Conditioned Locomotor Activity Research Articles

Decrease of glycogen synthase kinase 3β phosphorylation in the rat nucleus accumbens shell is necessary for amphetamineinduced conditioned locomotor activity.

Phosphorylation levels of glycogen synthase kinase 3β (GSK3β) negatively correlated with psychomotor stimulant-induced locomotor activity. Locomotor sensitization induced by psychomotor stimulants was previously shown to selectively accompany the decrease of GSK3β phosphorylation in the nucleus accumbens (NAcc) core, suggesting that intact GSK3β activity in this region is necessary for psychomotor stimulants to produce locomotor sensitization. Similarly, GSK3β in the NAcc was also implicated in mediating the conditioned effects formed by the associations of psychomotor stimulants. However, it remains undetermined whether GSK3β plays a differential role in the two sub-regions (core and shell) of the NAcc in the expression of drug-conditioned behaviors. In the present study, we found that GSK3β phosphorylation was significantly lower in the NAcc shell obtained from rats expressing amphetamine (AMPH)-induced conditioned locomotor activity. Further, we demonstrated that these effects were normalized by treatment with lithium chloride, a GSK3β inhibitor. These results suggest that the behavior produced by AMPH itself and a conditioned behavior formed by associations with AMPH are differentially mediated by the two sub-regions of the NAcc.

Swiprosin1/EFhd2 is involved in the monoaminergic and locomotor responses of psychostimulant drugs.

Psychostimulants are widely abused drugs that may cause addiction in vulnerable individuals. While the reward circuitry of the brain is involved in addiction establishment, various pathways in the brain may provide protection at the molecular level that limits the acute and chronic effects of drugs. These targets may be used for strategies designed to prevent and treat addiction. Swiprosin-1/EF hand domain 2 (EFhd2) is a Ca2+ -binding cytoskeletal adaptor protein involved in sensation-seeking behaviour, anxiety and alcohol addiction. Here, we tested how EFhd2 contributes to the physiological and behavioural effects of the psychostimulant drugs methamphetamine (METH) and cocaine. An in vivo microdialysis study in EFhd2 knockout mice revealed that EFhd2 controls METH- and cocaine-induced changes in extracellular dopamine, serotonin and noradrenaline levels through different mechanisms in the nucleus accumbens and prefrontal cortex. Electrophysiological recordings in a slice preparation showed that a lack of EFhd2 increases dopaminergic neuronal activity in the ventral tegmental area and increases the sensitivity of neurons to stimulation. We report a role of EFhd2 in METH-induced locomotor activation and in the conditioned locomotor effects. No role, however, was observed in the establishment of METH- or cocaine-induced conditioned place preference. These findings may suggest that EFhd2 modulates the activity of the dopaminergic system and the neurochemical effects of METH and cocaine, which translate into a modulation of the behavioural effects of these drugs at the level of the acute and conditioned locomotor activity.

Virus-mediated overexpression of radixin in the nucleus accumbens inhibits the development of amphetamine-induced conditioned locomotor activity

Virus-mediated overexpression of radixin in the nucleus accumbens inhibits the development of amphetamine-induced conditioned locomotor activity

Toll-like receptor 3 modulates the behavioral effects of cocaine in mice

BackgroundThe nucleus accumbens in the midbrain dopamine limbic system plays a key role in cocaine addiction. Toll-like receptors (TLRs) are important pattern-recognition receptors (PPRs) in the innate immune system that are also involved in drug dependence; however, the detailed mechanism is largely unknown.MethodsThe present study was designed to investigate the potential role of TLR3 in cocaine addiction. Cocaine-induced conditioned place preference (CPP), locomotor activity, and self-administration were used to determine the effects of TLR3 in the rewarding properties of cocaine. Lentivirus-mediated re-expression of Tlr3 (LV-TLR3) was applied to determine if restoration of TLR3 expression in the NAc is sufficient to restore the cocaine effect in TLR3−/− mice. The protein levels of phospho-NF-κB p65, IKKβ, and p-IκBα both in the cytoplasm and nucleus of cocaine-induced CPP mice were detected by Western blot.ResultsWe showed that both TLR3 deficiency and intra-NAc injection of TLR3 inhibitors significantly attenuated cocaine-induced CPP, locomotor activity, and self-administration in mice. Importantly, the TLR3−/− mice that received intra-NAc injection of LV-TLR3 displayed significant increases in cocaine-induced CPP and locomotor activity. Finally, we found that TLR3 inhibitor reverted cocaine-induced upregulation of phospho-NF-κB p65, IKKβ, and p-IκBα.ConclusionsTaken together, our results describe that TLR3 modulates cocaine-induced behaviors and provide further evidence supporting a role for central pro-inflammatory immune signaling in drug reward. We propose that TLR3 blockade could be a novel approach to treat cocaine addiction.

THE INFLUENCE OF ZINC DONATOR ACYZOL INTO RAT'S LOCOMOTOR BEHAVIOR

The aim of the article. The article is devoted to investigation of zinc donator acyzol influence to spontaneous or conditioned reflex locomotor activity of the rats. Materials and methods of research. The study was performed on adult male Wistar rats. Acyzol in volume of 0.1 ml was injected intraperitoneal (24 мg/kg) twice with the time gap of three days. Parameters of spontaneous locomotor activity were evaluated in “open field”, and values of conditioned reflex behavior of avoidance were evaluated in “shuttle box”. Results. Spontaneous locomotor activity of rats (especially the number of research rearing iterations) has lowered after the first injection under the influence of acyzol soon. The realization of avoidance conditioned reflexes was worsened after the second injection of acyzol. Conclusion. There is reason to propose, that acyzol, increasing the zinc content in the body, is able to lower the locomotor activity of rats; and it has the indirect influence on the avoidance conditioned reflex behavior. It should be considered when application of acyzol as a medical, protective or tonic drug.

Effects of ketamine on the unconditioned and conditioned locomotor activity of preadolescent and adolescent rats: impact of age, sex, and drug dose.

Ketamine is used by preadolescent and adolescent humans for licit and illicit purposes. The goal of the present study was to determine the effects of acute and repeated ketamine treatment on the unconditioned behaviors and conditioned locomotor activity of preadolescent and adolescent rats. To assess unconditioned behaviors, female and male rats were injected with ketamine (5-40mg/kg), and distance traveled was measured on postnatal day (PD) 21-25 or PD 41-45. To assess conditioned activity, male and female rats were injected with saline or ketamine in either a novel test chamber or the home cage on PD 21-24 or PD 41-44. One day later, rats were injected with saline and conditioned activity was assessed. Ketamine produced a dose-dependent increase in the locomotor activity of preadolescent and adolescent rats. Preadolescent rats did not exhibit sex differences, but ketamine-induced locomotor activity was substantially stronger in adolescent females than males. Repeated ketamine treatment neither caused a day-dependent increase in locomotor activity nor produced conditioned activity in preadolescent or adolescent rats. The activity-enhancing effects of ketamine are consistent with the actions of an indirect dopamine agonist, while the inability of ketamine to induce conditioned activity is unlike what is observed after repeated cocaine or amphetamine treatment. This dichotomy could be due to ketamine's ability to both enhance DA neurotransmission and antagonize N-methyl-D-aspartate (NMDA) receptors. Additional research will be necessary to parse out the relative contributions of DA and NMDA system functioning when assessing the behavioral effects of ketamine during early ontogeny.

Oxycodone-induced conditioned place preference and locomotor activity in adult female C57BL/6J mice

Oxycodone-induced conditioned place preference and locomotor activity in adult female C57BL/6J mice

Adenosine (A)2A receptor modulation of nicotine-induced locomotor sensitization. A pharmacological and transgenic approach

Preclinical evidence indicates an important role of adenosine (A)2A receptors in drug addiction while their therapeutic relevance is still a matter of debate. We examined the influence of the A2A receptor agonist CGS 21680 and the antagonist KW 6002 on nicotine sensitization and conditioned locomotor activity in adult (8-week old) male Sprague–Dawley rats (WT). Moreover, behavioral responses to nicotine were studied in rats overexpressing A2A receptors under the control of the neuronal specific enolase (NSE) promotor. Changes in the levels of dopamine, glutamate and γ-aminobutyric acid in wild type (WT) and NSEA2A rats were determined with using LC–MS. KW 6002 significantly enhanced expression of nicotine sensitization and conditioned locomotion, while CGS 21680 reduced all these effects in WT rats. A reduction of the expression of nicotine-evoked conditioned locomotor activity was also observed in the NSEA2A animals. The transgenic rats displayed a reduced basal tissue level of glutamate in the prefrontal cortex and hippocampus while dopamine basal levels in the nucleus accumbens were raised. Chronic nicotine treatment caused a significant reduction in the glutamate tissue level in the dorsal and ventral striatum, prefrontal cortex and cerebellum in wild type rats. In NSEA2A animals the same drug treatment instead produced a rise of glutamate levels in the hippocampus and dorsal striatum. Taken together, A2A receptor signaling in the rat brain can counteract locomotor sensitization and conditioned locomotion to nicotine which are related to nicotine reward-learning. It is suggested that treatment with A2A receptor agonists can help counteract the abuse actions of nicotine.

Effect of post-trial L-NAME administration on cocaine sensitization

This study determined if Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) administered after the cocaine-conditioning trial attenuated the development of sensitization to cocaine's locomotor-stimulating effect and secondly, determined if L-NAME blocked conditioned-locomotor activity (LMA) elicited by a saline-challenge injection. Results revealed that cocaine-injected animals (10 mg/kg, i.p.) showed enhanced locomotor activity across the three conditioning trials (all p's < .05). Cocaine-injected animals administered L-NAME (30 mg/kg, i.p.) after each conditioning trial showed a slight increase in cocaine-stimulated LMA from the first to the second conditioning trial (all p's < .05) and no further increases in LMA thereafter. A saline-challenge injection administered 72 hr after the last conditioning trial revealed that cocaine-injected animals displayed as much locomotor stimulation to a saline injection as they did during their initial exposure to cocaine on the first conditioning trial - indicating the development of cocaine-conditioned LMA.The present findings show that L-NAME administered after the cocaine-conditioning trial attenuates the development of sensitization to cocaine's locomotor-stimulating effect. The failure of L-NAME to block cocaine-conditioned LMA suggests that the pharmacological and conditioning mechanisms of sensitization can be dissociated. It is unlikely that L-NAME's effect is due to a sedative action produced by residual L-NAME since animals administered L-NAME (30 mg/kg, i.p.) for 10 consecutive days exhibited a similar responsiveness to a cocaine challenge administered 3 and 10 days following the termination of L-NAME administration. These data support a role for nitric oxide's involvement in the neuroadaptive responses that result from continued stimulant administration and demonstrate the importance of conditioned drug effects.

Expression and resilience of a cocaine-conditioned locomotor response after brief and extended drug-free periods

Conditioned associations between drug experience and its context are maintained long after drug use ceases, and may contribute to relapse after extended abstinence. These include operantly conditioned associations directed toward seeking drug, but also Pavlovian conditioned associations between drug reward and contextual cues present at the time of drug administration. The present study sought to determine whether expression of a Pavlovian conditioned locomotor (CL) response to a cocaine-associated context increases over time in the same manner observed for instrumental responses, and whether the CL memory is differentially susceptible to extinction and recovery after brief versus extended abstinence. Male rats received injections of cocaine (30mg/kg, i.p.) or vehicle once per day for 6 days. In Exp. 1, CL activity was measured 1, 7, 21, or 42 days later. Rats that had received cocaine injections displayed robust CL, regardless of when testing occurred. In Exp. 2, extinction and recovery of CL were assessed after 1 or 42 days. The CL response was more readily extinguished in rats tested 1 day after drug exposure, as compared to rats tested 42 days later. Exp. 3 confirmed that conditioning in the testing context was necessary for expression of CL. Overall, our results indicate that Pavlovian associations underlying the CL response are maintained long after drug experience. Although the expression of CL does not change with the passage of time, as has been observed for instrumental drug-related responses, the memory trace does appear to become more resilient over time.

Rapid eye movement sleep deprivation disrupts context-modulated effects on morphine locomotor sensitization in mice

Previous studies have shown that behavioral sensitization is modulated by drug-associated context, in which memory processes may be critically involved. Sleep has been suggested to play an important role in memory processes. However, the relationship between sleep and context-modulated effects on behavioral sensitization remains to be elucidated. In the present study, we designed three experiments to explore the effects of rapid eye movement sleep deprivation (RSD) on context-modulated effects on morphine locomotor sensitization in mice. Mice were subjected to 6 h RSD starting either immediately after morphine pairing training or 6 h later. The control mice were returned to their home cages immediately after pairing training and left undisturbed. In experiment 1, RSD from 0 to 6 h but not from 7 to 12 h disrupted paired context-modulated enhancement of locomotor activity. In experiment 2, RSD from 0 to 6 h but not from 7 to 12 h disrupted unpaired context-modulated suppression of locomotor activity. In experiment 3, RSD from either 0 to 6 h or 7 to 12 h had no effect on conditioned locomotor activity. Our findings suggest that sleep plays a critical role in memory processes underlying context-modulated effects on morphine locomotor sensitization.

Gene expression of conditioned locomotion and context-specific locomotor sensitization controlled by morphine-associated environment

The nucleus accumbens (NAc) is involved in contextual drug associations, which might be particularly important for environmental cue-induced relapse to drug seeking. In the present study, rats were first administered repeated morphine for 5 days (5 mg/kg, i.p.) in a contextually paired and unpaired design. After reexposure to the morphine-associated environment, which induced conditioned locomotor activity in the morphine-paired group, we performed a rat 27k 70-mer oligo array to profile gene expression in the NAc. One hundred fifty-five upregulated and 88 downregulated genes were found in the paired group compared with the unpaired group. Eight gene transcripts were then selected to confirm their alterations by quantitative real-time polymerase chain reaction (qRT-PCR). The identified genes generally play important roles in neuroactive receptor–ligand interactions, synapse plasticity, ion transport, and protein phosphorylation. Furthermore, the expression of the eight selected genes that were identified and confirmed to show significant fold changes in the first microarray experiment were again measured with qRT-PCR after morphine challenge (2 mg/kg, i.p.). As expected, 2 mg/kg morphine-induced context-specific sensitization. Meanwhile, mRNA expression of the selected genes showed marked upregulation in the morphine-paired group compared with the unpaired and acute groups. These results suggest that alterations in the expression of the identified genes in the NAc may contribute to the neuroplasticity underlying contextual cue-induced relapse to drug use.

The expression of morphine-induced behavioral sensitization depends more on treatment regimen and environmental novelty than on conditioned drug effects

Both conditioned responses (CRs) and sensitized behaviors induced by addictive drugs are considered to reflect drug-seeking motivation. Based on an excitatory conditioning model of behavioral sensitization, this work hypothesizes that conditioned locomotor activity and locomotor sensitization concomitantly occur using different drug treatment regimens. In the present study, conditioned locomotor activity and sensitized locomotion and stereotypy are assessed with pretreatment of two doses of morphine in a familiar or novel environment. When rats are trained with morphine (3 or 5 mg/kg) in an environment to which the animals are habituated, a CR but not contextual sensitization is induced when tested after 1 week of abstinence. When rats receive the 5 mg/kg dose of morphine immediately after placement into a novel environment, the same results are obtained, but when the drug dose is decreased to 3 mg/kg, both the CR and contextual sensitization are observed. Therefore, the sensitized behaviors, rather than the CR produced by morphine pretreatment, appear to be dependent on the drug treatment regimen and environmental novelty, suggesting that different mechanisms may be involved in the expression of the CR and contextual sensitization.

Differential effects of morphine on conditioned place preference and locomotor activity in adult and adolescent rats

Objective To test whether adolescent rats are more sensitive than adult rats to morphine' s rewarding actions and locomotor activating effects. Methods Conditioned place preference(CPP) procedure was used to examine drug-induced reward and locomotor activity. Adolescent ( Postnatal day 35 ) and adult ( P67 ) male rats received either saline or morphine (3 mg/kg) for 6 days and the locomotor response in the drug paired chamber was recorded during conditioned training. CPP effects were tested 24h after the last training. Results In adolescent rats, morphine CPP effect was not present [ saline group (20. 89 ±31. 14) s, morphine group (90. 75 ± 27.91)s, P = 0. 15], however, morphine CPP effect occurred in adult rats[saline group (31.5 ± 41. 24) s, morphine group(266. 13 ± 32. 26) s, P < 0. 001 ]. Adult rats presented higher CPP score than adolescent rats(P < 0.001). The locomotor response was significantly higher in day 3 ～ 6 than day 1 in the adolescent treated with morphine (P<0.05 or <0. 01). The locomotor response was significantly higher in day 2-6 than day 1 in the adolescent treated with morphine(P<0. 05 or < 0. 01 ) .which suggested that both adolescent and adult rats exhibited similar behavioral sensitization to morphine administration. Two-way ANOVA indicated that the main effect of age was not significant(F_(1,14) =0. 33, P = 0. 57) ,the interaction effect of age x treat was not significant(F_(5,70) = 0.85, P = 0.52) .there was no age difference between adolescent and adult rats in behavioral sensitization effects. Conclusion Compared with adult rats, adolescent rats don' t present morphine CPP, but show the similar morphine behavioral sensitization. Key words: Drug addiction; Morphine; Conditioned place preference; Locomotor sensitization

A comparison of amphetamine- and methamphetamine-induced locomotor activity in rats: evidence for qualitative differences in behavior

Methamphetamine (METH) is typically characterized as a more potent psychostimulant than amphetamine (AMPH), but few studies have directly compared the effects of these drugs at low, behaviorally activating doses that tend not to produce focused stereotypy. The objective of the study was to compare the effects of AMPH or METH treatment on locomotor activity in an open-field arena, focusing on their ability to produce conditioned locomotor activity, sensitization, and cross-sensitization. Adult male rats were given AMPH or METH (0.5 or 1.0 mg/kg) for 5 days, with half of the rats presented with discrete, salient stimuli (S+) during the postinjection period. After a 3-day withdrawal, they were given three different injections on successive days: a saline challenge to assess conditioned responding, a drug challenge to assess sensitization, and a cross-sensitization test to the same dose of the drug with which they were not pretreated. Except in certain conditions, AMPH and METH were equipotent at activating locomotor activity. The exceptions included when rats were presented with S+ on acute and drug challenge days and in tests of cross-sensitization. There were no consistent differences in the magnitude of sensitization produced by AMPH or METH, and both drugs produced similar amounts of conditioned locomotion after a saline injection. We have found specific conditions where METH is more potent than AMPH, but this study and others that used higher doses of these drugs are not consistent with the generalized characterization of METH as a more potent psychostimulant.

Neurokinin3 receptor antagonism attenuates cocaine's behavioural activating effects yet potentiates its dopamine‐enhancing action in the nucleus accumbens core

Several lines of evidence indicate a role for neurokinin3 receptors (NK3-Rs) in behavioural activation and mechanisms governing reinforcement processes. In this study we investigated the effect of pretreatment with the NK3-R antagonist, SR142801, (0.2 and 2.0 mg/kg) on the cocaine-induced (10.0 mg/kg i.p.) increase in extracellular dopaminergic activity in the nucleus accumbens (NAc). In vivo microdialysis in the NAc of freely moving rats showed that cocaine increased concentrations of dopamine (DA) to approximately 350% in the core and approximately 450% in the shell. Pre-treatment with SR142801 significantly potentiated this effect in the core (to approximately 550%), whereas this effect was not found in the shell. We also investigated the effects of NK3-Rs antagonism on cocaine-induced hyperactivity and conditioned place preference. SR142801 blocked the hyperactivity, but neither the conditioned place preference nor the conditioned locomotor activity induced by cocaine, although there was a slight tendency towards a reduced place preference. When given alone, SR142801 had no effects on behaviour or extracellular dopamine concentrations in any of the structures investigated. These data provide evidence for a contribution of NK3-Rs in the acute behavioural and neurochemical effects of cocaine, involving dopaminergic activity in the core of the nucleus accumbens.

The selective dopamine D3 receptor antagonist SB-277011A reduces nicotine-enhanced brain reward and nicotine-paired environmental cue functions

Increasing evidence suggests that enhanced dopamine (DA) neurotransmission in the nucleus accumbens (NAc) may play a role in mediating the reward and reinforcement produced by addictive drugs and in the attentional processing of drug-associated environmental cues. The meso-accumbens DA system is selectively enriched with DA D3 receptors, a DA receptor subtype increasingly implicated in reward-related brain and behavioural processes. From a variety of evidence, it has been suggested that selective DA D3 receptor antagonism may be a useful pharmacotherapeutic approach for treating addiction. The present experiments tested the efficacy of SB-277011A, a selective DA D3 receptor antagonist, in rat models of nicotine-enhanced electrical brain-stimulation reward (BSR), nicotine-induced conditioned locomotor activity (LMA), and nicotine-induced conditioned place preference (CPP). Nicotine was given subcutaneously within the dose range of 0.25-0.6 mg/kg (nicotine-free base). SB-277011A, given intraperitoneally within the dose range of 1-12 mg/kg, dose-dependently reduced nicotine-enhanced BSR, nicotine-induced conditioned LMA, and nicotine-induced CPP. The results suggest that selective D3 receptor antagonism constitutes a new and promising pharmacotherapeutic approach to the treatment of nicotine dependence.

Differential Regulation of the Consummatory, Motivational and Anticipatory Aspects of Feeding Behavior by Dopaminergic and Opioidergic Drugs

Various aspects of feeding behavior (eg consumption, motivation and anticipation) are regulated by homeostatic and hedonic systems, and are modulated by dopaminergic and opioid brain systems. Here, we have studied the modulation of these aspects of feeding behavior by opioid and dopaminergic neurotransmission while taking into account food palatability and homeostatic state. Foods that varied in palatability were presented to either food sated or food restricted rats following injections of different doses of naloxone, an opioid receptor antagonist, or flupenthixol, a dopaminergic receptor antagonist, in behavioral paradigms that measured different aspects of feeding. Naloxone decreased food intake in a dose-dependent manner in sated rats given access to palatable food, without modifying food intake in food restricted rats. Flupenthixol did not have any effect on food intake. With regard to motivation, which was tested in a straight alley, naloxone increased the latency to reach the food only in sated rats presented with palatable food. Flupenthixol did not modify the latency of any group. Conditioned locomotor activity to repeated food presentation, a measure of anticipation, is expressed only in food restricted rats. Naloxone did not modify anticipatory activity, whereas flupenthixol decreased it only in food restricted rats presented with palatable food. These results reinforce the idea that the opioid system regulates feeding through the modulation of the perceived palatability of food. The dopaminergic system seems to be more important for the regulation of anticipatory activity related to motivationally relevant stimuli.

The hippocampus and appetitive Pavlovian conditioning: Effects of excitotoxic hippocampal lesions on conditioned locomotor activity and autoshaping

The hippocampus (HPC) is known to be critically involved in the formation of associations between contextual/spatial stimuli and behaviorally significant events, playing a pivotal role in learning and memory. However, increasing evidence indicates that the HPC is also essential for more basic motivational processes. The amygdala, by contrast, is important for learning about the motivational significance of discrete cues. This study investigated the effects of excitotoxic lesions of the rat HPC and the basolateral amygdala (BLA) on the acquisition of a number of appetitive behaviors known to be dependent on the formation of Pavlovian associations between a reward (food) and discrete stimuli or contexts: (1) conditioned/anticipatory locomotor activity to food delivered in a specific context and (2) autoshaping, where rats learn to show conditioned discriminated approach to a discrete visual CS+. While BLA lesions had minimal effects on conditioned locomotor activity, hippocampal lesions facilitated the development of both conditioned activity to food and autoshaping behavior, suggesting that hippocampal lesions may have increased the incentive motivational properties of food and associated conditioned stimuli, consistent with the hypothesis that the HPC is involved in inhibitory processes in appetitive conditioning.

Patterns of Brain Activation Associated With Contextual Conditioning to Methamphetamine in Mice.

Classical conditioning is thought to play a key role in addiction. The authors used c-Fos immunohistochemistry to demonstrate a conditioned physiological response to methamphetamine (meth) in mice. Male outbred mice were placed into an environment where they had previously experienced 2 mg/kg meth or saline. The meth-paired mice displayed increased c-Fos in several brain regions, including the nucleus accumbens, prefrontal cortex, orbitofrontal cortex, basolateral amygdala, and bed nucleus of the stria terminalis. No conditioned locomotor activity was observed, but individual activity levels strongly correlated with c-Fos in many regions. A batch effect among immunohistochemical assays was demonstrated. Results implicate specific brain regions in classical conditioning to meth and demonstrate the importance of considering locomotor activity and batch in a c-Fos study.