Treatment with zolpidem after ethanol administration potentiates the expression of ethanol-induced behavioral sensitization in mice

Contradictory findings suggest that the behavioral and abuse-related effects of ethanol are mediated by its action at α1 subunit-containing GABAA (α1GABAA) receptors. In the present study, we investigated the effects of a sub-chronic post-ethanol administration treatment with zolpidem, an α1-preferring positive allosteric modulator at GABAA receptors, on the subsequent expression of ethanol-induced behavioral sensitization in mice. Animals received ethanol (1.8 g/kg, ip) or saline treatments every other day for 15 days (8 treatment sessions) and were subsequently treated with zolpidem (0.5 mg/kg, ip) or vehicle 4 times on alternate days. At the end of the treatment phase, animals were challenged with saline or ethanol on separate days for the evaluation of the expression of conditioned locomotion and behavioral sensitization. Eight-day treatment with ethanol did not lead to the development of ethanol-induced behavioral sensitization. Animals treated with ethanol and subsequently administered vehicle showed similar locomotion frequencies during the last ethanol challenge compared to the control group receiving ethanol for the first time. Animals treated with ethanol and subsequently administered zolpidem expressed behavioral sensitization to ethanol during the ethanol challenge. The present study adds to the literature by providing further evidence of a role of α1GABAA receptors on the behavioral effects of ethanol. Because of the current highly prevalent co-abuse of ethanol and benzodiazepine drugs in humans, the use of zolpidem and other α1GABAA receptor ligands during ethanol withdrawal should be monitored carefully.

Behavioral cross-sensitization between testosterone and fenproporex in adolescent and adult rats

The abuse of psychoactive drugs is considered a global health problem. During the last years, a relevant number of studies have investigated the relationship between anabolic-androgenic steroids (AAS) and other psychoactive drugs. AAS, such as testosterone, can cause a dependence syndrome that shares many features with the classical dependence to psychoactive substances. Pre-clinical evidence shows that there are interactions between testosterone and psychoactive drugs, such as cocaine. However, few studies have been performed to investigate the effect of repeated testosterone treatment on behavioral effects of amphetamine derivatives, such as fenproporex. The purpose of the present study was to investigate the effects of repeated testosterone administration on fenproporex-induced locomotor activity in adolescent and adult rats. Adolescent male Wistar rats were injected with testosterone (10 mg/kg sc for 10 days). After 3 days, animals received an acute injection of fenproporex (3.0 mg/kg ip) and the locomotor activity was recorded during 40 min. Thirty days later, the same animals received the same treatment with testosterone followed by a fenproporex challenge injection as described above. Our results demonstrated that repeated testosterone induced behavioral sensitization to fenproporex in adolescent but not in adult rats. These findings suggest that repeated AAS treatment might increase the dependence vulnerability to amphetamine and its derivatives in adolescent rats.

Effect of agmatine co-administration with yohimbine on morphine-induced behavioral sensitization in mice / 国际药学研究杂志

Objective To investigate the effect of agmatine or agmatine combined with yohimbine on morphine-induced psychological dependence in mice. Methods 1. Testing the effect of agmatine or agmatin combined with yohimbine on basal locomotor activity in 60 minutes. C57BL/6J male mice were divided into four groups: control group, agmatine (1,10,20,40 and 80 mg/kg) groups, yohimbine (0.3,1,2 and 8 mg/kg) groups and yohimbine (2 mg/kg) + agmatine (80 mg/kg) group. 2. Testing theeffects of drug pretreatment on morphine-induced hyperlocomotion in 60 minutes. Mice were divided into five groups: control group, morphine (10 mg/kg) group, agmatine (1,20 and 80 mg/kg) + morphine (10 mg/kg) group,yohimbine (2 mg/kg) + morphine (10 mg/kg) group and yohimbine (2 mg/kg) + agmatine (80 mg/kg) + morphine (10 mg/kg) group. 3. Observing the effects of agmatine or agmatine combined with yohimbine on morphine induced behavioral sensitization. The mice were administrated with morphine (10 mg/kg) on the 1st , 4th and 7th day and the locomotor activity of mice was recorded for 60 minutes. Mice were divided into four groups: control group, morphine (10 mg/kg) group, agmatine (1,20 and 80 mg/kg) + morphine (10 mg/kg) groups and yohimbine (2 mg/kg) + agmatine (80 mg/kg) + morphine (10 mg/kg) group. Results Our present study showed that agmatine (1-80 mg/kg) or yohimbine (0.3-2 mg/kg), a selective antagonist of a2-adrenoceptor, had no significant effect on basal locomotor and acute morphine-induced hyperlocomotion compared with those of control group. However, the distance in the group of agmatine combined with yohimbine followed by morphine for 60 min was (22 581.6&11 694.0) cm, which was significantly lower than the acute morphine group(37 577.9±9 657.4) cm(#<0.05). In the mophine-induced behavioral sensitization model, agmatine (1,20 and 80 mg/kg) alone had no effect on morphine-induced development of behavioral sensitization in mice. But, the combination of the two drugs significantly attenuated morphine-induced behavioral sensitization. The locomotor activities in the combination treatment groups were (21 112.7±5 586.7) cm, (37 672.7±10 518.8) cm and 47 681.0±15 845.3 cm, which were lower than those of morphine group (31 156.4&8 010.5) cm(#<0.01), (51 724.9&11 364.51) cm (P<0.05) and (63 572.2&12 151.2) cm (P<0.05) on the 1st , 4th and 7th day of experiment, respectively. Conclusion Our current results demonstrated that agmatine combined with yohimbine could decrease morphine-induced psychological dependence in mice. It may provide a new strategy for psychological dependence of morphine.

Effect of agmatine co-administration with yohimbine on morphine-induced behavioral sensitization in mice / 国际药学研究杂志

Objective To investigate the effect of agmatine or agmatine combined with yohimbine on morphine-induced psychological dependence in mice. Methods 1. Testing the effect of agmatine or agmatin combined with yohimbine on basal locomotor activity in 60 minutes. C57BL/6J male mice were divided into four groups:control group, agmatine (1,10,20,40 and 80 mg/kg) groups, yohimbine(0.3,1,2 and 8 mg/kg) groups and yohimbine(2 mg/kg)+ agmatine(80 mg/kg) group. 2. Testing the effects of drug pretreatment on morphine-induced hyperlocomotion in 60 minutes. Mice were divided into five groups: control group, morphine(10 mg/kg) group, agmatine(1,20 and 80 mg/kg)+ morphine(10 mg/kg) group,yohimbine(2 mg/kg)+ morphine(10 mg/kg) group and yohimbine(2 mg/kg)+ agmatine(80 mg/kg)+ morphine(10 mg/kg) group. 3. Observing the effects of agmatine or agmatine combined with yohimbine on morphine induced behavioral sensitization. The mice were administrated with morphine(10 mg/kg) on the 1st , 4th and 7th day and the locomotor activity of mice was recorded for 60 minutes. Mice were divided into four groups: control group, morphine(10 mg/kg) group, agmatine(1,20 and 80 mg/kg) + morphine(10 mg/kg) groups and yohimbine (2 mg/kg)+ agmatine(80 mg/kg)+ morphine(10 mg/kg) group. Results Our present study showed that agmatine(1-80 mg/kg) or yohimbine (0.3-2 mg/kg), a selective antagonist of α2-adrenoceptor, had no significant effect on basal locomotor and acute morphine-induced hyperlocomotion compared with those of control group. However, the distance in the group of agmatine combined with yohimbine followed by morphine for 60 min was(22 581.6±11 694.0) cm,which was significantly lower than the acute morphine group(37 577.9±9 657.4)cm(P<0.05). In the mophine-induced behavioral sensitization model, agmatine(1,20 and 80 mg/kg) alone had no effect on morphine-induced development of behavioral sensitization in mice. But, the combination of the two drugs significantly attenuated morphine-induced behavioral sensitization. The locomotor activities in the combination treatment groups were (21 112.7±5 586.7)cm,(37 672.7±10 518.8)cm and(47 681.0±15 845.3)cm, which were lower than those of morphine group (31 156.4±8 010.5) cm(P<0.01),(51 724.9±11 364.51)cm(P<0.05) and(63 572.2±12 151.2) cm(P<0.05) on the 1st , 4th and 7th day of experiment, respectively. Conclusion Our current results demonstrated that agmatine combined with yohimbine could decrease morphine-induced psychological dependence in mice. It may provide a new strategy for psychological dependence of morphine.

The Role of AMPA Receptors in Synaptic Plasticity by Drugs of Abuse / 대한정신약물학회지

Dopamine has long time considered as the main player in drug addiction. However, growing body of literature strongly supports a role for glutamate in addiction. 2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, one of the ionotropic glutamate receptors, are known to be involved in different forms of synaptic plasticity, and behaviors such as learning and memory. As drug addiction is a chronic brain disease with characteristics of craving and relapse, it is often considered as a maladapted form of drug-induced long-term memory. Experimental evidence strongly indicates that AMPA receptor has an important role in the development of drug addiction. Studies with animal models of drug addiction, such as behavioral sensitization and drug self-administration, demonstrate that AMPA receptor-mediated synaptic plasticity may underlie the neuronal mechanisms for such important characteristics of addiction as drug craving.

Cocaine-Induced Behavioral Sensitization in Mice: Effects of Microinjection of Dopamine D2 Receptor Antagonist into the Nucleus Accumbens

To determine the role of dopamine D2 receptor (D2R) in the nucleus accumbens (NAc) core in cocaine-induced behavioral sensitization, D2R antagonist, raclopride was bilaterally microinjected (2.5 or 5 nmol) into the NAc core of WT and D2R-/- mice and the initiation and expression phase of cocaine-mediated locomotor sensitization were analyzed. WT and D2R knockout (D2R-/-) mice received bilateral injections of either saline, or raclopride at the NAc core 30 min before each of five daily repeated injections of saline or cocaine (15 mg/kg i.p.). Following 2 weeks of withdrawal after repeated exposure to cocaine, the animals were pre-treated with an intra-accumbal injection of vehicle or raclopride before receiving a systemic cocaine challenge for the expression of sensitization. Animals which had been microinjected raclopride into NAc core displayed the enhancement of cocaine-induced behavioral response for the initiation but also for the expression of sensitization in WT as well as in D2R-/- mice, which was thus unaltered as compared to vehicle-injected control group. These results suggest that D2R in NAc core is not involved in cocaine-induced behavioral sensitization.

Effects of baicalin on morphine-induced behavioral sensitization in mice / 中华行为医学与脑科学杂志

Objective To investigate the effects of baicalin on morphine-induced behavioral sensitization.Methods Locomotor activity was measured for 2h after administration with baicalin in mice.Hyperlocomotion induced by acute morphine (10 mg· kg-1,ip) and behavioral sensitization induced by repeated morphine were established.The level of dopamine of ventral tegmental area(VTA) and prefrontal cortex(PFC) in mice was tested by ELISA assay.Results Baiealin inhibited significantly both locomotor activity in mice (control (1095.8 ± 174.5) times,baicalin (899.6± 187.2),(724.2± 221.4),(609.1 ± 154.6) times ; P＜ 0.01) and hyperlocomotion induced by acute morphine(model (1518.2± 185.8) times,baicalin (1385.4±224.2),(1205.1 ± 174.6),(1100.3±235.1) times ; P＜0.01).Similar inhibition was also seen in the development and expression of morphine-induced behavioral sensitization(model(2096.2±304.6) times,baicalin (2004.2 ± 218.5),(1998.7-± 224.3),(1836.1 ± 233.5) times,P＜ 0.05 ; model (2124.2 ± 189.6) times,baicalin (1922.2± 314.7),(1524.1±289.2),(1477.4± 219.3) times,P＜0.01).Baicalin inhibited dopamine release in VTA and PFC of morphine-sensitized mice(model(457.6± 92.1,589.2 ±102.5) μg · L-1,baicalin(391.1±56.8) μg · L-1,(448.6± 99.3) μg · L-1; (324.5±66.2) μg · L-1,(368.7±45.9) μg · L 1 ; (234.3± 52.6) μg · L-1,(305.3±84.1) μg · L-1 ; P＜0.01,P＜0.01).Conclusion Baicalin inhibits the development and the expression of morphine-induced behavioral sensitization in mice,and this effect is related to the inhibition of dopamine release in VTA and PFC of mice.

Blockade of ERK Phosphorylation in the Nucleus Accumbens Inhibits the Expression of Cocaine-induced Behavioral Sensitization in Rats

Repeated administration of psychostimulants such as cocaine leads to the development of behavioral sensitization. Extracellular signal-Regulated Kinase (ERK), an enzyme important for long-term neuronal plasticity, has been implicated in such effects of these drugs. Although the nucleus accumbens (NAcc) is the site mediating the expression of behavioral sensitization by drugs of abuse, the precise role of ERK activation in this site has not been determined. In this study we demonstrate that blockade of ERK phosphorylation in the NAcc by a single bilateral microinjections of PD98059 (0.5 or 2.0micro g/side), or U0126 (0.1 or 1.0microg/side), into this site dose-dependently inhibited the expression of cocaine-induced behavioral sensitization when measured at day 7 following 6 consecutive daily cocaine injections (15 mg/kg, i.p.). Acute microinjection of either vehicle or PD98059 alone produced no different locomotor activity compared to saline control. Further, microinjection of PD98059 (2.0micro g/side) in the NAcc specifically lowered cocaine-induced increase of ERK phosphorylation levels in this site, while unaffecting p-38 protein levels. These results indicate that ERK activation in the NAcc is necessary for the expression of cocaine-induced behavioral sensitization, and further suggest that repeated cocaine evokes neuronal plasticity involving ERK pathway in this site leading to long-lasting behavioral changes.

Repeated exposure of adolescent rats to oral methylphenidate does not induce behavioral sensitization or cross-sensitization to nicotine

Several lines of evidence indicate that the use of stimulant drugs, including methylphenidate (MPD), increases tobacco smoking. This has raised concerns that MPD use during adolescence could facilitate nicotine abuse. Preclinical studies have shown that repeated treatment with an addictive drug produces sensitization to that drug and usually cross-sensitization to other drugs. Behavioral sensitization has been implicated in the development of drug addiction. We examined whether repeated oral MPD administration during adolescence could induce behavioral sensitization to MPD and long-lasting cross-sensitization to nicotine. Adolescent male Wistar rats were treated orally with 10 mg/kg MPD or saline (SAL) from postnatal day (PND) 27 to 33. To evaluate behavioral sensitization to MPD in adolescent rats (PND 39), the SAL pretreated group was subdivided into two groups that received intragastric SAL (1.0 mL/kg) or MPD (10 mg/kg); MPD pretreated rats received MPD (10 mg/kg). Cross-sensitization was evaluated on PND 39 or PND 70 (adulthood). To this end, SAL- and MPD-pretreated groups received subcutaneous injections of SAL (1.0 mL/kg) or nicotine (0.4 mg/kg). All groups had 8 animals. Immediately after injections, locomotor activity was determined. The locomotor response to MPD challenge of MPD-pretreated rats was not significantly different from that of the SAL-pretreated group. Moreover, the locomotor response of MPD-pretreated rats to nicotine challenge was not significantly different from that of the SAL-pretreated group. This lack of sensitization and cross-sensitization suggests that MPD treatment during adolescence does not induce short- or long-term neuroadaptation in rats that could increase sensitivity to MPD or nicotine.

Effects of Y-IP5 on morphine-induced behaviorals ensitization and conditioned place preference in mice / 中国药理学通报

Aim To investigate the effects of Y-IP5 on morphine-induced behavioral sensitization and CPP in mice.Methods Locomotor activity was detected after Y-IP5 administration or co-administration of Y-IP5 with morphine in mice.Mice were treated with morphine to induce behavioral sensitization. Then the effects of Y-IP5 on the development, transfer and expression of morphine-induced behavioral sensitization were investigated. Mice were treated with morphine to induce CPP. Then the effect of Y-IP5 on the acquisition of morphine-induced CPP was studied.Results Y-IP5 itself didn′t influence locomotor activity of mice.Co-administration of Y-IP5 with morphine inhibited morphine-induced hyperactivity (P<0.05) and the development of morphine-induced behavioral sensitization in mice (P<0.05), however, did not influence the transfer and expression of morphine-induced behavioral sensitization.Co-administration of Y-IP5 with morphine also inhibited the acquisition of morphine-induced CPP (P<0.05).Conclusion Y-IP5 may inhibit the psychological dependence induced by morphine.

Repeated Exposure to beta-phenylethylamine Produces Locomotor Sensitization to Amphetamine, but Not Vice Versa, in the Rat

Repeated administration of amphetamine (AMPH) produces behavioral sensitization, a proposed model for the escalation of drug use characteristic of human addicts. beta-Phenylethylamine (PEA) is an endogenous trace amine found in mammalian brain and resembles AMPH both structurally and behaviorally. Previously, it has been reported that chronic PEA administration produces behavioral sensitization to the challenges of AMPH. However, these data were obtained with very high amount of PEA for a relatively long period of time. Further, the effect of PEA challenge on the expression of behavioral sensitization developed by AMPH pre-exposures has not been tested yet. Thus, we examined in the present experiment the expression of behavioral sensitization with AMPH challenge after a mild chronic PEA treatment. Rats were repeatedly administered with systemic injections of saline, beta-phenylethylamine (PEA) (10 or 50 mg/kg), or amphetamine (AMPH) (1.5 mg/kg). When challenged a week after the last pre-injection, rats pre-exposed to either PEA or AMPH showed behavioral sensitization to AMPH (1.0 mg/kg), while these effects were not observed to PEA (50 mg/kg) itself. These results demonstrate that repeated exposure to PEA produces behavioral sensitization to AMPH challenge, while PEA challenge has no effect on the expression of behavioral sensitization developed by AMPH pre-exposures, suggesting that PEA may play a role in the development of locomotor sensitization to AMPH, but not in the expression of it.

The Role of Metabotropic Glutamate Receptors in Psychomotor Stimulant Addiction / 대한정신약물학회지

For many years, determining the role of dopamine has been the major focus of the drug abuse research. New evidence, however, suggests that glutamate may play more important roles in the process of development of addictive behaviors. Metabotropic glutamate receptors are abundant in the brain and known to consist of three different groups of subtypes. Experimental data apparently show that they, especially group I and II, have important roles in the process of behaviors indicative of addiction such as locomotor activity, behavioral sensitization, conditioned place preference by psychomotor stimulants, and self-administration of these drugs. Although it has not been yet discovered how they differentially regulate neuronal processes to produce addictive behaviors, they have been suggested as a new possible therapeutic target for the treatment of drug addiction.

Role of behavioral sensitization animal model in evaluation of drug dependence / 中国药理学通报

Drug abuse and addiction are increasingly severe, which is both a serious social problem and an important medical research work. It is very significant to evaluate dependence potential of centrally acting drugs. Several lines of evidence have shown that there is a close relationship between drug sensitization and drug abuse and addiction. More attention has been directed to sensitization of abused drugs. We introduce the establishment of behavioral sensitization animal model, review neurobiological mechanisms underlying development and expression of behavioral sensitization, and further discuss the role of behavioral sensitization animal model in evaluation of drug dependence.

The Dual Models of behavioral Sensitization and kindling in the Pathophysiology of Mood Disorders: On the Basis of Molecular Mechanisms / 대한정신약물학회지

Recurrent mood disorders show tendencies toward cycle acceleration over time-shorter and shorter well intervals belween successive episodes. On the other hand, clinical findings suggest that psychosocial stresses ore impl icated more prominently in early episodes of mood disorders, whereas less prominent stressors or conditioned behavioral factors are associated with the onset of later episodes. The dual models of behavioral sensitization and kindling may help to explain the pattern of apparent clinical course in th natural history of mood disorders and to link older psychoanclytic and neurobiologic concepts of illness evaluation. The unified approach suggests that psychosocial precipitants are involved in initial episodes, but later ones occur more autonomously : both the stresses and episodes themselves may leave behind changes in the individual's neurobiology by affecting gene expression. From the standpoint of treatment the dual models place a high premium on effective early pharmacologic interventions and their long term maintenance, and support the combination of psychotherapeutic and pharmacologic interventions, accepting the usefulness of psychodynamic or cognitive therapy.