Behavioral Sensitization In Rats Research Articles

The 5-HT7 receptors in the VLO contribute to the development of morphine-induced behavioral sensitization in rats

The 5-hydroxytryptamine 7 receptor (5-HT7R) is one of the most recently cloned serotonin receptors which have been implicated in many physiological and pathological processes including drug addiction. Behavioral sensitization is the progressive process during which re-exposure to drugs intensified the behavioral and neurochemical responses to drugs. Our previous study has demonstrated that the ventrolateral orbital cortex (VLO) is critical for morphine-induced reinforcing effect. The aim of the present study was to investigate the effect of 5-HT7Rs in the VLO on morphine-induced behavioral sensitization and their underlying molecular mechanisms. Our results showed that a single injection of morphine, followed by a low challenge dose could induce behavioral sensitization. Microinjection of the selective 5-HT7R agonist AS-19 into the VLO during the development phase significantly increased morphine-induced hyperactivity. Microinjection of the 5-HT7R antagonist SB-269970 suppressed acute morphine-induced hyperactivity and the induction of behavioral sensitization, but had no effect on the expression of behavioral sensitization. In addition, the phosphorylation of AKT (Ser 473) was increased during the expression phase of morphine-induced behavioral sensitization. Suppression of the induction phase could also block the increase of p-AKT (Ser 473). In conclusion, we demonstrated that 5-HT7Rs and p-AKT in the VLO at least partially contribute to morphine-induced behavioral sensitization.

Phosphorylation of Neurofilament Light Chain in the VLO Is Correlated with Morphine-Induced Behavioral Sensitization in Rats.

Neurofilament light chain (NF-L) plays critical roles in synapses that are relevant to neuropsychiatric diseases. Despite postmortem evidence that NF-L is decreased in opiate abusers, its role and underlying mechanisms remain largely unknown. We found that the microinjection of the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) into the ventrolateral orbital cortex (VLO) attenuated chronic morphine-induced behavioral sensitization. The microinjection of TSA blocked the chronic morphine-induced decrease of NF-L. However, our chromatin immunoprecipitation (ChIP)-qPCR results indicated that this effect was not due to the acetylation of histone H3-Lysine 9 and 14 binding to the NF-L promotor. In line with the behavioral phenotype, the microinjection of TSA also blocked the chronic morphine-induced increase of p-ERK/p-CREB/p-NF-L. Finally, we compared chronic and acute morphine-induced behavioral sensitization. We found that although both chronic and acute morphine-induced behavioral sensitization were accompanied by an increase of p-CREB/p-NF-L, TSA exhibited opposing effects on behavioral phenotype and molecular changes at different addiction contexts. Thus, our findings revealed a novel role of NF-L in morphine-induced behavioral sensitization, and therefore provided some correlational evidence of the involvement of NF-L in opiate addiction.

The CaMKII-dependent phosphorylation of GABAB receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.

Previous studies have established that the regulation of prolonged, distal neuronal inhibition by the GABAB heteroreceptor (GABAB R) is determined by its stability, and hence residence time, on the plasma membrane. Here, we show that GABAB R in the nucleus accumbens (NAc) of rats affects the development of cocaine-induced behavioral sensitization by mediating its perinucleus internalization and membrane expression. By immunofluorescent labeling, flow cytometry analysis, Co-immunoprecipitation and open field test, we measured the role of Ca2+ /calmodulin-dependent protein kinase II (CaMKII) to the control of GABAB R membrane anchoring and cocaine induced-behavioral sensitization. Repeated cocaine treatment in rats (15 mg/kg) significantly decreases membrane levels of GABAB1 R and GABAB2 R in the NAc after day 3, 5 and 7. The membrane fluorescence and protein levels of GABAB R was also decreased in NAc GAD67 + neurons post cocaine (1 μM) treatment after 5 min. Moreover, the majority of internalized GABAB1 Rs exhibited perinuclear localization, a decrease in GABAB1 R-pHluroin signals was observed in cocaine-treated NAc neurons. By contrast, membrane expression of phosphorylated CaMKII (pCaMKII) post cocaine treatment was significantly increased after day 1, 3, 5 and 7. Baclofen blocked the cocaine induced behavioral sensitization via inhibition of cocaine enhanced-pCaMKII-GABAB1 R interaction. These findings reveal a new mechanism by which pCaMKII-GABAB R signaling can promote psychostimulant-induced behavioral sensitization.

Phosphorylation of GluA1-Ser831 by CaMKII Activation in the Caudate and Putamen Is Required for Behavioral Sensitization After Challenge Nicotine in Rats.

BackgroundPhosphorylation of the glutamate receptor (GluA1) subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor plays a crucial role in behavioral sensitization after exposure to psychostimulants. The present study determined the potential role of serine 831 (Ser831) phosphorylation in the GluA1 subunit of the caudate and putamen (CPu) in behavioral sensitization after challenge nicotine.MethodsChallenge nicotine (0.4 mg/kg) was administered subcutaneously (s.c.) after 7 days of repeated exposure to nicotine (0.4 mg/kg, s.c.) followed by 3 days of withdrawal in rats. Bilateral intra-CPu infusions of drugs were mainly performed to test this hypothesis.ResultsChallenge nicotine increased both phosphorylated (p)Ser831 immunoreactivity (IR) and pCa2+/calmodulin-dependentprotein kinases II (pCaMKII)-IR in the medium spiny neurons (MSNs) of the CPu. These increases were prevented by bilateral intra-CPu infusion of the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP (0.5 nmol/side) and the N-methyl-D-aspartate (NMDA) receptor antagonist MK801 (2 nmol/side). However, the dopamine D1 receptor (D1R) antagonist SCH23390 (7.5 nmol/side) prevented only pSer831-IR alone. Bilateral intra-CPu infusion of the Tat-GluA1D peptide (25 pmol/side), which interferes with the binding of pCaMKII to GluA1-Ser831, decreased the challenge nicotine–induced increase in locomotor activity.ConclusionsThese findings suggest that the GluA1-Ser831 phosphorylation in the MSNs of the CPu is required for the challenge nicotine–induced behavioral sensitization in rats. CaMKII activation linked to mGluR5 and NMDA receptors, but not to D1R, is essential for inducing the CaMKII-Ser831 interaction.

Saffron (Crocus sativus L.) stigma reduces symptoms of morphine-induced dependence and spontaneous withdrawal in rats

ABSTRACT Background: Chronic morphine induces physical and psychological dependence signs. Saffron (Crocus sativus L.) stigma has been shown to have anxiolytic, antidepressant, and antinociceptive properties and to alleviate naloxone-precipitated withdrawal signs. Objectives: Therefore, this study was designed to examine the effects of saffron aqueous extract on the severity of physical-psychological dependence, voluntary morphine consumption, and the cerebrospinal fluid (CSF) serotonin levels following locomotor sensitization in morphine-dependent rats and in rats undergoing morphine withdrawal. Materials: Adult male rats were treated with morphine (10 mg/kg, sc twice daily) for 10 days. Rats received saffron extract (60 mg/kg, ip) daily, during the induction of morphine dependence and/or withdrawal. Then, rats were tested for spontaneous withdrawal signs, anxiety using the elevated plus-maze, depression using sucrose preference test, and voluntary morphine consumption using a two-bottle choice paradigm, and then challenged with morphine (1 mg/kg, ip) to evaluate of locomotor sensitization and CSF serotonin levels. Results: The results showed saffron extract during induction of morphine dependence decreased the severity of withdrawal signs (P = .05), while it had no effect on anxiety and depression-like behaviors. Saffron extract during morphine withdrawal exhibited an increase in the percentage (or ratio) of open/total arm entries (P = .017), higher levels of sucrose preference (P = .0001), a lower morphine preference ratio (P = .02) and also, a decrease in locomotor activity (P = .004) and an increase in the CSF serotonin levels (P = .041) in rats challenged to morphine. Conclusions: Saffron extract may exert a protective effect against morphine-induced behavioral sensitization in rats, probably through increasing serotonin levels.

Molecular changes in the nucleus accumbens and prefrontal cortex associated with the locomotor sensitization induced by coca paste seized samples.

In previous studies, we have demonstrated that seized samples of a smokable form of cocaine, also known as coca paste (CP), induced behavioral sensitization in rats. Interestingly, this effect was accelerated and enhanced when the samples were adulterated with caffeine. While the cocaine phenomenon is associated with persistent functional and structural alterations in the prefrontal cortex (PFC) and nucleus accumbens (NAc), the molecular mechanisms underlying the CP sensitization and the influence of caffeine remains still unknown. We examined the gene expression in NAc and mPFC after the expression caffeine-adulterated and non-adulterated CP locomotor sensitization. The locomotor sensitization was established in C57BL/6 mice, repeatedly treated with a CP-seized sample adulterated with caffeine (CP-2) and a non-adulterated one (CP-1). We then assessed the mRNA expression of receptor subunits of the dopaminergic and glutamatergic systems in the medial PFC (mPFC) and NAc. Other molecular markers (e.g., adenosinergic, endocannabinoid receptor subunits, and synaptic plasticity-associated genes) were also analyzed. Only CP-2-treated mice expressed locomotor sensitization. This phenomenon was associated with increased Drd1a, Gria1, Cnr1, and Syn mRNA expression levels in the NAc. Drd3 mRNA expression levels were only significantly increased in mPFC of CP-2-treated group. Our results demonstrated that caffeine actively collaborates in the induction of the molecular changes underlying CP sensitization. The present study provides new knowledge on the impact of active adulterants to understand the early dependence induced by CP consumption.

Repeated restraint stress potentiates methylphenidate and modafinil-induced behavioral sensitization in rats.

Stress increases the susceptibility of drug abuse and drugs of abuse impair behavioral tolerance. It has been shown that stress exposure enhances the sensitivity to the reinforcing properties of drugs, augments locomotor sensitization effects of drugs of abuse and impairs behavioral tolerance. Previously, it has been shown that long-term administration of psychostimulants (Methylphenidate and Modafinil) induced locomotor sensitization effect that was more pronounced after 13days of drug administration and was greater at high dose. The present study is designed to investigate the relationship between restraint stress and psychostimulants (Methylphenidate and Modafinil) that induced sensitization. Methylphenidate (10mg/kg/day twice a day), modafinil (75mg/kg/day once daily), and saline (0.9% NaCl; 1ml/kg/day) were administered orally to treated and control animals. Rats were exposed to immobilization stress for 30days (until locomotor sensitization produced) to monitor any change in drug-induced behavioral sensitization. The motor activity was compared daily by using familiar environment of home cage and weekly by novel environment of open field. The results show that the methylphenidate and modafinil-induced locomotor sensitization is enhanced and impaired behavioral tolerance in repeated restrained rats. It shows that the psychostimulants like methylphenidate and modafinil produce greater locomotor sensitization in stressful environment, suggesting addictive effects of stress and psychostimulants (methylphenidate/modafinil) on dopaminergic neurotransmission. These finding may be helpful to develop potential pharmacotherapies for the patients with co-occurring depression and substance abuse/dependence disorder.

Cocaine + nicotine mixture enhances induction and expression of behavioral sensitization in rats

BackgroundPsychoactive substance abuse is a health problem worldwide. Has been reported a high prevalence of use of tobacco and cocaine, either separately or in combination. Clinical and animal studies have suggested that the concurrent use of cocaine and nicotine reinforces the potency of one or both drugs and that nicotine may enhance the reinforcing effects of cocaine. Our study evaluated the combined effects of cocaine and nicotine on locomotor activity during the induction and expression phases of locomotor sensitization—a physiological mechanism that plays an important role in establishing some of the defining characteristics of drug abuse. MethodsWe used Wistar rats which were dosed with cocaine, nicotine or cocaine and nicotine combination and recorded their locomotor activity in different phases of the experiment. ResultsWe found that a daily dose of cocaine combined with nicotine enhanced cocaine- and nicotine-induced locomotor activity, as well as induction and expression of locomotor sensitization. Moreover, we found that pretreatment with nicotine enhanced the locomotor sensitization expression. ConclusionThese results suggest that concurrent use of cocaine and nicotine may result in co-abuse of these drugs.

Muscarinic receptors in the nucleus accumbens shell play different roles in context-induced or morphine-challenged expression of behavioral sensitization in rats

Both drug-related cues and drug priming are the main factors that induce relapse of drug addiction. Previous research has reported that blockade of the muscarinic receptors could significantly depress addictive behavior, suggesting that the muscarinic receptors might be involved in drug use and relapse behavior. The nucleus accumbens (NAc), especially the shell of the NAc, where the muscarinic receptors are expressed, is critical for craving and relapse. This study investigated the effects of microinfusion of the muscarinic receptor antagonist scopolamine into the NAc shell on context- and morphine-induced expression of behavioral sensitization. Behavioral sensitization was established by exposure to 5mg/kg morphine once daily for five consecutive days. Expression of behavioral sensitization was induced by saline challenge or 5mg/kg morphine challenge. The results showed that: (a) the muscarinic receptor antagonist scopolamine (10.8μg/rat) microinjected into the NAc shell blocked expression of conditional sensitization; (b) acetylcholinesterase inhibitor huperzine-A (0.5 and 0.1μg/rat), but not scopolamine (10.8μg/rat), microinjected into the NAc shell blocked morphine-induced expression of sensitization; and (c) pre-infusion of scopolamine (10.8μg/rat) reversed the inhibitory effect of huperzine-A (0.5μg/rat) on morphine-induced sensitization. Our findings suggest that muscarinic receptors in the NAc shell play different roles in context-induced and morphine-challenged expression of behavioral sensitization.

Muscarinic acetylcholine receptor but not nicotinic acetylcholine receptor plays a role in morphine-induced behavioral sensitization in rats

Background and AimThe cholinergic system can affect drug reward. The present study aimed to examine the roles of muscarinic acetylcholine receptor (mAChR) and nicotinic acetylcholine receptor (nAChR) in morphine-induced behavioral sensitization. MethodsTo analyze the roles of mAChR and nAChR in behavioral sensitization induced by morphine (5mg/kg), seven experiments were designed. Experiments 1 and 2 examined the effects of 3, 1, and 0.3 mg/kg scopolamine and 0.2, 0.1, and 0.05mg/kg scopolamine, respectively, on the locomotor activity when administered alone. Experiments 3 and 4 explored the effect of scopolamine on morphine-induced behavioral sensitization. Experiment 5 studied the effect of mecamylamine on morphine-induced behavioral sensitization. Experiments 6 and 7 investigated the effects of scopolamine+huperzine A and mecamylamine+huperzine A, respectively, on morphine-induced behavioral sensitization. ResultsThe results revealed that 3mg/kg scopolamine, which significantly enhanced locomotor activity when administered alone, inhibited the acquisition of morphine-induced sensitization. However, mecamylamine (0.5, 1, 2mg/kg) did not have these effects. The co-administration of scopolamine (0.05 mg/kg)+huperzine A (0.4mg/kg) or mecamylamine (1mg/kg)+huperzine A (0.4mg/kg) did not affect the acquisition of morphine-induced behavioral sensitization. Scopolamine (0.05mg/kg) which did not affect the locomotor activity when administered alone, but not mecamylamine (1mg/kg), reversed the acute attenuation effect of huperzine A (0.4mg/kg) on morphine-induced locomotor activity at the acquisition stage and reversed the inhibition of huperzine A on the expression of morphine-induced sensitization. ConclusionThe mAChR might play a more important role in morphine-induced locomotor activity and the expression of morphine-induced behavioral sensitization. The mechanisms of mAChR and nAChR were relatively separate in morphine-induced sensitization.

Characteristics of ethanol-induced behavioral sensitization in rats: Molecular mediators and cross-sensitization between ethanol and cocaine

Repeated exposure to drugs of abuse can induce a progressive increase in locomotor activity, known as behavioral sensitization. However, little is known about behavioral sensitization to ethanol. We examined whether ethanol could induce behavioral sensitization and investigated several molecular changes accompanying sensitization. We also assessed whether “cross-sensitization” occurred between ethanol and cocaine, another abused drug. Ethanol-induced sensitization was examined in rats after ethanol treatment (0.5 or 2g/kg) for 15days. The biochemical effects of low- or high-dose ethanol were examined in terms of N-methyl-d-aspartate (NMDA) receptor subunit phosphorylation or expression. Neuronal activity after ethanol treatment was assessed by measuring the level of early growth response (Egr-1) expression. Ethanol-induced behavioral sensitization was observed at the low dose (0.5g/kg) but not the high dose (2g/kg). Although acute treatment with the sensitizing dose of ethanol robustly increased Egr-1 protein and mRNA levels, the expression and phosphorylation of NMDA receptor subunits were not affected. The biochemical responses to ethanol seemed to be enhanced in ethanol-sensitized animals. Cross-sensitization between ethanol and cocaine was observed, which supports the hypothesis that there are commonalities among substances in the pathophysiology of substance dependence.

Dose- and time-dependent effects of mirtazapine on the expression of cocaine-induced behavioral sensitization in rats

Relapse to cocaine use is a major problem in the clinical treatment of cocaine dependence. Antidepressant medications have been studied as potential therapeutic drugs to relieve a cocaine dependence disorder. Mirtazapine is an antidepressant implicated in reducing behavioral alterations induced by drugs of abuse. We have reported elsewhere that 30mg/kg mirtazapine administered for 30 days during cocaine extinction significantly attenuated the induction and expression of cocaine-induced locomotor sensitization and decreased the duration of the cocaine-induced locomotor effect. This study focused on exploring whether different mirtazapine dosing regimens could optimize and/or improve the effect of 30mg/kg mirtazapine administered for 30 days on cocaine-induced locomotor activity during the expression phase of behavioral sensitization. Our study revealed that the daily dosing regimen with a fixed dose of mirtazapine (30mg/kg ip) over 60 days improved the decrease in cocaine-induced locomotor activity and behavioral sensitization obtained by dosing of 30mg mirtazapine for 30 days. In addition, it showed that a dosing regimen of 30mg/Kg mirtazapine for 30 days managed to reduce cocaine toxicity. These results suggested that dosage of mirtazapine for 30 consecutive days may be an effective therapy.

The role of adenylyl cyclase in the medial prefrontal cortex in cocaine-induced behavioral sensitization in rats

Repeated exposure to cocaine progressively increases drug-induced locomotor activity, which is termed behavioral sensitization. Previous research has demonstrated that in the medial prefrontal cortex (mPFC) modulation of cocaine-induced motor activity by agonists of Gi-coupled receptors, such as dopamine D2, GABAB and Group II metabotropic glutamate receptors, is reduced in sensitized animals, suggesting a loss in receptor function. Stimulation of each of these receptors acts in part to inhibit adenylyl cyclase activity, and thus, the formation of cAMP. The present studies tested the hypothesis that intra-mPFC inhibition of adenylyl cyclase by infusion of an inhibitor, SQ22536, could bypass the loss of inhibitory receptor function seen in this region, and thereby inhibit the expression of cocaine sensitization. Additional studies determined whether activation of mPFC adenylyl cyclase with NKH 477 could enhance the motor-stimulant response to cocaine. Initial studies demonstrated that cocaine-induced (15 mg/kg, i.p.) motor activity was dose-dependently reduced by injection of SQ22536 (5-75 nmol/side) into the mPFC, whereas NKH 477 (1.25–40 nmol/side) produced no significant effects. Additional studies showed that intra-mPFC injection of SQ22536 (50 nmol/side) attenuated the initiation of cocaine-induced behavioral sensitization and blocked the expression of sensitization following 1, 7 or 30 days of abstinence from cocaine. Also, intra-mPFC injection of NKH 477 enhanced cocaine-induced behavioral sensitization following 21 days of abstinence from cocaine. The results of the present study suggest modulation of adenylyl cyclase in the medial prefrontal cortex plays a key role in the expression of cocaine sensitization.

Mirtazapine prevents induction and expression of cocaine-induced behavioral sensitization in rats

Cocaine abuse is a major health problem worldwide. Treatment based on both 5-HT2A/C and 5-HT3 receptor antagonists attenuate not only the effects of cocaine abuse but also the incentive/motivational effect related to cocaine-paired cues.Mirtazapine, an antagonist of postsynaptic α2-adrenergic, 5-HT2A/C and 5HT3 receptors and inverse agonist of the 5-HT2C receptor, has been shown to effectively modify, at the preclinical and clinical levels, various behavioral alterations induced by drugs abuse. Therefore, it is important to assess whether chronic dosing of mirtazapine alters locomotor effects of cocaine as well as induction and expression of cocaine sensitization.Our results reveal that a daily mirtazapine regimen administered for 30days effectively induces a significant attenuation of cocaine-dependent locomotor activity and as well as the induction and expression of behavioral sensitization. These results suggest that mirtazapine may be used as a potentially effective therapy to attenuate induction and expression of cocaine-induced locomotor sensitization.

Repeated amphetamine injections alter behavior and induce a delayed behavioral sensitization modulated by reactivity to novelty: Similarities and differences with trauma consequences

Supporting our hypothesis of common biological bases for post-traumatic stress disorder (PTSD) and addiction, we recently reported that rats exposed to a single prolonged stress (SPS), a PTSD model, develop a delayed behavioral sensitization of the noradrenergic system, similar to that observed in mice after four repeated drug administrations. However, sensitization after trauma was modulated by reactivity to novelty, and this aspect that had not been explored in the addiction model. The first aim of the paper was thus to investigate the influence of reactivity to novelty on delayed behavioral sensitization in rats after four repeated amphetamine injections. Injections were either distributed over 4 days, as conducted in mouse models of addiction, or massed during a single session, reproducing SPS conditions. The second aim was to investigate whether repeated amphetamine injections have similar behavioral consequences to those induced by PTSD.Our results showed that massed amphetamine injections induced more anxiety than distributed injections, and led to avoidance of drug-associated cues avoidance, while distributed injections somewhat reduced the startle response, such as is seen in SPS. In addition, massed amphetamine injections induced a delayed behavioral sensitization clearly affected by the reactivity to novelty, reproducing results observed following exposure to traumatic events. Finally, all rats receiving repeated amphetamine injections exhibited a behavioral sensitization in response to exposure to drug-associated cues. Taken together, these data strengthen the position that drug addiction and PTSD share some common mechanisms that we tried to clarify in this paper.

The α1 adrenoceptors in ventrolateral orbital cortex contribute to the expression of morphine-induced behavioral sensitization in rats

The aim of the present study was to investigate the effect of microinjection of benoxathian, selective α1 adrenoceptor antagonist, into the ventrolateral orbital cortex (VLO) on morphine-induced behavioral sensitization and its underlying molecular mechanism in rats. A single morphine treatment protocol was used in establishing the behavioral sensitization model. The effect of bilateral intra-VLO benoxathian injection on locomotor activity was examined and the protein expression levels of α1 adrenoceptors and activation of extracellular signal-regulated kinase (ERK) in the VLO were detected after locomotor test. The results showed that a single injection of morphine could induce behavioral sensitization by a low challenge dosage of morphine after a 7-days drug free period. Benoxathian significantly suppressed the expression but not the development of morphine-induced behavioral sensitization. Morphine treatment significantly elicited ERK phosphorylation and downregulated the expression level of α1 adrenoceptors in the VLO. In addition, intra-VLO benoxathian injection enhanced the expression levels of α1 adrenoceptors and phosphorylated ERK. These results suggest that α1 adrenoceptors in the VLO are involved in regulating the expression of morphine-induced behavioral sensitization. The effect of decreased locomotor activity by blocking α1 adrenoceptors might be associated with activation of ERK in the VLO.

Tipepidine increases dopamine level in the nucleus accumbens without methamphetamine-like behavioral sensitization

We previously reported that the novel antidepressant-like effect of tipepidine may be produced at least partly through the activation of mesolimbic dopamine neurons via inhibition of G protein-coupled inwardly rectifying potassium channels. In this study, we investigated whether tipepidine increases dopamine levels in the nucleus accumbens (NAc) in rats using an in vivo microdialysis technique. We further assessed whether tipepidine at antidepressant-like effective doses induces behavioral- and cross-sensitization of locomotor activity in rats using the open field test. We found that acute administration of tipepidine increased dopamine levels in the NAc in freely moving rats without increasing locomotor activity. Tipepidine at antidepressant-like effective doses (20 and 40mg/kg, i.p.) did not cause behavioral sensitization in rats. Furthermore, cross-sensitization between tipepidine and methamphetamine was not observed in rats. These results further support our working hypothesis that tipepidine may produce a novel antidepressant-like effect through activation of ventral tegmental area-NAc dopaminergic neurons whose mechanisms differ from those contributing to the reinforcing effects of addictive drugs.

Inhibition of apomorphine-induced behavioral sensitization in rats pretreated with fluoxetine.

Despite a number of clinically useful effects, there is growing evidence that psychosis and impulse control disorders develop in patients on apomorphine therapy. Evidence suggests a critical role of serotonin-1A receptors in psychosis, drug abuse, and in the mechanism of action of the prototypical selective serotonin reuptake inhibitor fluoxetine. We investigated whether fluoxetine can prevent apomorphine-induced behavioral sensitization in a rat model of psychosis. Animals treated with fluoxetine (5 and 10 mg/kg) for 2 weeks were subsequently cotreated with apomorphine (1.0 mg/kg) for 7 days. A single injection of apomorphine increased motor activity, whereas repeated daily injections produced a progressive sensitization of motor behavior. The sensitization effects of apomorphine did not occur in fluoxetine-pretreated and subsequently cotreated animals. To further elucidate the mechanism involved in the inhibition of apomorphine sensitization in fluoxetine-treated animals, we found that apomorphine-induced motor behavior was much greater in repeated apomorphine-treated than repeated saline-treated animals. It was also greater in apomorphine and fluoxetine-cotreated animals, but not in animals pretreated and cotreated with fluoxetine. The mechanism involved in the inhibition of apomorphine sensitization in fluoxetine-pretreated animals is discussed. The findings introduce an innovative approach for extending the therapeutic use of apomorphine and classical psychostimulant drugs.

Microinjection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens inhibits the cocaine-induced upregulation of dopamine receptors and locomotor sensitization

Repeated exposure to addictive drugs enhances dopamine receptor (DR) signaling and the ultimate phosphorylation of the cyclic adenosine 5′-monophosphate (cAMP)-response element-binding protein (CREB)-regulated cocaine- and amphetamine-regulated transcript (CART) expression in the nucleus accumbens (NAcc). These effects are known to contribute to the expression of behavioral sensitization. CART peptides are neuropeptides that modulate drug reward and reinforcement. The present experiments investigated the effects of CART 55–102 microinjection into the NAcc on (1) the phosphorylation of CREB, (2) cAMP/protein kinase A (PKA) signaling and (3) extracellular signal-regulated kinase (ERK) phosphorylated kinase signaling. Here, we show that repeated microinjections into the NAcc of CART 55–102 peptides (1.0 or 2.5μg, 0.5μl/side) attenuates cocaine-induced enhancements of D1R, D2R and D3R phosphorylation in this sites. Furthermore, the microinjection of CART 55–102 followed by repeated injections of cocaine (15mg/kg) dose-dependently blocked the enhancement of cAMP levels, PKA activity and pERK and pCREB levels on the fifth day of cocaine administration. The cocaine-induced locomotor activity and behavioral sensitization in rats were also inhibited by the 5-day-microinjection of CART peptides. These results suggest that the phosphorylation of CREB by cocaine in the NAcc was blocked by the CART 55–102 peptide via the inhibition of D1R and D2R stimulation, D3R phosphorylation, cAMP/PKA signaling and ERK phosphorylated kinase signaling. These effects may have played a compensatory inhibitory role in the behavioral sensitization of rats that received microinjections of CART 55–102.

The trace amine associated receptor 1 agonist RO5263397 attenuates the induction of cocaine behavioral sensitization in rats

The trace amine associated receptor (TAAR) 1 is a new G protein coupled receptor that critically modulates central dopaminergic system. Recently, several selective TAAR 1 ligands have been described to possess antipsychotic and antidepressant-like activities. However, it is unknown of the role of these ligands in modulating psychostimulant-induced neurobehavioral plasticity. This study examined the effects of a selective TAAR 1 agonist, RO5263397, on cocaine induced behavioral sensitization in rats, a rodent model of drug-induced behavioral plasticity. Daily treatment with 15mg/kg cocaine (i.p., 7 days) induced robust locomotor sensitization in rats. RO5263397 (1–10mg/kg, i.p.) alone did not significantly alter the locomotor activity. Acute treatment with RO5263397 (3.2 and 10mg/kg) did not significantly modify cocaine-induced hyperactivity; however, the induction of locomotor sensitization was significantly blocked after 7 days of daily RO5263397 treatment. More importantly, the expression of locomotor sensitization remained significantly attenuated when rats were re-tested 7 days after the last drug treatment. The marked attenuation of cocaine sensitization was also evidenced by the suppression of the dose-effect function (3.2–32mg/kg) of cocaine sensitization. Together, these data represent the first to report a critical modulatory role of TAAR 1 agonists in cocaine-induced behavioral plasticity, which may be indicative of its potential role for altering other long-lasting behavioral maladaptations of cocaine including drug addiction.