Behavioral Sensitization In Mice Research Articles

Identification of the circRNA-miRNA-mRNA network for treating methamphetamine-induced relapse and behavioral sensitization with cannabidiol.

This study aims to investigate the pharmacological effects and the underlying mechanism of cannabidiol (CBD) on methamphetamine (METH)-induced relapse and behavioral sensitization in male mice. The conditioned place preference (CPP) test with a biased paradigm and open-field test were used to assess the effects of CBD on METH-induced relapse and behavioral sensitization in male mice. RNA sequencing and bioinformatics analysis was employed to identify differential expressed (DE) circRNAs, miRNAs, and mRNAs in the nucleus accumbens (NAc) of mice, and the interaction among them was predicted using competing endogenous RNAs (ceRNAs) network analysis. Chronic administration of CBD (40 mg/kg) during the METH withdrawal phase alleviated METH (2 mg/kg)-induced CPP reinstatement and behavioral sensitization in mice, as well as mood and cognitive impairments following behavioral sensitization. Furthermore, 42 DEcircRNAs, 11 DEmiRNAs, and 40 DEmRNAs were identified in the NAc of mice. The circMeis2-miR-183-5p-Kcnj5 network in the NAc of mice is involved in the effects of CBD on METH-induced CPP reinstatement and behavioral sensitization. This study constructed the ceRNAs network for the first time, revealing the potential mechanism of CBD in treating METH-induced CPP reinstatement and behavioral sensitization, thus advancing the application of CBD in METH use disorders.

Distinctive Neuroanatomic Regions Involved in Cocaine-Induced Behavioral Sensitization in Mice

The present study aimed to characterize the phenomenon of behavioral sensitization to cocaine and to identify neuroanatomical structures involved in the induction and expression phases of this phenomenon. For this, in experiment 1 (induction phase), mice were treated with saline or cocaine every second day for 15 days (conditioning period), in the open-field or in their home-cages. In experiment 2 (expression phase), the same protocol was followed, except that after the conditioning period the animals were not manipulated for 10 days, and after this interval, animals were challenged with cocaine. Neuroanatomical structures involved in the induction and expression phases were identified by stereological quantification of c-Fos staining in the dorsomedial prefrontal cortex (dmPFC), nucleus accumbens core (NAc core and shell (NAc shell), basolateral amygdala (BLA), and ventral tegmental area (VTA). Neuroanatomical analysis indicated that in the induction phase, cocaine-conditioned animals had higher expression of c-Fos in the dmPFC, NAc core, BLA, and VTA, whereas in the expression phase, almost all areas had higher expression except for the VTA. Therefore, environmental context plays a major role in the induction and expression of behavioral sensitization, although not all structures that compose the mesolimbic system contribute to this phenomenon.

The roles of K+-dependent Na+/Ca2+ exchanger 2 (NCKX2) in methamphetamine-induced behavioral sensitization and conditioned place preference in mice

Drug addiction, including methamphetamine (METH) addiction, is a significant public health and social issue. Perturbations in intracellular Ca2+ homeostasis are associated with drug addiction. K+-dependent Na+/Ca2+ exchanger 2 (NCKX2) is located on neuronal cell membranes and constitutes a Ca2+ clearance mechanism, with key roles in synaptic plasticity. NCKX2 is associated with motor learning, memory, and cognitive functions. However, the role of NCKX2 in METH addiction remains unclear. In this study, we investigated the expression levels of NCKX2 in four addiction-related brain regions: the prefrontal cortex (PFc), nucleus accumbens (NAc), dorsal striatum (DS), and hippocampus (Hip) in a C57/BL6 mouse model of METH-induced conditioned place preference (CPP) and behavioral sensitization. Levels of NCKX2 were unchanged in these brain regions in mice with METH-induced CPP but were decreased in the PFc and NAc of mice with METH-induced behavioral sensitization. Adeno-associated virus (AAV)-mediated overexpression of NCKX2 in the PFc attenuated the expression phase of METH-induced behavioral sensitization in mice, whereas AAV-mediated knockdown of NCKX2 enhanced the effects of METH. Collectively, our results suggest that NCKX2 is involved in METH-induced behavioral sensitization but does not affect conditioned reward-related memory, highlighting the potential of NCKX2 as a molecular target for studying the mechanisms underscoring METH addiction.

Alpha-pyrrolidinopentiothiophenone (α-PVT) activates the TLR–NF-κB–MAPK signaling pathway and proinflammatory cytokine production and induces behavioral sensitization in mice

Synthetic cathinones are chemical derivatives of cathinone, a structural analog to amphetamine. It has been shown that synthetic cathinones have abuse potentials similar to psychomotor stimulants such as amphetamine and induce neuroinflammation. Among the novel synthetic cathinones, α-pyrrolidinopentiothiophenone (α-PVT) has been known to produce rewarding and reinforcing effects in rodent models. However, it has not yet been determined whether α-PVT induces neuroinflammation in vivo. In the present study, mice were exposed to repeated saline or α-PVT (20 mg/kg, intraperitoneally) for 7 days to test changes in locomotor activity and neuroinflammation-related factors in the striatum of mice. Repeated administration of α-PVT significantly induced locomotor sensitization. In addition, repeated α-PVT administration significantly increased the number of microglial cells, accompanied by marked increases in TLR1, TLR4, TLR6, and TLR7 mRNA levels in the striatum of mice. Furthermore, acute or repeated α-PVT administration increased the levels of phosphorylated NF-κB, ERK, p38, and JNK MAPK activation and repeated α-PVT, but not acute, increased the levels of TNF-α and IL-6 mRNA in the striatum of mice. Finally, systemic administration of TAK-242 (5 mg/kg, i.p.) or MPLA (50 μg/kg, i.p.), each an inhibitor or activator of TLR4, did not change α-PVT-induced behavioral sensitization in mice. These results suggest that the activation of TLR4 by repeated α-PVT administration may lead to neuroinflammation via TLR-mediated NF-κB and MAPK signaling pathways and the production of TNF-α and IL-6 in the striatum of mice, at least without the regulation of behavioral sensitization.

Intact amphetamine-induced behavioral sensitization in mice with increased or decreased neuronal glutamate transporter SLC1A1/EAAT3

Repeated amphetamine treatment results in locomotor sensitization, a phenomenon that may relate to the development of psychosis and addiction. Evidence suggests that interactions between dopaminergic and glutamatergic systems are involved in amphetamine sensitization. We previously demonstrated that the neuronal excitatory amino acid transporter (Slc1a1/EAAT3) produces bidirectional, expression-dependent effects on the response to acute amphetamine. Here, using mice with decreased or increased expression of EAAT3, we found that chronic alterations in EAAT3 expression do not significantly impact amphetamine-induced locomotor sensitization. Compensation by other glutamate transporters cannot be ruled out in this important neuroadaptive phenomenon.

Environmental Enrichment Components Required to Reduce Methamphetamine-Induced Behavioral Sensitization in Mice: Examination of Behaviors and Neural Substrates.

Environmental enrichment (EE) involves the presentation of various sensory, physical, social, and cognitive stimuli in order to alter neural activity in specific brain areas, which can ameliorate methamphetamine (MAMPH)-induced behavioral sensitization and comorbid anxiety symptoms. No previous studies have comprehensively examined which EE components are critical for effectively reducing MAMPH-induced behavioral sensitization and anxiety. This study examined different housing conditions, including standard housing (SH, No EE), standard EE (STEE), physical EE (PEE), cognitive EE (CEE), and social EE (SEE). In the beginning, mice were randomly assigned to the different combinations of housing conditions and injections, consisting of No EE/Saline, No EE/MAMPH, STEE/MAMPH, PEE/MAMPH, CEE/MAMPH, and SEE/MAMPH groups. Then, the mice received intraperitoneal injections of 1 mg/kg MAMPH or normal saline daily for 7 days, followed by a final injection of 0.5 mg/kg MAMPH or normal saline. After behavioral tests, all mice were examined for c-Fos immunohistochemical staining. The results showed that MAMPH induced behavioral sensitization as measured by distance traveled. MAMPH appeared to induce lowered anxiety responses and severe hyperactivity. All EE conditions did not affect MAMPH-induced lowered anxiety behaviors. STEE was likely more effective for reducing MAMPH-induced behavioral sensitization than PEE, CEE, and SEE. The c-Fos expression analysis showed that the medial prefrontal cortex (i.e., cingulate cortex 1 (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL)), nucleus accumbens (NAc), basolateral amygdala (BLA), ventral tegmental area (VTA), caudate-putamen (CPu), and hippocampus (i.e., CA1, CA3, and dentate gyrus (DG)) contributed to MAMPH-induced behavioral sensitization. The Cg1, IL, NAc, BLA, VTA, CPu, CA3, and DG also mediated STEE reductions in MAMPH-induced behavioral sensitization. This study indicates that all components of EE are crucial for ameliorating MAMPH-induced behavioral sensitization, as no individual EE component was able to effectively reduce MAMPH-induced behavioral sensitization. The present findings provide insight into the development of non-pharmacological interventions for reducing MAMPH-induced behavioral sensitization.

Effect of 4-Fluoro-N-(4-Sulfamoylbenzyl) Benzene Sulfonamide on Acquisition and Expression of Nicotine-Induced Behavioral Sensitization and Striatal Adenosine Levels.

IntroductionBehavioral sensitization is a phenomenon that develops from intermittent exposure to nicotine and other psychostimulants, which often leads to heightened locomotor activity and then relapse. Sulfonamides that act as carbonic anhydrase inhibitors have a documented role in enhancing dopaminergic tone and normalizing neuroplasticity by stabilizing glutamate release.ObjectiveThe aim of the current study was to explore synthetic sulfonamides derivative 4-fluoro-N-(4-sulfamoylbenzyl) benzene-sulfonamide (4-FBS) (with documented carbonic anhydrase inhibitory activity) on acquisition and expression of nicotine-induced behavioral sensitization.MethodsIn the acquisition phase, selected 5 groups of mice were exposed to saline or nicotine 0.5mg/kg intraperitoneal (i.p) for 7 consecutive days. Selected 3 groups were administered with 4-FBS 20, 40, and 60 mg/kg p.o. along with nicotine. After 3 days of the drug-free period, ie, day 11, a challenge dose of nicotine was injected to all groups except saline and locomotor activity was recorded for 30 minutes. In the expression phase, mice were exposed to saline and nicotine only 0.5 mg/kg i.p for 7 consecutive days. After 3 days of the drug-free period, ie, day 11, 4-FBS at 20, 40, and 60 mg/kg were administered to the selected groups, one hour after drug a nicotine challenge dose was administered, and locomotion was recorded. At the end of behavioral experiments, all animals were decapitated and the striatum was excised and screened for changes in adenosine levels, using HPLC-UV.ResultsTaken together, our findings showed that 4-FBS in all 3 doses, in both sets of experiments significantly attenuated nicotine-induced behavioral sensitization in mice. Additionally, 4-FBS at 60mg/kg significantly lowered the adenosine level in the striatum.ConclusionThe behavioral and adenosine modulation is promising, and more receptors level studies are warranted to explore the exact mechanism of action of 4-FBS.

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.

Involvement of Gq/11 in methamphetamine-induced behavioral sensitization in mice

Involvement of Gq/11 in methamphetamine-induced behavioral sensitization in mice

The role of striatal Gαq/11 protein in methamphetamine-induced behavioral sensitization in mice

Gαq/11 protein transduces signals from neurotransmitter receptors and has been implicated in several functions of the central nervous system. In this study, the role of Gαq/11 protein in methamphetamine (METH)-induced behavioral sensitization was investigated using neurochemical and behavioral approaches. Repeated treatment with METH (2mg/kg, intraperitoneally) significantly increased behavioral sensitization as well as Gαq/11 protein expression and Gα protein activity in the striata of mice, while a single treatment of METH at the same dose did not affect these parameters. Repeated intrastriatal injections of a Gαq/11 inhibitor, [D-Trp7,9,10]-substance P, significantly reduced behavioral sensitization and striatal dopamine (DA) level in response to METH, with no effect on striatal tyrosine hydroxylase expression. These results suggest that Gαq/11 protein facilitates METH-induced behavioral sensitization by modulating DA release in the mouse striatum.

THC inhibits the expression of ethanol-induced locomotor sensitization in mice.

The motivational circuit activated by ethanol leads to behavioral changes that recruit the endocannabinoid system (ECS). Case reports and observational studies suggest that the use of Cannabis sp. mitigates problematic ethanol consumption in humans. Here, we verified the effects of the two main phytocannabinoid compounds of Cannabis sp., cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), in the expression of ethanol-induced locomotor sensitization in mice. Male adult DBA/2 mice were exposed to locomotor sensitization by daily intraperitoneal injections of ethanol (2.5g/kg) for 12 days; control groups received saline. After the acquisition phase, animals were treated with cannabinoids: CBD (2.5mg/kg); THC (2.5mg/kg); CBD+THC (1:1 ratio), or vehicle for 4 days with no access to ethanol during this period. One day after the last cannabinoid injection, all animals were challenged with ethanol (2.0g/kg) to evaluate the expression of the locomotor sensitization. Mice treated with THC alone or THC+CBD showed reduced expression of locomotor sensitization, compared to the vehicle control group. No effects were observed with CBD treatment alone. Our findings showing that phytocannabinoid treatment prevents the expression of behavioral sensitization in mice provide insight into the potential therapeutic use of phytocannabinoids in alcohol-related problems.

Epigenetic mechanisms and alcohol use disorders: a potential therapeutic target

Alcohol use disorder is a devastating illness with a profound health impact, and its development is dependent on both genetic and environmental factors. This disease occurs over time and requires changes in brain gene expression. There is converging evidence suggesting that the epigenetic processes may play a role in the alcohol-induced gene regulations and behavior such as the intervention of DNA methylation and histone acetylation. Histone acetylation, like histone methylation, is a highly dynamic process regulated by two classes of enzymes: histone acetyltransferases and histone deacetylases (HDACs). To date, 18 human HDAC isoforms have been characterized, and based on their sequence homologies and cofactor dependencies, they have been phylogenetically categorized into 4 main classes: classes I, II (a and b), III, and IV. In the brain, expression of the different classes of HDACs varies between cell types and also in their subcellular localization (nucleus and/or cytosol). Furthermore, we recently showed that a single ethanol exposure inhibits HDAC activity and increases both H3 and H4 histone acetylation within the amygdala of rats. In the brain of alcoholic patients, ethanol has been shown to induce histone-related and DNA methylation epigenetic changes in several reward regions involved in reward processes such as hippocampus, prefrontal cortex, and amygdala. We recently demonstrated alteration of histone H3 acetylation levels in several brain regions from the reward circuit of rats made dependent to alcohol after chronic and intermittent exposure to ethanol vapor. In neuronal cell line culture, ethanol was shown to induce HDAC expression. In mouse and rat brain, numerous studies reported epigenetic alterations following ethanol exposure. We also demonstrated that both the expression of genes and the activity of enzymes involved in epigenetic mechanisms are changed after repeated administrations of ethanol in mice sensitized to the motor stimulant effect of ethanol (a model of drug-induced neuroplasticity). Numerous studies have shown that HDAC inhibitors are able to counter ethanol-induced behaviors and the ethanol-induced changes in the levels of HDAC and/or levels of acetylated HDAC. For example, trichostatin A (TSA) treatment caused the reversal of ethanol-induced tolerance, anxiety, and ethanol drinking by inhibiting HDAC activity, thereby increasing histone acetylation in the amygdala of rats. Another study demonstrated that TSA prevented the development of ethanol withdrawal induced anxiety in rats by rescuing deficits in histone acetylation induced by increased HDAC activity in the amygdala. We have demonstrated that treatment with the HDAC inhibitor sodium butyrate blocks both the development and the expression of ethanol-induced behavioral sensitization in mice. In this context, converging evidence indicates that HDAC inhibitors could be useful in counteracting ethanol-induced gene regulations via epigenetic mechanisms, that is, HDAC inhibitors could affect different acetylation sites and may also alter the expression of different genes that could in turn counteract the effect of ethanol. Recent work in rodents has shown that systemic administration of pan HDAC class I and II inhibitors, TSA and N-hydroxy-N-phenyl-octanediamide [SuberoylAnilide Hydroxamic Acid] (SAHA), and of the more selective inhibitor (mainly HDAC1 and HDAC9) MS-275, decrease binge-like alcohol drinking in mice. SAHA selectively reduced ethanol operant self-administration and seeking in rats. Our previous study revealed that MS-275 strongly decreased operant ethanol self-administration in alcohol-dependent rats when administered 30 minutes before the session at the second day of injection. We also demonstrated that intra-cerebro-ventricular infusion of MS-275 increases acetylation of Histone 4 within the nucleus accumbens and the dorsolateral striatum, associated to a decrease in ethanol self-administration by about 75%. MS-275 also diminished both the motivation to consume ethanol (25% decrease), relapse (by about 50%) and postponed reacquisition after abstinence. Both literature and several of our studies strongly support the potential therapeutic interest of targeting epigenetic mechanisms in excessive alcohol drinking and strengthen theinterest of focusing on specific isoforms of histone deacetylases.

052 — (OLI0150) Long-lasting facilitating effect of food restriction on fenproporex-induced behavioral sensitization in mice: Role of corticosterone secretion

052 — (OLI0150) Long-lasting facilitating effect of food restriction on fenproporex-induced behavioral sensitization in mice: Role of corticosterone secretion

009 — (BOR0113) Prenatal POLY:IC treatment potentiated amphetamine-induced behavioral sensitization in mice

009 — (BOR0113) Prenatal POLY:IC treatment potentiated amphetamine-induced behavioral sensitization in mice

Luteolin inhibits behavioral sensitization by blocking methamphetamine-induced MAPK pathway activation in the caudate putamen in mice.

GoalTo investigate the effect of luteolin on methamphetamine (MA)-induced behavioral sensitization and mitogen-activated protein kinase (MAPK) signal transduction pathway activation in mice.MethodsMice received a single dose of MA to induce hyperactivity or repeated intermittent intraperitoneal injections of MA to establish an MA-induced behavioral sensitization mouse model. The effect of luteolin on the development and expression of MA-induced hyperactivity and behavioral sensitization was examined. The expression and activity of ΔFosB and the levels of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), phosphorylated c-Jun N-terminal kinase (pJNK), and phosphorylated p38 mitogen-activated protein kinase (pp38) in the caudate putamen (CPu) were measured by western blot.ResultsLuteolin significantly decreased hyperactivity as well as the development and expression of MA-induced behavioral sensitization in mice. ΔFosB, pERK1/2, and pJNK levels in the CPu were higher in MA-treated mice than in control mice, whereas the pp38 level did not change. Injection of luteolin inhibited the MA-induced increase in ΔFosB, pERK1/2, and pJNK levels, but did not affect the pp38 level.ConclusionsLuteolin inhibits MA-induced hyperactivity and behavioral sensitization in mice through the ERK1/2/ΔFosB pathway. Furthermore, the JNK signaling pathway might be involved in MA-induced neurodegeneration in the CPu, and luteolin inhibits this process.

Effects of baicalin on morphine-induced behavioral sensitization in mice

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 Baicalin 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. Key words: Baicalin; Morphine; Behavioral sensitization; Dopamine

Comparison of single versus repeated methamphetamine injection induced behavioral sensitization in mice

Repeated exposure to drugs of abuse produces a persistent behavioral sensitization to stimulants, which is often used to study drug-associated behavioral plasticity. Interestingly, even a single exposure to some drugs of abuse is sufficient to elicit long-lasting behavioral sensitization. However, few studies have directly compared the magnitude of sensitization between single versus repeated drug treatments. This study examined the magnitude and duration of single methamphetamine (METH) injection-induced behavioral sensitization and compared it to the more typical repeated drug injection-induced sensitization in mice. Different groups of mice were injected with METH (0.5, 1.0, 2.0mg/kg, i.p.) only once or daily for 7 consecutive days. A challenge dose of METH (1.0mg/kg, i.p.) was tested 7 days later. The time-course of a single METH injection-induced behavioral sensitization was assessed where METH (2.0mg/kg, i.p.) was injected and a challenge dose of METH (1.0mg/kg, i.p.) was tested after different drug-free periods. Single METH injection produced similar magnitude of behavioral sensitization as compared to repeated injection. Such a sensitized locomotor response peaked 8 days after METH injection and lasted for at least 21 days. This long lasting behavioral alteration induced by single METH injection suggests the value of future studies to explore the underlying neural mechanisms, particularly in comparison to those underlying repeated METH-induced sensitization.

Acute total sleep deprivation potentiates amphetamine-induced locomotor-stimulant effects and behavioral sensitization in mice

It has been demonstrated that a prolonged period (48h) of paradoxical sleep deprivation (PSD) potentiates amphetamine (AMP)-induced behavioral sensitization, an animal model of addiction-related neuroadaptations. In the present study, we examined the effects of an acute short-term deprivation of total sleep (TSD) (6h) on AMP-induced behavioral sensitization in mice and compared them to the effects of short-term PSD (6h). Three-month-old male C57BL/6J mice underwent TSD (experiment 1—gentle handling method) or PSD (experiment 2—multiple platforms method) for 6h. Immediately after the sleep deprivation period, mice were tested in the open field for 10min under the effects of saline or 2.0mg/kg AMP. Seven days later, to assess behavioral sensitization, all of the mice received a challenge injection of 2.0mg/kg AMP and were tested in the open field for 10min. Total, peripheral, and central locomotion, and grooming duration were measured. TSD, but not PSD, potentiated the hyperlocomotion induced by an acute injection of AMP and this effect was due to an increased locomotion in the central squares of the apparatus. Similarly, TSD facilitated the development of AMP-induced sensitization, but only in the central locomotion parameter. The data indicate that an acute period of TSD may exacerbate the behavioral effects of AMP in mice. Because sleep architecture is composed of paradoxical and slow wave sleep, and 6-h PSD had no effects on AMP-induced hyperlocomotion or sensitization, our data suggest that the deprivation of slow wave sleep plays a critical role in the mechanisms that underlie the potentiating effects of TSD on both the acute and sensitized addiction-related responses to AMP.

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.

Metabotropic glutamate receptor 7 (mGluR7) allosteric agonist, AMN082 attenuates the acquisition and expression of cocaine-induced behavioral sensitization in mice

Metabotropic glutamate receptor 7 (mGluR7) allosteric agonist, AMN082 attenuates the acquisition and expression of cocaine-induced behavioral sensitization in mice