect of CP93,129, the most selective of the 5-HT_1B agonists, to inhibit the response-potentiating effect of d-amphetamine was reversed by the5-HT_1B/1D antagonist GR127935 (3 mg/kg). The results indicate that activation of 5-HT_1B receptors within the nucleus accumbens attenuates the effects of a dopamine-dependent behaviour, and that activation of these receptors can oppose the behavioural effects of elevated mesolimbic dopamine transmission. Received: 22 April 1998/Final version: 28 July 1998     

Aggression heightened by alcohol or social instigation in mice: reduction by the 5-HT1B receptor agonist CP-94,253

Rationale: Models of heightened aggression may be particularly relevant in exploring pharmacological options for the clinical treatment of aggressive and impulsive disorders. Objectives: To investigate and compare the effects of a 5-HT_1B selective agonist, CP-94,253, on aggression that was heightened as a result of 1) social instigation or 2) alcohol treatment. Methods: Male CFW mice were administered 1.0 g/kg EtOH and were subsequently confronted by an intruder in their home cage. In a separate experimental procedure, resident male mice were instigated to aggressive behavior by brief exposure to a provocative stimulus male. To test the hypothesis that activation of the 5-HT_1B receptor subtype would preferentially attenuate heightened aggression, in comparison to the moderate levels of species-typical aggressive behaviors, the selective agonist, CP-94,253 (1.0–30 mg/kg, IP), and antagonists to the 5-HT_1B (GR 127935; 10 mg/kg, IP) and the 5-HT_1A receptor (WAY 100,635; 0.1 mg/kg IP) were used. Results: CP-94,253 suppressed non-heightened aggressive behavior (ED₅₀=7.2 mg/kg ). GR 127935, but not WAY 100,635 shifted the ED₅₀ for CP-94,253 to 14.5 mg/kg. Importantly, the anti-aggressive effects of CP-94,253 were not accompanied by locomotor sedation. Alcohol-heightened and instigation-heightened aggression were suppressed at lower doses than those necessary to suppress non-heightened aggression (ED₅₀=3.8 and 2.7 mg/kg, respectively). Conclusions: The current results support the hypothesis that activation of 5-HT_1B receptors modulates very high levels of aggressive behavior in a pharmacologically and behaviorally specific manner. Received: 5 January 1999 / Final version: 16 April 1999     

5-HT3 receptor over-expression enhances ethanol sensitivity in mice

 Ethanol sensitivity may play a role in the risk of developing alcoholism. The role of 5-HT₃ receptors in sensitivity to ethanol was assessed in mice over-expressing the 5-HT₃ receptor in the forebrain. Sleep time and ED₅₀ for loss of righting reflex (LRR) were used to assess the effect of a high dose of ethanol in transgenic versus non-transgenic mice. The ED₅₀ for ethanol-induced increase in open field activity was used to measure differences in sensitivity to low dose ethanol. The ED₅₀ for ethanol-induced increase in activity was 41% lower in the 5-HT₃ receptor over-expressing transgenic mice compared to non-transgenic mice. However, 5-HT₃ receptor over-expressing mice did not differ from control mice in ethanol metabolism, ED₅₀ for LRR, and ethanol sleep time. Over-expression of 5-HT₃ receptors in mouse forebrain results in an enhanced sensitivity to the stimulating effects of a low dose of ethanol without altering ethanol sedating effects or ethanol metabolism. These data suggest that 5-HT₃ receptors modulate low dose ethanol sensitivity and may explain why, in previous studies, these mice consume less ethanol. Received: 11 December 1998 / Final version: 24 February 1999     

Self-administration of intravenous amphetamine: effect of nucleus accumbens CCKB receptor activation on fixed-ratio responding

Rationale: The mesolimbic dopamine (DA) system is implicated in psychostimulant drug self-administration. The neuropeptide cholecystokinin (CCK) is co-localised with DA and inhibits nucleus accumbens (NAcc) DAergic neurotransmission via CCK_B receptors. Objectives: The present experiment was designed to examine the effects of intra-NAcc CCK_B receptor stimulation on fixed-ratio (FR) amphetamine self-administration. Methods: Wistar rats with intravenous catheters and NAcc cannulae were trained to self-administer amphetamine under a FR3 schedule of reinforcement. Animals performing stable self-administration were microinjected with pentagastrin and assessed during 3-h sessions. Results: Intra-NAcc pentagastrin dose dependently increased amphetamine intake. Conclusions: These results are consistent with the notion that NAcc CCK_B receptor activation attenuates amphetamine reward. Received: 6 May 1999 / Final version: 4 August 1999     

NMDA receptor antagonists enhance 5-HT2 receptor-mediated behavior, head-twitch response, in PCPA-treated mice

Previous work in our laboratory has shown that the N-methyl-D-aspartate (NMDA) receptor antagonists, AP-5, CPP, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced enhancement of 5-hydroxytryptamine (5-HT)-induced head-twitch response (HTR) in intact mice, suggesting the involvement of NMDA receptors in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT2 receptors. The purpose of this study was to extend our previous work on the behavioral interaction between glutamatergic and serotonergic receptors. In the present study, both competitive (AP-5 and CPP) and noncompetitive (MK-801, ketamine, dextrorphan and dextromethorphan) NMDA receptor antagonists markedly enhanced 5-HT-induced selective serotonergic behavior, HTR, in p-chlorophenylalanine (PCPA)-treated mice which were devoid of any involvement of indirect serotonergic function, to establish the involvement of the NMDA receptor in 5-HT-induced HTR at the postsynaptic 5-HT2 receptors. In addition, the enhancement of 5-HT-induced HTR was inhibited by a dopamine agonist, apomorphine, NMDA receptor antagonist, NMDA and a serotonin 5-HT2 receptor antagonist, cyproheptadine, in PCPA-treated mice. Therefore, the present results support our previous conclusion that the NMDA receptors play an important role in the glutamatergic modulation of serotonergic function at the postsynaptic 5-HT2 receptors.     

再生障碍性贫血患者外周血单个核细胞产生某些细胞因子能力的变化及意义

观察再生障碍性贫血患者外周血单个核细胞（ＰＢＭＮＣ）产生 ＩＬ－１α、ＩＬ－２的能力及外周血清ｓＩＬ－２Ｒ水平,探讨这些变化的意义。方法：应用ＥＬＩＳＡ法测定细胞因子活性。结果〔显示再障患者ＰＢＭＮＣ产生ＩＬ－１α的能力明显低于对照组（Ｐ＜０．０１）;而产生 ＩＬ－２的能力则明显高于对照组（Ｐ＜０．０１）;血清 ｓＩＬ－２Ｒ水平明显高于对照组（Ｐ＜０．０１）。结论：这三项检测结果对于认识再障贫血的发病机制、辅助诊断疾病的严重程度、指导治疗和估计预后有一定意义。     

Hypozincaemia in febrile convulsion

To understand further the role of trace elements in the pathogenesis of febrile convulsions, serum zinc (Zn), copper (Cu), magnesium (Mg) and CSF Zn, Cu, Mg and protein levels were measured by spectrometry in patients with febrile convulsion (n=19), bacterial meningitis (n=9), viral CNS infection (n=16) and in the control groupn=10) which consisted of children with signs of meningeal irritation due to upper respiratory tract infection but normal CSF findings. Samples were obtained within 6 h after admission to hospital. Mean serum and CSF Zn levels in the febrile convulsion group were significantly lower than in the other groups (for serum Zn: 0.66±0.03 mg/l vs 0.98±0.07 mg/l, 1.06±0.08 mg/l, 1.05±0.09 mg/lP<0.05; for CSF Zn: 22.96±1.62 g/l vs 75.47 ±6.9 g/l, 50.32±5.235 g/l, 39.85 ±2.81 g/lP<0.05). A linear relationship was established between serum Zn and CSF Zn levels (P<0.001). Mean CSF Zn, Cu and protein levels in the bacterial meningitis group were significantly higher than in the other groups (for CSF Cu 63.94±6.33 g/l vs 38.77±2.70 g/l, 35.84±3.48 g/l, 33.86±2.88 g/lP<0.05; for CSF protein 0.80 ± 0.12 g/l vs 0.22±0.02 g/l, 0.53±0.08 g/l, 0.19±0.01 g/lP<0.05). In children with meningitis, the elevation of the mean CSF Zn and Cu levels may result from the breakdown of the blood-brain barrier and subsequent leakage of trace elements and protein from serum to CSF. There was no significant difference between the four groups in terms of mean serum Mg and mean CSF Mg levels.Conclusion Serum and CSF Zn levels are decreased in children with febrile seizures. Zinc deprivation may play a role in the pathogenesis of febrile seizures.     

Salmon calcitonin nasal spray : An effective alternative to estrogen therapy in select postmenopausal women

The efficacy and safety of estrogen replacement therapy (ERT) and salmon calcitonin in the treatment of postmenopausal osteoporosis are reviewed with special consideration given to patients for whom ERT, the primary antiresorptive therapy for osteoporosis, is not indicated, tolerable, or is refused. The various formulations of estrogen and salmon calcitonin, for which the nasal spray formulation was recently approved for use in the United States, are reviewed in depth with reference to dose ranges, side effects, and convenience. Data regarding increases in bone mineral density (BMD) produced by each agent are presented. Specifically, the range of increases in BMD induced by ERT and salmon calcitonin are comparable. Given the substantial public health consequences of postmenopausal osteoporosis and osteoporotic fractures, the primary care physician is increasingly faced with the need to educated and recruit postmenopausal patients to appropriate therapy with the optimal agent for that particular patient. In the many patients who are unable or unwilling to accept, initiate, and comply with prescribed ERT, alternative therapeutic options are necessary Based on the established safety profile of salmon calcitonin, ease of administration, an uncomplicated dosing regimen, no reported drug interactions, and the lack of uterine bleeding associated with ERT or gastrointestinal adverse effects of other agents used to treat osteoporosis, salmon calcitonin nasal spray is an appropriate alternative approach for the treatment of postmenopausal bone loss.