Effect of fluoxetine and paroxetine on the conditional position preference effect of drugs
Abstract 目的AIM: To investigate the effects of serotonin selective reuptake inhibitor (SSRI) fluoxetine and paroxetine on drug (MA)-induced conditional position preference (CPP).
Method: A propensity experimental procedure was used. ♂Wistar rats were injected intraperitoneally with MA (0.5 mg · kg-1) and trained for 8 days, d9
The effect of the rat on the kit was measured and the effect of different doses (2.5 - 10. 0 mg · kg - 1 ) of fluoxetine and paroxetine was measured 30 min before the test.
RESULTS: 0. 5 mg · kg -1 of MA induced a significant conditional position preference in the kits; pre-test injections of fluoxetine and paroxetine reduced the conditional position induced by MA in a dose-dependent manner. The expression of the preference effect.
Conclusion: Fluoxetine and paroxetine have an inhibitory effect on the potentiation of MA, suggesting that these drugs have the potential to treat the drug's mental dependence.
Key words dextrorotatory drug, fluoxetine, paroxetine, conditional position preference
The global abuse of amphetamine-type stimulants represented by drugs (met hamp hetamine, MA) is rapidly spreading [1], seriously jeopardizing the physical and mental health of adolescents. Therefore, it is urgent to study the neurobiological mechanism of addiction. And effective treatment. Increased dopamine levels in the midbrain marginal system are the primary neurobiological basis for the amphetamine-rewarding effect. However, in recent years, the role of non-dopaminergic neurotransmitter systems [such as excitatory amino acids, inhibitory amino acids, histamine, serotonin (5-HT) and norepinephrine in drug reward effects has also attracted researchers' attention. [2]. 5-HT is an important neurotransmitter in the central nervous system. Studies have shown that 5 - HT has a regulatory effect on the reward effect of amphetamine-type stimulants. Direct injection of 5-HT into the nucleus accumbens or promotion of the 5-HT release drug fenfluramine can reduce the conditional reward effect of amphetamine [3]. Fluoxetine can reduce the sensitivity of rats to rewarded brain stimulation [4], reducing the dose of amphetamine in the administration of rats [5,6]. Since MA has a stronger effect on the 5-HTergic nervous system than amphetamine [7,8], the authors believe that 5-HT selective reuptake inhibitors (SSRI)-fluoxetine and paroxetine ) may have the ability to adjust the MA reward effect. This article explores the effects of these two drugs on MA-induced conditional position preference (CPP) in rats.
1 Materials and methods
1. 1 animal
90 Wistar rats, sputum, weighing 160-180 g, were purchased from the Experimental Animal Center of Peking University Medical School. Animals were randomized into groups of 7-8 each. Animals were acclimated for 7 days in the clean room before the experiment and were taken once a day. Drinking water and eating freely throughout the experiment.
1. 2 reagent
Drug, fluoxetine hydrochloride powder, paroxetine hydrochloride powder. The above drugs were all dissolved in physiological saline, and the administration volume was 1 ml·kg-1.
1. 3 experimental device
The CPP experimental box is mainly composed of a soundproof box and a position preference box (two boxes of equal volume in the middle, a black box on one side, a smooth floor on one side, a white box on one side, a rough floor) and a computer.
1. 4 methods
The CPP experiment is divided into three phases: a pre-test phase, a training phase, and a test phase.
1. 4. 1 Pre-test stage will open the middle partition of the preference box, put the rat into the middle zone, let it run freely in the preference box for 15min once a day for 3 consecutive days. D3 computer recorded the average residence time of 50 rats in white box and black box to determine the natural preference tendency of the rats. The rats were then trained with the non-natural preference box as a kit.
1. 4. 2 During the training phase, the black and white box channel is closed with a partition. The animals in the control group were given ip saline for 8 consecutive days, and placed in the kit or the other side every other day. The rats in the MA group were placed in the kit with the ip MA every other day, or the ip saline was placed on the other side. Animals stayed in the box for 30 min each time.
1. 4. 3 The test phase is tested at d2 after the training is completed. The septum was opened prior to testing to allow the rat to freely move within the black and white box to record the residence time in the white box (e.g., pre-test phase) in the non-administered state.
1. 5 experimental design
1. 5. 1 MA induced CPP effect Animals were divided into 4 groups. One group was the control group, the other three groups were the MA group, and the latter were ip 0.25 mg·kg-1, 0.5 mg·kg-1, 1.0 mg·kg-1 MA. The d2 after the completion of the training measures the residence time of the animals in the kit, and evaluates the intensity of CPP effects induced by different doses of MA. The following experiment was performed by selecting a drug dose that allows the animal to have a significant preference for the accessory kit.
1. 5. 2 Effect of fluoxetine and paroxetine on MA-induced CPP
Effect of expression Rats were divided into 7 groups and animals were trained according to the optimal dose of MA obtained in 1.5.1. Ip normal saline (1ml·kg-1), fluoxetine (2.5 mg·kg-1, 5. 0mg·kg-1 and 10. 0 mg·kg-1) and paroxetine (30 min before the test) 2. 5 mg · kg - 1, 5. 0 mg · kg - 1 and 10.0 mg · kg -1 ), record the residence time of the rats in the kit.
1. 6 statistical processing
The experimental results were analyzed by one-way ANOVA and t-test using SPSS statistical software package.
2 results
2. 1 Rat's natural preference for position preference box
5d s 126. 0 s ± s 126. 0 s and 680. 5 s ± s 126. 0 s ( P < 0. 01), measured at d3 in the pre-test phase. It indicates that the rat has a natural preference for the black box, so a propensity experimental procedure is adopted, and the white box which is not naturally preferred by the rat is used as a kit in the training stage.
2. 2 MA induced rat CPP effect
After 8 days of training, the average residence time of the rats in the control group (salt group) was 187. 7 s ± s 94. 5 s, while different doses of MA (0. 25 - 1. 0 mg · kg - 1 were injected. The average residence time of the rat in the white box was 454. 1 s ± s 267. 9 s (0. 25 mg · kg - 1, P < 0.05), 654. 5 s ± s 73. 7 s (0. 5mg ·kg- 1, P < 0. 01) and 478. 4 s ±s 198. 3 s (1. 0mg · kg- 1, P < 0.05) (Figure 1), indicating that the animal has The white box produces CPP [ F (3 , 27) = 9. 538 , P < 0.01]. The MA of 0.5 mg·kg-1 produced the most obvious CPP effect, so the MA dose used in the following experiment was 0.5 mg·kg-1.
2. 3 The effect of fluoxetine and paroxetine on the expression of MA CPP
8 s ±s 118. 7 s , the average residence time of the rats in the white box was 63. 8 s ± s 118. 7 s, after the ip physiological saline was used for 30 min before the test. It indicated that the experimental animals had established a stable preference for the concomitant kit; the injection of fluoxetine 30 min earlier dose-dependently decreased the expression of MA-induced CPP effect [ F (3 , 24) = 3. 573 , P < 0. 05 ] , the average residence time of the animals in the white box is 449. 0 s ± s 261. 3 s (2.5 mg · kg - 1, P < 0.05), 375. 2 s ± s 210. 7 s (5. 0 mg · kg - 1, P < 0.05) and 294. 0 s ± s 296. 5 s (10. 0 mg · kg - 1, P < 0.01). Similarly, injection of paroxetine 30 minutes earlier also dose-dependently decreased the expression of MA-induced CPP effects [ F (3 , 24) = 7. 787 , P < 0.01], and the mean residence time of animals in the white box was 469. 4 s ±s 277. 8 s (2.5 mg · kg - 1, P < 0.05), 348. 8 s ± s 272. 3 s (5. 0 mg · kg - 1, P < 0 01) and 148.2 s ± s 131. 8 s (10. 0 mg · kg - 1, P < 0.01).
3 Discussion
The CPP experiment is an effective method for evaluating the psychotropic dependence potential of drugs, and can also be used to study drug-dependent neurobiological mechanisms or to screen effective drugs for drug dependence [9]. The ip 0.5 mg · kg-1 MA can induce the CPP effect of the rat on the kit, which proves that the drug has a certain degree of mental dependence; once the stable CPP effect is established, the ip fluoxetine and ip 30 min before the test Paroxetine dose-dependently reduced the residence time of rats in the white box, indicating that these two drugs have the effect of reducing the expression of MA CPP effect, so increasing the 5-HT concentration in the synaptic cleft can reduce the reward effect of MA. Dopamine release from the midbrain dopamine system is an important neural basis for the apocalyptic effect of amphetamine-type stimulants.
There is an interaction between the 5-HT transmitter system and the dopamine system, ie, 5-HT neurons derived from the medial and dorsal nucleus of the nucleus have axonal-axonal connections with midbrain-derived dopaminergic neurons; 5-HT Antagonism of dopamine-mediated behavior, 5-HT injection into the nucleus accumbens can inhibit the conditional reward effect caused by amphetamine [7]. 5 -HT reuptake inhibitors not only reduce the intake of amphetamine in addicted animals, but also reduce the intake of cocaine in addicted animals [10], suggesting that 5-HT has a regulatory effect on the reward effect of central stimulants. . Fluoxetine and paroxetine are effective drugs for the treatment of depressive diseases in the clinic, and no abuse reports have been reported. This experiment demonstrates that the dose-dependent inhibition of MA-induced CPP effects by these two drugs indicates that they can reduce the reward effect of MA and therefore have potential application value for therapeutic drug addiction.
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