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1.
Behavioral manifestations of the nicotine abstinence syndrome in the rat: peripheral versus central mechanisms 总被引:8,自引:8,他引:0
B. E. Hildebrand G. G. Nomikos C. Bondjers M. Nisell T. H. Svensson 《Psychopharmacology》1997,129(4):348-356
The nicotine abstinence syndrome was studied in the rat utilizing a modified rating scale of the opiate abstinence syndrome.
Rats were infused with 10.27 mg/kg per day nicotine hydrogen tartrate for 7 days via subcutaneous minipumps. The behavior
of each animal was observed before, during and after termination of the nicotine infusion. The abstinence signs in the withdrawal
sessions included gasps, genital licks, ptosis, shakes, teeth chatter, yawns and changes in locomotor activity. Abstinence
was induced through surgical removal of the pump or through administration of a nicotinic receptor antagonist, acting either
centrally and peripherally (mecamylamine 1 mg/kg SC) or peripherally only (chlorisondamine 1 mg/kg SC). Statistical evaluation
revealed a significant increase in overall abstinence signs both at 16 (P < 0.05) and 40 h (P < 0.01) after termination of the nicotine infusion, as compared to the number of signs in the nicotine treated animals’ baseline
sessions and to the number of signs in control animals (P < 0.05). There was also a significant reduction in locomotor activity during both withdrawal sessions. Animals injected with
mecamylamine or chlorisondamine displayed a larger increase in the abstinence score (P < 0.001) than the spontaneously abstinent animals. Acute administration of different doses of nicotine or of the peripherally
acting nicotinic receptor agonist tetramethylammonium (0.8 mg/kg SC) reversed the behavioral nicotine abstinence syndrome.
Our results show that a nicotine abstinence syndrome can be elicited in rats on a chronic nicotine regimen either by acute
withdrawal of nicotine or by the administration of nicotinic receptor antagonists and that peripheral nicotinic receptors
may contribute significantly to the overall withdrawal reaction.
Received: 21 March 1996/Final version: 30 September 1996 相似文献
2.
M. Shoaib Charles W. Schindler Steven R. Goldberg James R. Pauly 《Psychopharmacology》1997,134(2):121-130
Chronic exposure of rats to nicotine can result in sensitization to the stimulant effects of nicotine on locomotor activity.
At a biochemical level, chronic exposure to nicotine increases the number of CNS nicotinic binding sites, and this has been
suggested as the basis for sensitization to nicotine. The present experiment was conducted to examine the effects of MK801,
an NMDA receptor antagonist, on sensitization to nicotine. In addition, the hypothesis that MK801 may block behavioural sensitization
by preventing the up-regulation of nicotinic receptors was tested by measuring receptor numbers in the same individuals using
quantitative autoradiography with [3H]-cytisine and [3H]-MK801. Male Sprague-Dawley rats were chronically treated with nicotine (0.4 mg/kg SC) or saline daily for 7 days. Over
the next 2 days, in a counterbalanced order, rats were challenged with nicotine (0.4 mg/kg SC) or saline and locomotor activity
was monitored. In saline-pretreated rats, nicotine produced a small increase in activity. Nicotine-pretreated rats exhibited
higher levels of activity following a nicotine challenge. This sensitized response was attenuated in rats administered MK801
(0.3 mg/kg IP) 30 min before each daily nicotine injection. Rats pretreated with MK801 alone showed activity scores no different
from saline pretreated control groups. Biochemical studies revealed increased [3H]-cytisine binding following chronic nicotine treatment; however, receptor increases were significantly attenuated by MK801
pretreatment. Binding of [3H]-MK801 remained unchanged across the four groups. The results suggest that MK801 prevents behavioural sensitization to nicotine
via the prevention of receptor up-regulation. Although the findings support the notion that receptor up-regulation may be
the basis for the increased responsiveness to nicotine, other interpretations are possible.
Received: 23 January 1997/Final version: 8 May 1997 相似文献
3.
The influence of nicotine pretreatment on mesoaccumbens dopamine overflow and locomotor responses to D-amphetamine 总被引:2,自引:2,他引:0
Pretreatment with psychostimulant drugs causes sensitisation of their effects on locomotor activity and dopamine (DA) overflow
in the nucleus accumbens (NAcc) and there is evidence for similarities in the mechanisms involved. This study used in vivo
microdialysis in conscious freely moving rats to investigate the extent to which pretreatment with nicotine causes sensitisation
to D-amphetamine. Pretreatment with nicotine (0.4 mg/kg SC daily for 5 days) caused sensitisation of the locomotor responses to
D-amphetamine (0.1–0.5 mg/kg SC) but not cocaine (15 mg/kg IP). Nicotine pretreatment did not influence the increase in DA
overflow into dialysis probes, located in the core of the NAcc, evoked by systemic injections of D-amphetamine or cocaine (15 mg/kg IP) but decreased the overflow evoked by the administration of D-amphetamine (1 × 10–6 M) through the dialysis probe. The results provide further evidence for a dissociation between the expression of sensitised
locomotor responses to psychostimulant drugs and sensitisation of their stimulatory effects on DA overflow in the core of
the NAcc. The results suggest that the sensitisation of the effects of nicotine on DA overflow in this subdivision of the
NAcc may be pharmacologically specific to nicotinic drugs.
Received: 23 July 1997/Final version: 19 March 1998 相似文献
4.
Malin DH Lake JR Smith TD Khambati HN Meyers-Paal RL Montellano AL Jennings RE Erwin DS Presley SE Perales BA 《Psychopharmacology》2006,184(3-4):494-503
Rationale Bupropion reduces discomfort and craving associated with smoking cessation. This study determined whether a rat model of nicotine
dependence could detect such nicotine abstinence-alleviating effects.
Objectives Experiments determined whether the abstinence-alleviating effects of bupropion were detectable by (1) behavioral abstinence
signs precipitated by the nicotinic antagonist mecamylamine, (2) place aversion conditioned to mecamylamine-precipitated nicotine
abstinence, and (3) spontaneous behavioral abstinence signs after abrupt nicotine withdrawal.
Methods In experiments 1 and 2, nicotine-dependent rats were coinfused for 7 days with 3.15 mg/kg/day nicotine and 20 mg/kg/day bupropion
or with nicotine alone. They were then challenged with 1 mg/kg mecamylamine and observed for behavioral abstinence signs (experiment
1) or place aversion conditioned to precipitated abstinence (experiment 2). In experiment 3, rats were nicotine-infused for
7 days as above. A day after termination of nicotine infusion, rats were observed for spontaneous nicotine abstinence signs
before and after injection with saline or bupropion.
Results In experiment 1, rats coinfused with nicotine and bupropion had significantly fewer mecamylamine-precipitated abstinence signs
than rats infused with nicotine alone but similar numbers to rats infused with saline alone. In experiment 2, bupropion pretreatment
significantly reduced the aversiveness of mecamylamine-precipitated nicotine abstinence. In experiment 3, a single bupropion
injection dose-dependently alleviated spontaneous nicotine abstinence syndrome.
Conclusions These results suggest that these rat models of nicotine dependence and abstinence syndrome may be useful in detecting nicotine
abstinence-alleviating effects of potential medications for smoking cessation. The effects of acute bupropion administration
raise interesting questions regarding bupropion's mechanism of action. 相似文献
5.
Adrenalectomy (ADX) in mice can potentiate several physiological and behavioural responses to nicotine. The present experiments
sought to examine this issue in the rat by characterising the influence of ADX upon the locomotor depressant, activating and
dopamine-releasing properties of nicotine. Nicotine (0.8–1.2 mg/kg SC) dose-dependently depressed locomotor activity, an effect
that was potentiated by ADX, while the locomotor activating effects of a smaller dose (0.4 mg/kg) were attenuated by ADX.
In both SHAM and ADX rats chronically treated with nicotine for 5 days (daily injections of 0.4 mg/kg SC), the locomotor depressant
effects of nicotine did not differ from saline-treated controls. Nicotine (0.4 mg/kg SC) increased extracellular levels of
dopamine in the nucleus accumbens. This response was unaffected in rats pretreated with nicotine for 5 days (daily injections
of 0.4 mg/kg SC). However, both ADX groups of rats showed smaller increases in dopamine following administration of nicotine.
The results suggest that depletion of circulating corticosteroids can modulate sensitivity to nicotine in rats. The suppressant
effects of ADX on nicotine-induced locomotor activity may be due to its effects on dopamine release in the nucleus accumbens.
Received: 13 July 1995/Final version: 28 July 1996 相似文献
6.
Comparison of 7-nitroindazole with other nitric oxide synthase inhibitors as attenuators of opioid withdrawal 总被引:3,自引:0,他引:3
D. Bruce Vaupel Alane S. Kimes Edythe D. London Edythe D. London 《Psychopharmacology》1995,118(4):361-368
Previously, we demonstrated that two nonselective inhibitors of nitric oxide synthase (NOS),l-N
G-nitroarginine (l-NNA) andl-N
G-nitroarginine methyl ester (l-NAME), reduced some signs of morphine withdrawal in rats. The present work extended these studies to include 7-nitroindazole (7-NI), an inhibitor specific for cerebral NOS, andN(5)-(1-iminoethyl)-l-ornithine (l-NIO), a potent inhibitor of endothelial NOS. Behavioral effects of these four NOS inhibitors and clonidine, an
2-adrenoceptor, agonist, on morphine withdrawal in rats were assessed. Rats received one 75-mg morphine pellet subcutaneously (SC). Three days later, NOS inhibitors were administered IP 1 h before withdrawal was precipitated with naloxone (0.5 mg/kg, SC) and scored. 7-NI,l-NIO,l-NAME andl-NNA produced dose-related decreases in weight loss, diarrhea, wet dog shakes and grooming. 7-NI also reduced mastication, salivation and genital effects. Clonidine produced effects similar to 7-NI. In awake, morphine-naive and morphine-dependent rats not subjected to withdrawal, 7-NI was the only NOS inhibitor that did not increase blood pressure. Because 7-NI attenuated more signs of opioid withdrawal thanl-NNA,l-NAME orl-NIO without causing hypertension, 7-NI appears to warrant further testing as a potential candidate for human use.Abstracts were presented at the annual meetings of the College on Problems of Drug Dependence, West Palm Beach, Fla., 18–23, June 1994; International Narcotics Research Conference, North Falmouth, Cape Cod, Mass., 16–21, July 1994; and a Satellite Symposium to IUPHAR, Montreal, Canada, 22–24, July 1994. 相似文献
7.
R. D. Hurt K. P. Offord I. T. Croghan G. A. Croghan L. C. Gomez-Dahl T. D. Wolter L. C. Dale T. P. Moyer 《Psychopharmacology》1998,140(1):98-104
Nicotine nasal spray and nicotine gum have been found to be effective in relieving nicotine withdrawal symptoms. In this
randomized single-blind study, 91 cigarette smokers were randomly assigned to a single 1 mg dose of active nicotine nasal
spray (n = 29), active 4 mg nicotine gum (n = 31), saline placebo nasal spray (n = 16) or placebo gum (n = 15). Following overnight abstinence, subjects repeatedly completed visual analog scales for assessing nicotine withdrawal
symptoms over 30 min preceding (time -30 min to time 0) and 120 min following a single dose of study medication. This sequence
was performed 3 times during the day. Nicotine withdrawal symptoms were assessed on a 41-point visual analog scale (1 = no
withdrawal, 41 = extreme withdrawal). At the initial session only, blood samples for serum nicotine levels were taken at baseline,
then at 5, 10, 30 and 120 min following study drug administration. The mean (± SD) age of the subjects was 38.6 (±10.1) years,
48% were females, smoking rate was 24.5 (±7.8) cigarettes per day, and years of smoking was 19.9 (±10.0). A single 1 mg dose
of nicotine nasal spray provided more immediate relief for craving for a cigarette compared to a single 4 mg dose of nicotine
gum. Serum venous nicotine levels for the active nicotine nasal spray and nicotine gum were comparable at 5 and 10 min while
the levels were higher for nicotine gum at 30 and 120 min. Changes in withdrawal symptoms were not found to be related to
serum venous nicotine levels. Our findings provide a rationale for the as needed use of nicotine nasal spray to control withdrawal
symptoms, possibly in combination with other medications with longer acting effects.
Received: 18 February 1998/Final version: 1 May 1998 相似文献
8.
These studies aim to characterize the discriminative stimulus effects of nicotine in two inbred strains of mice that differ
in many pharmacological responses, and to investigate the feasibility of IV self-administration studies with nicotine in one
of the strains. For discrimination studies, three groups of C57BL/6 and one group of DBA/2 mice were trained in a two-lever
operant conditioning paradigm with a tandem VI-30″ FR-10 schedule of food reinforcement. After 40 training sessions, accuracy
reached 57.5, 77.5 and 90.0% in C57BL/6 mice trained with (–)-nicotine (SC) in doses of 0.4, 0.8 and 1.6 mg/kg, respectively
(n = 8). DBA/2 mice trained with 0.8 mg/kg nicotine attained similar (73.3%) accuracy (n = 9). Results from extinction tests showed that all groups of mice yielded orderly dose-response curves for nicotine (0.03–1.6
mg/kg), but stimulus control remained notably weaker for the mice trained with 0.4 mg/kg nicotine than for any other group.
Overall rates of responding in the undrugged state were lower for DBA/2 than for C57BL/6 mice; DBA/2 mice were also slightly
less sensitive than C57BL/6 mice to the response rate-reducing effect of nicotine. The nicotine antagonist mecamylamine (1.5 mg/kg
SC) blocked the discriminative stimulus effect of the training dose of nicotine in all groups. The results of the IV self-administration
study suggest that nicotine (0.1 mg/kg) can serve as a positive reinforcer in drug–naive C57BL/6J mice (n = 13). Behaviour maintained by 0.1 mg/kg nicotine injections was significantly greater than behaviour maintained by vehicle
injections, and it was maintained under an intermittent schedule of reinforcement (FR4). The methods described provide possible
approaches for genetic analyses of strain differences in sensitivity to the discriminative and reinforcing stimulus properties
of nicotine.
Received: 11 April 1998/Final version: 28 June 1998 相似文献
9.
In this study, effects of histamine (HA) agents on methamphetamine (METH)-induced stereotyped behavior and behavioral sensitization
were examined in rats. Pretreatment with a precursor of HA, L-histidine (750 mg/kg), significantly inhibited the METH (3 mg/kg)-induced stereotyped behavior, whereas pretreatment with
an inhibitor of HA synthesis, α-fluoromethylhistidine (FMH) (100 mg/kg), an H1 antagonist pyrilamine (5 mg/kg) or an H2 antagonist zolantidine (5 mg/kg) enhanced it. The inhibitory effect of L-histidine on METH-induced stereotyped behavior was significantly blocked by coadministration of pyrilamine and zolantidine,
indicating that the effect is mediated through H1 and H2 receptors. Moreover, chronic treatment with METH (3 mg/kg) significantly enhanced stereotyped behavior at the rechallenge
with METH (1 mg/kg). Chronic treatment with L-histidine (750 mg/kg) plus METH inhibited the METH-induced argumentation of stereotyped behavior, while that with FMH (100 mg/kg),
pyrilamine (5 mg/kg) or zolantidine (5 mg/kg) potentiated it. These findings suggest that the HA neuron system has an inhibitory
role in METH-induced stereotyped behavior and behavioral sensitization.
Received: 1 July 1996/Final version: 26 November 1996 相似文献
10.
The nicotinic antagonist mecamylamine precipitates nicotine abstinence syndrome in the rat 总被引:6,自引:6,他引:0
David H. Malin J. Ronald Lake Victoria A. Carter J. Scott Cunningham Kathleen M. Hebert Delia L. Conrad Owen B. Wilson 《Psychopharmacology》1994,115(1-2):180-184
Recently, a rodent model of nicotine abstinence syndrome has been developed based on observing the frequency of spontaneous behavioral signs following termination of continuous subcutaneous infusion of nicotine tartrate. In the present study, the nicotinic antagonist mecamylamine precipitated an abstinence syndrome in nicotine-dependent rats. Twelve rats were each infused for 7 days with 9 mg/kg per day nicotine tartrate in saline via Alzet osmotic minipumps; another 12 rats were shamoperated and remained nicotine-naive. Six rats from each group received 1 mg/kg mecamylamine in saline SC immediately before a 30-min observation, while the remaining six rats from each group received saline alone. Nicotine-infused rats receiving mecamylamine exhibited significantly more (P<0.01), overall abstinence signs than all other groups. In terms of categories of signs, they displayed significantly more gasps/writhes, teeth chatter/chews, shakes/tremors and ptosis. In a second experiment utilizing only nicotine-naive rats, a far higher dose of mecamylamine (5 mg/kg sc) induced a quasi-nicotine abstinence syndrome. The results provide further validation for this rodent model of nicotine abstinence syndrome. 相似文献
11.
Cytisine binds with high affinity and specificity to neuronal nicotinic receptors but its physiological and behavioural effects
are complex and differ from those of nicotine. The present study explores the behavioural aspects further by comparing the
discriminative stimulus effects of cytisine with those of nicotine. Two groups of rats were trained to discriminate cytisine
(2 mg/kg SC) or nicotine (0.2 mg/kg SC) from saline in a two-lever operant conditioning procedure with food reinforcers presented
on a tandem VI FR schedule. A third group of rats was trained to discriminate cytisine (3 mg/kg SC). Rats acquired these discriminations
within 50 training sessions. The stimulus effects of both cytisine and nicotine appeared within 4 min of SC injection. In
generalization tests, rats trained with either cytisine or nicotine showed steep dose-response curves (generalization gradients)
for their respective training drug. However, rats trained with cytisine showed full dose-related, generalization to nicotine
(93%), whereas rats trained with nicotine exhibited only partial generalization to cytisine (54%). Rats trained with either
cytisine or nicotine exhibited similar, partial generalization (76–77%) to (+)-amphetamine. The nicotine antagonist mecamylamine
blocked the discriminative stimulus effects of both cytisine and nicotine; it was confirmed that the block of nicotine (0.2 mg/kg)
was complete, whereas the block of cytisine (2 and 3 mg/kg) was incomplete in two separate experiments. Overall, the results
showed that cytisine, like nicotine, can serve as a robust discriminative stimulus but, in contrast to its relatively high
affinity in binding experiments, cytisine was much less potent than nicotine in the behavioural studies. Although the stimulus
effects of the two drugs were very similar, there were some subtle differences such as the asymmetrical cross-generalizations
between them and possible small differences in susceptibility to antagonism by mecamyl-amine. These effects were interpreted
either in terms of a putative partial agonist effect of cytisine, or by assuming that nicotine produces a compound stimulus.
Such a stimulus would be mediated through two or more subtypes of nicotinic receptor, and cytisine would act at some, but
not all, of these receptor subtypes.
Received: 17 June 1996/Final version: 6 September 1996 相似文献
12.
Edward A. Lock Andrew Gyte Peter Widdowson Michael Simpson Ian Wyatt 《Archives of toxicology》1995,69(9):640-643
We have examined the effect of L- and D-2-chloropropionic acid (L-CPA and D-CPA) on the concentrations of pyruvate, lactate, glucose and β-hydroxybutyrate in the blood at various times after doses
which produce cerebellar granule cell necrosis. Blood pyruvate and lactate concentrations were reduced in these animals 4 h
after dosing and remained below those of controls for up to 48 h. No changes were seen in concentrations of plasma glucose
of β-hydroxybutyrate at any time point. Similarly, no changes in cerebellar glucose, pyruvate or lactate were seen 24 h after
750 mg/kg L-CPA. Oxidation of [14C] pyruvate or [14C] glucose to [14CO2] by cerebellar slices from control rats was not altered by the presence of L- or D-CPA (1–10 mM for 2 h). Nor were these parameters affected in cerebellar slices from rats killed 24 h after a dose of 750 mg/kg
L-CPA. We conclude that activation of the pyruvate dehydrogenase complex is unlikely to be a critical factor in the selective
toxicity of CPA to the cerebellum.
Received: 22 November 1994 / Accepted: 9 March 1995 相似文献
13.
Naloxone precipitates nicotine abstinence syndrome in the rat 总被引:4,自引:4,他引:0
David H. Malin J. Ronald Lake Victoria A. Carter J. Scott Cunningham Owen B. Wilson 《Psychopharmacology》1993,112(2-3):339-342
Recently, a rodent model of nicotine abstinence syndrome has been developed based on continuous subcutaneous infusion of nicotine tartrate and observing the frequency of spontaneous behavioral signs following termination of infusion. The observed signs closely resemble those commonly seen in rat opiate abstinence syndrome, raising the possibility that there is an endogenous opioid component in nicotine dependence. The present study demonstrates that the opiate antagonist naloxone can precipitate an abstinence syndrome in nicotine-dependent rats. Fourteen rats were infused for 7 days with 9 mg/kg/day nicotine tartrate in saline via an Alzet osmotic minipump. Fourteen rats were sham-operated and remained nicotine-naive. Half of each group received 4.5 mg/kg naloxone SC immediately before a blind 15-min observation, while the other half received saline alone. ANOVA revealed significant nicotine infusion, naloxone injection and interaction effects. Post-hoc analysis showed that the nicotine-infused rats injected with naloxone had significantly more signs than all other groups (P<0.01). In a second experiment, 2 mg/kg morphine sulfate SC produced a significant (P<0.01) 91.2% reduction of spontaneous abstinence signs observed 21 h after termination of nicotine infusion. These results are consistent with the hypothesized endogenous opioid component in nicotine dependence and abstinence syndrome. 相似文献
14.
Rationale Nitric oxide (NO) is implicated in both acute effects of addictive drugs and development of dependence to them. We investigated the role of NO in nicotine-induced locomotor sensitization.Objectives The effects of N-nitro-l-arginine methyl ester (l-NAME), a NO synthase inhibitor, and a combination of a NO precursor l-arginine and l-NAME on nicotine-induced locomotor sensitization were investigated in Swiss Webster mice.Methods Sensitization to psychomotor stimulating effect of nicotine was rendered by seven injections of nicotine (1 mg/kg) on every other day. To investigate their effect on the development of sensitization to nicotine, l-NAME (15–60 mg/kg) and l-arginine (1 g/kg) were given before nicotine administration during the first seven sessions. To investigate the effect of these compounds on the expression of nicotine sensitization, after a 4-day drug-free period another group of mice received a challenge injection of nicotine on day 18.Results Nicotine (1 mg/kg) produced a robust locomotor sensitization in mice. The doses of 30 mg/kg and 60 mg/kg of l-NAME blocked the development of sensitization to nicotine; and, l-arginine (1 g/kg) pretreatment reversed this effect of l-NAME. Likewise, the doses of 30 mg/kg and 60 mg/kg of l-NAME inhibited the expression of sensitization to nicotine on day 18; and, l-arginine (1 g/kg) pretreatment reversed this inhibitory effect of l-NAME.Conclusions Our results suggest that NO is implicated in the development and expression of nicotine-induced locomotor sensitization in mice. 相似文献
15.
This study evaluates the effects of three nitric oxide synthase (NOS) inhibitors (L-NNA, L-NAME, L-NMMA) in attenuating the precipitated nicotine withdrawal syndrome in rats. Male albino Wistar rats were made dependent on nicotine by subcutaneous infusion of nicotine (9.0 mg/kg/day) via a 7 day osmotic pump, whereas control rats received saline via osmotic pumps. Test doses of each NOS inhibitor were administered 30 min prior to mecamylamine (1 mg/kg) challenge in control and test rats on the 7th day. Somatic signs of withdrawal were scored for 15 min by using the global Gellert-Holtzman rating scale followed by a measurement of motor activity. A comparison of NOS inhibitors treated rats with the mecamylamine-precipitated nicotine rats showed that at highest dose L-NNA appears to produce a more complete attenuation of all aspects of withdrawal syndrome. On the other hand, L-NAME appears to do so both at moderate and highest doses. This could be due to an incomplete reversal of some signs of withdrawals by L-NMMA. However, motor activity increased in nicotine dependent rats with the administration of NOS inhibitors. This study demonstrates that NO plays an important role in the expression of behavioral signs of nicotine withdrawal syndrome and suggests a potential use of NOS inhibitors as an aid in tobacco smoking cessation. 相似文献
16.
A therapeutic dosage of amlodipine prevents vascular hyporeactivity induced in rats by lipopolysaccharide 总被引:1,自引:0,他引:1
Salvatore Salomone Nicole Morel Théophile Godfraind 《Naunyn-Schmiedeberg's archives of pharmacology》1998,357(3):252-259
The aim of this work was to investigate whether treatment with the 1,4-dihydropyridine Ca2+ antagonist amlodipine could affect the vascular hyporesponsiveness induced by cytokines. Endotoxemia was induced by Salmonella
typhosa lipopolysaccharide (LPS) injection (4 mg kg–1, i.p.). In endothelium-denuded rings of thoracic aorta from untreated rats, contractile response to noradrenaline was decreased
after LPS injection, this effect was partially overcome by the addition of Nω-nitro-l-arginine (l-NNA, 100 μM) into the bathing solution. In amlodipine-pretreated rats (15 mg kg–1 day–1, orally, for one week), the effect of LPS was lower than in untreated ones and it was completely reversed by l-NNA. The relaxation of the noradrenaline-induced tone evoked by l-arginine (10 μM) in aortae of LPS-injected rats was reduced in amlodipine-pretreated rats. Amlodipine-treatment reduced both
the LPS-induced Ca2+-independent NOS activity in homogenates of heart and the expression of iNOS mRNA in aortae of LPS-injected rats. However,
the vascular hyporeactivity induced by exposing aortae to interleukin-1β in vitro was not influenced by amlodipine (10 nM).
Amlodipine (10 μM) also did not affect the production of nitrite in primary aortic smooth muscle cell culture challenged by
LPS although nitrite production in macrophage culture challenged with LPS was significantly inhibited. The results show that
rat pretreatment with amlodipine prevented the decrease of vascular responsiveness induced by LPS, an effect that may be at
least partly related to reduction of in vivo NOS induction. The weak effect of amlodipine on the in vitro NOS induction indicates
that the protective action in endotoxemia did not result from a short term interaction with L-type Ca2+ channels in vascular smooth muscle. Alternative mechanisms are discussed.
Received: 1 April 1997 / Accepted: 6 November 1997 相似文献
17.
The escape behaviour induced in rats by injecting D,L-homocysteic acid (DLH) into the dorsal periaqueductal grey area (DPAG) was used as an animal model of panic attacks to investigate
the effect of imipramine, a drug used for the treatment of panic disorder, on the sensitivity of 5-HT1A receptors in the DPAG. Rats given imipramine (10 mg/kg per day SC for 3 weeks or IP for 2–3 days) received 250 nl saline
or the 5-HT1A agonist 8-OH-DPAT (8.6 nmol) into the DPAG 10 min before inducing the escape response with DLH. As expected, 8-OH-DPAT produced
a marked decrease in the average speed of the DLH-induced flight response. The short-term treatment with imipramine changed
neither the DLH-induced escape behaviour nor the effect of prior 8-OH-DPAT administration on this response. In contrast, long-term
treatment with imipramine enhanced the 5-HT1A-mediated inhibition, as the decrement in the amplitude of the flight response produced by 8-OH-DPAT was 96% after this treatment
compared to 41% in controls. The injection of 8-OH-DPAT also significantly decreased the amplitude of the freezing behaviour
observed at the end of the flight response in rats given imipramine for 3 weeks, but not in controls. The long-term imipramine
treatment, however, did not significantly decrease the amplitude of DLH-induced flight and freezing behaviours in absence
of prior 8-OH-DPAT administration. Finally, 8-OH-DPAT failed to inhibit the DLH-induced flight and freezing behaviours in
rats withdrawn from imipramine after long-term treatment (10 mg/kg per day × 21 days). It is suggested that an alteration
at the level of the DPAG-5-HT1A receptor system is implicated in the therapeutic and withdrawal effect of imipramine in panic disorder.
Received: 15 August 1996/Final version: 24 January 1997 相似文献
18.
Rodent model of nicotine abstinence syndrome. 总被引:12,自引:0,他引:12
D H Malin J R Lake P Newlin-Maultsby L K Roberts J G Lanier V A Carter J S Cunningham O B Wilson 《Pharmacology, biochemistry, and behavior》1992,43(3):779-784
Few animals models are currently in use for the recognized clinical problem of nicotine dependence and abstinence. This study introduces a rapid and convenient model using the rat. Sixteen male rats were rendered nicotine dependent by 7 days of continuous subcutaneous infusion of either 3 mg/kg/day (n = 8) or 9 mg/kg/day (n = 8) nicotine tartrate salt; 8 control rats were infused with saline alone. Rats were observed for 15 min before, during, and after the drug infusion period using a tally sheet modified from a standard checklist of opiate abstinence signs. There were few signs observed in any group at baseline and at the end of the infusion period. However, nicotine-infused rats showed a significant, dose-related increase over the control group at 16 h after the end of infusion, largely subsiding by 40 h. The most frequently observed signs during withdrawals included: teeth-chattering/chews, writhes/gasps, ptosis, tremors/shakes, and yawns. A significant drop in locomotor activity and increase in weight gain following termination of nicotine infusion provided additional evidence of an abstinence syndrome. This syndrome was alleviated by SC administration of 0.4 mg/kg nicotine tartrate. 相似文献
19.
In this study, the behavioural response to dopamine D1-like receptor agonists (SKF 38393, SKF 81297 and SKF 77434) and D2-like receptor agonists (quinpirole and RU 24213), administered alone and in combination to rats treated repeatedly with electroconvulsive
shock (five ECS over 10 days) or sham, was tested. Agonist-induced behaviour was monitored by automated activity meters and
direct observation using a checklist scoring method. Repeated ECS (compared to sham controls) had no significant effect on
the behavioural response to SKF 38393 (7.5 mg/kg SC), SKF 81297 (0.2 mg/kg SC), SKF 77434 (0.1 mg/kg SC), quinpirole (0.1
and 0.25 mg/kg SC) or RU 24213 (0.3 mg/kg SC), when administered alone. In contrast, repeated ECS markedly increased locomotion
(activity counts and scores) induced by the non-selective dopamine agonist apomorphine (0.5 mg/kg SC) and by co-administration
of a D1-like agonist plus a D2-like agonist [SKF 38393 (7.5 mg/kg SC) plus quinpirole (0.25 mg/kg SC), SKF 81297 (0.2 mg/kg SC) plus quinpirole (0.1 mg/kg
SC), and SKF 77434 (0.1 mg/ kg SC) plus RU 24213 (0.3 mg/kg SC)]. This ECS-induced enhancement of dopamine-mediated behaviour
was observed for up to 3 weeks after cessation of ECS treatment. In addition, ECS also enhanced the locomotor response to
intra-accumbens SKF 38393 plus quinpirole (0.4 and 1.0 μg/side, respectively). These results provide evidence that the enhancement
of dopamine function by repeated ECS requires concomitant stimulation of both D1-like and D2-like receptors, and that this effect is long-lasting.
Received: 24 January 1997 /Final version: 5 March 1997 相似文献
20.
The present experiment evaluated the ability of the 5-HT3 antagonist, ondansetron, administered during chronic cocaine administration, to block the development of sensitization and
tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg
per day cocaine for 14 days by either SC injections or osmotic minipumps, or 0.9% saline, administered by SC injection. During
this chronic (cocaine) treatment, all rats received a daily SC injection of 0–1.0 mg/kg ondansetron. The rats were then withdrawn
from the pretreatment regimen for 7 days. On day 7 of withdrawal from the cocaine pretreatment all subjects received a 15.0 mg/kg
IP cocaine challenge, and their behavior was then rated according to the modified Ellinwood and Balster scale for 60 min.
The results indicated that daily injections of ondansetron had no consistent or significant effect on the subsequent behavioral
response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron with cocaine significantly
blocked the development of sensitization with an inverted U-shape dose-response curve. In the continuous cocaine group ondansetron
injections also attenuated the development of behavioral tolerance. The results therefore indicate that 5-HT3 receptor stimulation during continuous and intermittent cocaine administration is an important link in the development of
behavioral tolerance and sensitization.
Received: 1 July 1996/Final version: 25 September 1996 相似文献