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961.
The augmentation effect of (–)pindolol as used in combination with SSRI to treat major depression has been ascribed to blocking
of dorsal raphe nucleus cell body 5-HT autoreceptors. In this study, the radioligand [carbonyl-11C]WAY-100635 and positron emission tomography were used to establish whether pindolol at a clinical dose level (10 mg s.o.d.)
occupies 5-HT1A receptors in the human brain in vivo. Three healthy males were recruited and each subject was used as his own control. The
5-HT1A receptor occupancy was calculated for the frontal and temporal cortex and the raphe nuclei, using and a ratio analysis with
the cerebellar cortex as the reference region. Maximal pindolol plasma concentration was reached within 3 h after drug administration.
Two hours after pindolol administration, the regional 5-HT1A receptor occupancy was within the range 7–21% in the three subjects. The study confirms that the 5-HT1A-receptor may be a clinically significant target for pindolol.
Received: 8 March 1999 / Final version: 15 March 1999 相似文献
962.
L-701,324, a selective antagonist at the glycine site of the NMDA receptor, counteracts haloperidol-induced muscle rigidity in rats 总被引:1,自引:1,他引:0
J. Konieczny Krystyna Ossowska Gert Schulze Helmut Coper Stanislaw Wolfarth 《Psychopharmacology》1999,143(3):235-243
Rationale: It has recently been suggested that the overactivity of glutamatergic neurotransmission may contribute to the pathophysiology
of Parkinson’s disease. Therefore, a search for new compounds which block glutamatergic receptors and show antiparkinsonian
properties in animal models of this disease seems to be justified. Objective: The aim of this study was to determine whether L-701,324 [7-chloro-4-hydroxy-3(3-phenoxy) phenylquinoline-2-(H)-one], a selective
and full antagonist at the glycine site of the NMDA receptor, counteracts parkinsonian-like muscle rigidity and catalepsy
induced by haloperidol in rats. Methods: The muscle tone was measured as the resistance developed to passive flexion and extension of the hind limb. Electromyographic
(EMG) activity was additionally recorded in the gastrocnemius and tibialis anterior muscles. Results: L-701,324 (2.5–40 mg/kg IP) dose-dependently decreased the muscle tone enhanced by haloperidol (1–5 mg/kg IP). Likewise, the
haloperidol-enhanced resting EMG activity and the EMG reflex response to passive movements were diminished by lower and almost
abolished by higher doses of L-701,324. However, up to a dose of 20 mg/kg IP, L-701,324 did not influence haloperidol (0.5
mg/kg IP)-induced catalepsy. Moreover, L-701,324 (1.25–5 mg/kg IP) given alone or together with haloperidol (0.5–1 mg/kg IP)
disturbed rotarod performance. Gross observation of behaviour indicated that rats injected with L-701,324 in doses equal to
or higher than 5 mg/kg, alone or in combination with haloperidol, were markedly ataxic, i.e. rats showed signs of disturbed
balance and loss of control over their hind limbs. Conclusions: The present study suggests that L-701,324 exhibits a beneficial action in the animal model of parkinsonian rigidity, but not
that of parkinsonian akinesia. Nonetheless, this compound is not devoid of motor side-effects.
Received: 1 February 1998 / Final version: 20 October 1998 相似文献
963.
Rationale: Defining the mechanism of tolerance development to hallucinogenic drugs will help to explain their mechanism of action. Objectives: The present study was conducted to determine first, if tolerance develops to the discriminative stimulus (DS) properties
of the hallucinogen, 2,5 dimethoxy-4-iodo-amphetamine (DOI) and second, the mechanism mediating tolerance. Methods: Rats were trained to discriminate 0.75 mg/kg DOI from saline on a concurrent VI-30-min schedule of reinforcement with a
15-min time-out for incorrect responses. To evaluate tolerance development, rats were assigned to one of four groups and treated
with either chronic saline or chronic DOI. Prior to chronic treatment, two groups were tested for choice behavior following
vehicle administration while the remaining two groups were tested following the administration of 0.375 mg/kg DOI. One group
from each pre-test condition was injected with either saline or DOI (1 mg/kg) for 8 days. Twenty-four hours after the last
chronic injection the pre-test treatments were replicated. Using receptor autoradiography, the density of 5-HT2A and 5-HT2C receptors was measured in independent groups of rats that had received identical treatment conditions. Results: Animals receiving chronic DOI showed a 60% decrease in DOI lever responding (from 100% to 40%) when tested on 0.375 mg/kg
DOI, while animals receiving chronic saline showed no change in percent choice (100%) on the DOI lever. Significant changes
in binding were observed in 5-HT2A receptors but not 5-HT2C receptors. The results of tests with antagonists were consistent with the changes in binding. Conclusions: These results suggest that behavioral tolerance to DOI reflects neuroadaptive changes in 5-HT2A receptors.
Received: 17 July 1998 / Final version: 19 January 1999 相似文献
964.
Tizabi Y Overstreet DH Rezvani AH Louis VA Clark E Janowsky DS Kling MA 《Psychopharmacology》1999,142(2):193-199
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 相似文献
965.
Activation of 5-HT1B receptors in the nucleus accumbens reduces amphetamine-induced enhancement of responding for conditioned reward 总被引:2,自引:2,他引:0
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-HT1B receptors, albeit with differing selectivities. The effect of CP93,129, the most selective of the 5-HT1B agonists, to inhibit the response-potentiating effect of d-amphetamine was reversed by the5-HT1B/1D antagonist GR127935 (3 mg/kg). The results indicate that activation of 5-HT1B 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 相似文献
966.
Aggression heightened by alcohol or social instigation in mice: reduction by the 5-HT1B receptor agonist CP-94,253 总被引:1,自引:1,他引:0
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-HT1B 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-HT1B 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-HT1B (GR 127935; 10 mg/kg, IP) and the 5-HT1A 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-HT1B receptors modulates very high levels of aggressive behavior in a pharmacologically and behaviorally specific manner.
Received: 5 January 1999 / Final version: 16 April 1999 相似文献
967.
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 相似文献
968.
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 CCKB receptors. Objectives: The present experiment was designed to examine the effects of intra-NAcc CCKB 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 CCKB receptor activation attenuates amphetamine reward.
Received: 6 May 1999 / Final version: 4 August 1999 相似文献
969.
970.
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. 相似文献