Synergistic effects of MDMA and ethanol on behavior: Possible effects of ethanol on dopamine D2 -receptor-related signaling.

Polydrug abuse is common among drug abusers. In particular, psychostimulants are often taken with ethanol, and the combination of 3,4-methylenedioxymethamphetamine (MDMA) and alcohol is one of the most common forms of polydrug abuse. However, the mechanism by which these drugs influence behavior remains unclear. The present study was designed to delineate the mechanisms that underlie the effects of the interaction between MDMA and ethanol on behavior in rodents. The combination of MDMA with ethanol enhanced their locomotor-increasing, rewarding, and discriminative stimulus effects without enhancing their effects on the release of dopamine from the nucleus accumbens in rodents. In addition, ethanol potently enhanced locomotor activity produced by the dopamine receptor agonist apomorphine in mice. In antagonism tests, the dopamine D1 -receptor antagonist SCH23390, but not the D2 -receptor antagonist haloperidol, completely suppressed hyperlocomotion induced by MDMA. However, hyperlocomotion induced by the co-administration of MDMA and ethanol was potently suppressed by haloperidol. These results suggest that the synergistic effects of MDMA and ethanol are mediated through dopamine transmission, especially through postsynaptical regulation of D2 -receptor-mediated functions.

Effect of ghrelin on the motor deficit caused by the ablation of nigrostriatal dopaminergic cells or the inhibition of striatal dopamine receptors.

Ghrelin plays roles in a wide range of central functions by activating the growth hormone secretagogue receptor (GHSR). This receptor has recently been found in the substantia nigra (SN) to control dopamine (DA)-related physiological functions. The dysregulation of DA neurons in the SN pars compacta (SNc) and the consequent depletion of striatal DA are known to underlie the motor deficits observed in Parkinson's disease (PD). In the present study, we further investigated the role of the SN-ghrelin system in motor function under the stereotaxic injection of AAV-CMV-FLEX-diphtheria toxin A (DTA) into the SN of dopamine transporter (DAT)-Cre (DATSN::DTA) mice to expunge DA neurons of the SNc. First, we confirmed the dominant expression of GHSR1a, which is a functional GHSR, in tyrosine hydroxylase (TH)-positive DA neurons in the SNc of control mice. In DATSN::DTA mice, we clearly observed motor dysfunction using several behavioral tests. An immunohistochemical study revealed a dramatic loss of TH-positive DA neurons in the SNc and DAT-labeled axon terminals in the striatum, and an absence of mRNAs for TH and DAT in the SN of DATSN::DTA mice. The mRNA level of GHSR1a was drastically decreased in the SN of these mice. In normal mice, we also found the mRNA expression of GHSR1a within GABAergic neurons in the SN pars reticulata (SNr). Under these conditions, a single injection of ghrelin into the SN failed to improve the motor deficits caused by ablation of the nigrostriatal DA network using DATSN::DTA mice, whereas intra-SN injection of ghrelin suppressed the motor dysfunction caused by the administration of haloperidol, which is associated with the transient inhibition of DA transmission. These findings suggest that phasic activation of the SNc-ghrelin system could improve the dysregulation of nigrostriatal DA transmission related to the initial stage of PD, but not the motor deficits under the depletion of nigrostriatal DA. Although GHSRs are found in non-DA cells of the SNr, GHSRs on DA neurons in the SNc may play a crucial role in motor function.

Changes in the expression of IL-6-Mediated MicroRNAs in the dorsal root ganglion under neuropathic pain in mice.

A multiplex analysis for profiling the expression of candidate microRNAs (miRNAs), which are small noncoding RNAs that function as key post-transcriptional regulators, may lead to a better understanding of the complex machinery of neuropathic pain. In the present study, we performed a miRNA array analysis using tissues of the dorsal root ganglion (DRG), a primary site for pain processing, obtained from mice with partial sciatic nerve ligation. Among 1135 total miRNAs, 26 miRNAs showed up-regulation (more than 2-fold change) and only 4 miRNAs showed down-regulation (less than 0.5-fold change) in the DRG of nerve-ligated mice. In a RT-qPCR assay, the levels of miR-21, miR-431, and miR-511-3p were significantly increased on the ipsilateral side of the DRG from 3 to 7 days after sciatic nerve ligation. These elevations were almost absent in IL-6 knockout mice. Furthermore, the expression level of miR-21, but not those of miR-431 or miR511-3p, was significantly increased in exosomes extracted from blood of nerve-ligated mice. These findings suggest that the increased expression of IL-6-regulated miR-21, miR-431, and miR-511-3p in the DRG and increased exosomal miR-21 extracted from blood after sciatic nerve ligation may play at least a partial role in neuropathic pain. Synapse 70:317-324, 2016. © 2016 Wiley Periodicals, Inc.

Effects of (+)-pentazocine on the antinociceptive effects of (-)-pentazocine in mice.

Previous studies have shown that sigma-1 receptor chaperone (Sig-1R) ligands can regulate pain-related behaviors, and Sig-1R itself can regulate µ-opioid receptor functions as well as signal transduction. Even though (±)-pentazocine has been used clinically for the treatment of pain through opioid receptors, (+)-pentazocine is known to be a selective Sig-1R agonist. To the best of our knowledge, there is no information available regarding the involvement of Sig-1R agonistic action in the antinociceptive effects of (±)-pentazocine. Therefore, the present study was designed to investigate the effects of (+)-pentazocine on the antinociceptive effects of (-)-pentazocine in mice. Both and (-)-pentazocine induced biphasic antinociceptive effects as measured by the warm-plate test. The early phase, but not the delayed phase, of the antinociceptive effects induced by (-)-pentazocine, which are mediated by the activation of µ-opioid receptors, were suppressed by pretreatment with (+)-pentazocine. These results suggest that the innate antinociceptive action of (±)-pentazocine could be marginally reduced by the effects of (+)-pentazocine, but (+)-pentazocine can suppress the antinociceptive effects of (-)-pentazocine at certain time points.

Involvement of µ- and δ-opioid receptor function in the rewarding effect of (±)-pentazocine.

Most opioid receptor agonists have abuse potential, and the rewarding effects of opioids can be reduced in the presence of pain. While each of the enantiomers of pentazocine has a differential pharmacologic profile, (±)-pentazocine has been used clinically for the treatment of pain. However, little information is available regarding which components of pentazocine are associated with its rewarding effects, and whether the (±)-pentazocine-induced rewarding effects can be suppressed under pain. Therefore, the present study was performed to investigate the effects of pain on the acquisition of the rewarding effects of (±)-pentazocine, and to examine the mechanism of the rewarding effects of (±)-pentazocine using the conditioned place preference paradigm. (±)-Pentazocine and (-)-pentazocine, but not (+)-pentazocine, produced significant rewarding effects. Even though the rewarding effects induced by (±)-pentazocine were significantly suppressed under pain induced by formalin, accompanied by increase of preprodynorphin mRNA levels in the nucleus accumbens, a high dose of (±)-pentazocine produced significant rewarding effects under pain. In the normal condition, (±)-pentazocine-induced rewarding effects were blocked by a low dose of naloxone, whereas the rewarding effects induced by high doses of pentazocine under pain were suppressed by naltrindole (a δ-opioid receptor antagonist). Interestingly, (±)-pentazocine did not significantly affect dopamine levels in the nucleus accumbens. These findings suggest that the rewarding effects of (-)-pentazocine may contribute to the abuse potential of (±)-pentazocine through µ- as well as δ-opioid receptors, without robust activation of the mesolimbic dopaminergic system. We also found that neural adaptations can reduce the abuse potential of (±)-pentazocine under pain.

Differential substitution for the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine and methylphenidate in rats.

Previous studies have demonstrated that methylphenidate, MDMA (3,4-methylenedioxymethamphetamine), and other psychostimulants exert stimulant-like subjective effects in humans. Furthermore, MDMA and methylphenidate substitute for the discriminative stimulus effects of psychostimulants, such as amphetamine and cocaine, in animals, which suggests that MDMA and methylphenidate may produce similar discriminative stimulus effects in rats. However, there is no evidence regarding the similarities between the discriminative stimulus effects of MDMA and methylphenidate. To explore this issue, cross-substitution, substitution, and combination tests were conducted in rats that had been trained to discriminate between MDMA (2.5 mg/kg) or methylphenidate (5.0 mg/kg) and saline. In the cross-substitution tests, MDMA and methylphenidate did not cross-substitute for each other. In the substitution test, methamphetamine substituted for the discriminative stimulus effects of methylphenidate, but not for those of MDMA. Furthermore, ephedrine and bupropion, which activate dopaminergic and noradrenergic systems, substituted for the discriminative stimulus effects of methylphenidate. On the other hand, serotonin (5-HT) receptor agonists 5-HT1A and 5-HT2 fully substituted for the discriminative stimulus effects of MDMA. These results suggest that activation of the noradrenergic and dopaminergic systems is important for the discriminative stimulus effects of methylphenidate, whereas activation of the serotonergic system is crucial for the discriminative stimulus effects of MDMA. Even though MDMA, like psychostimulants, exerts stimulant-like effects, our findings clearly indicate that the discriminative stimulus effects of MDMA are distinctly different from those of other psychostimulants in rats.

The contribution of Gi/o protein to opioid antinociception in an oxaliplatin-induced neuropathy rat model.

Oxaliplatin is a chemotherapeutic agent that induces chronic refractory neuropathy. To determine whether opioids effectively relieve this chronic neuropathy, we investigated the efficacies of morphine, oxycodone, and fentanyl, and the mechanisms underlying opioid antinociception, in oxaliplatin-induced neuropathy in rats. Rats exhibited significant mechanical allodynia following 2 weeks of chronic oxaliplatin administration. Within the range of doses that did not induce sedation and/or muscle rigidity, morphine (3 mg/kg, subcutaneously, s.c.) and oxycodone (0.3-0.56 mg/kg, s.c.) completely reversed oxaliplatin-induced mechanical allodynia, whereas fentanyl (0.017-0.03 mg/kg, s.c.) showed partial antinociception. The antinociception of the optimal doses of morphine and oxycodone were completely inhibited by pertussis toxin (PTX; 0.5 µg/rat, i.c.v.), a Gi/o protein inhibitor, while the partial effect of fentanyl was not affected in the oxaliplatin model. In the [(35)S]-GTPγS binding assay, activation of µ-opioid receptor by fentanyl, but not by morphine or oxycodone, in the mediodorsal thalamus was significantly reduced in oxaliplatin-treated rats. These results indicate that the lower antinociceptive potency of fentanyl in the oxaliplatin model might in part result from the loss of PTX-sensitive Gi/o protein activation, and the degree of Gi/o protein activation might be related to the potency of antinociception by opioids in this model.

Establishment of opioid-induced rewarding effects under oxaliplatin- and Paclitaxel-induced neuropathy in rats.

The rewarding effects of µ-receptor agonists can be suppressed under several pain conditions. We recently showed that clinically used µ-receptor agonists possess efficacies for relieving the neuropathic pain induced by chemotherapeutic drug in rats; however, it is possible that the use of µ-receptor agonists may trigger the rewarding effects even under chemotherapeutic drug-induced neuropathic pain. Nevertheless, no information is available regarding whether µ-receptor agonists produce psychological dependence under chemotherapeutic drug-induced neuropathic pain. Therefore, we examined the effects of neuropathy induced by chemotherapeutic drugs on the rewarding effects of morphine, oxycodone, and fentanyl in rats. Repeated treatment with oxaliplatin or paclitaxel produced neuropathy as measured by the von Frey test. Rewarding effects produced by antinociceptive doses of µ-receptor agonists were not suppressed under oxaliplatin- or paclitaxel-induced neuropathy. Furthermore, the morphine-induced increase in the release of dopamine from the nucleus accumbens, which is a critical step in the rewarding effects of µ-receptor agonists, was not altered in paclitaxel-treated rats. These results suggest that the rewarding effects of µ-receptor agonists can still be established under oxaliplatin- or paclitaxel-induced neuropathic pain. Therefore, patients should be carefully monitored for psychological dependence on µ-receptor agonists when they are used to control chemotherapeutic drug-induced neuropathic pain.

Inhibitory effects of SA4503 on the rewarding effects of abused drugs.

Previous findings have shown that sigma-1 receptors (Sig-1Rs) are upregulated by the self-administration of methamphetamine, whereas Sig-1R antisense can attenuate the behavioral effects of psychostimulants in rodents. Sig-1R is an endoplasmic reticulum chaperone protein. However, the effects of Sig-1R agonist on the rewarding effects of abused drugs are not fully understood. Therefore, we examined the effects of selective Sig-1R agonists, such as SA4503 and (+)-pentazocine, on the rewarding effects of abused drugs such as methamphetamine, cocaine and morphine in rats, as measured by the conditioned place preference. Methamphetamine, cocaine and morphine induced a significant place preference. SA4503, but not (+)-pentazocine, significantly attenuated the abused drug-induced place preference. We recently showed that (+)-pentazocine exerts U50,488H-like discriminative stimulus effects, which are related to its psychotomimetic/aversive effects. However, SA4503 did not generalize to the discriminative stimulus effects of U50,488H. These results suggest that SA4503 inhibits the rewarding effects of abused drugs, and that psychotomimetic/aversive effects may not play a role in the attenuating effects of SA4503 on the rewarding effects of abused drugs.

Involvement of the K+-Cl- co-transporter KCC2 in the sensitization to morphine-induced hyperlocomotion under chronic treatment with zolpidem in the mesolimbic system.

Benzodiazepines are commonly used as sedatives, sleeping aids, and anti-anxiety drugs. However, chronic treatment with benzodiazepines is known to induce dependence, which is considered related to neuroplastic changes in the mesolimbic system. This study investigated the involvement of K(+) -Cl(-) co-transporter 2 (KCC2) in the sensitization to morphine-induced hyperlocomotion after chronic treatment with zolpidem [a selective agonist of γ-aminobutyric acid A-type receptor (GABAA R) α1 subunit]. In this study, chronic treatment with zolpidem enhanced morphine-induced hyperlocomotion, which is accompanied by the up-regulation of KCC2 in the limbic forebrain. We also found that chronic treatment with zolpidem induced the down-regulation of protein phosphatase-1 (PP-1) as well as the up-regulation of phosphorylated protein kinase C γ (pPKCγ). Furthermore, PP-1 directly associated with KCC2 and pPKCγ, whereas pPKCγ did not associate with KCC2. On the other hand, pre-treatment with furosemide (a KCC2 inhibitor) suppressed the enhancing effects of zolpidem on morphine-induced hyperlocomotion. These results suggest that the mesolimbic dopaminergic system could be amenable to neuroplastic change through a pPKCγ-PP-1-KCC2 pathway by chronic treatment with zolpidem.

Mechanisms that underlie µ-opioid receptor agonist-induced constipation: differential involvement of µ-opioid receptor sites and responsible regions.

Reducing the side effects of pain treatment is one of the most important strategies for improving the quality of life of cancer patients. However, little is known about the mechanisms that underlie these side effects, especially constipation induced by opioid receptor agonists; i.e., do they involve naloxonazine-sensitive versus -insensitive sites or central-versus-peripheral µ-opioid receptors? The present study was designed to investigate the mechanisms of µ-opioid receptor agonist-induced constipation (i.e., the inhibition of gastrointestinal transit and colonic expulsion) that are antagonized by the peripherally restricted opioid receptor antagonist naloxone methiodide and naloxonazine in mice. Naloxonazine attenuated the fentanyl-induced inhibition of gastrointestinal transit more potently than the inhibition induced by morphine or oxycodone. Naloxone methiodide suppressed the oxycodone-induced inhibition of gastrointestinal transit more potently than the inhibition induced by morphine, indicating that µ-opioid receptor agonists induce the inhibition of gastrointestinal transit through different mechanisms. Furthermore, we found that the route of administration (intracerebroventricular, intrathecally, and/or intraperitoneally) of naloxone methiodide differentially influenced the suppressive effect on the inhibition of colorectal transit induced by morphine, oxycodone, and fentanyl. These results suggest that morphine, oxycodone, and fentanyl induce constipation through different mechanisms (naloxonazine-sensitive versus naloxonazine-insensitive sites and central versus peripheral opioid receptors), and these findings may help us to understand the characteristics of the constipation induced by each µ-opioid receptor agonist and improve the quality of life by reducing constipation in patients being treated for pain.

Involvement of dopamine D2 receptor signal transduction in the discriminative stimulus effects of the κ-opioid receptor agonist U-50,488H in rats.

We have reported previously that the inhibition of both dopaminergic and psychotomimetic/hallucinogenic components plays a role in the discriminative stimulus effects of U-50,488H. However, the mechanisms that underlie the discriminative stimulus effects of U-50,488H, and especially the component that plays a significant role, have not yet been clarified. The present study was designed to further investigate the mechanism(s) of the discriminative stimulus effects of the κ-opioid receptor agonist U-50,488H in rats that had been trained to discriminate between 3.0 mg/kg U-50,488H and saline. The dopamine D2 receptor antagonist sulpiride, but not the D1 receptor antagonist SCH23390, generalized to the discriminative stimulus effects of U-50,488H. The mood-stabilizing agents lithium chloride and valproic acid, which have attenuating effects on the Akt/GSK3 pathway, also partially generalized to the discriminative stimulus effects of U-50,488H. In contrast, the 5-HT-related compound racemic 3,4-methylenedioxymethamphetamine, the cannabinoid receptor agonist WIN55,212-2, and the µ-opioid receptor agonist morphine failed to generalize to the discriminative stimulus effects of U-50,488H. These results suggest that the inhibition of the dopaminergic activity mediated by the postsynaptic D2 receptor, followed by suppression of the Akt/GSK3 pathway may be critical for the induction of the discriminative stimulus effects induced by U-50,488H.

Involvement of serotonin receptor mechanisms in the discriminative stimulus effects of ketamine in rats.

We have demonstrated previously that the ketamine-induced discriminative stimulus effect is likely to reflect the phencyclidine-like psychotomimetic effects. Therefore, the present study was designed to investigate the effects of the antipsychotics and 5-HT2 receptor antagonist on the discriminative stimulus effects of ketamine in rats. While sulpiride did not attenuate the discriminative stimulus effects of ketamine, both clozapine and ketanserin attenuated those of ketamine, suggesting that the discriminative stimulus effects of ketamine are mediated by multiple receptors, especially the 5-HT2 receptor, but not the D2 receptor. Furthermore, our findings imply that atypical antipsychotics could be useful for the treatment of psychotomimetic effects induced by ketamine.

Acamprosate suppresses ethanol-induced place preference in mice with ethanol physical dependence.

The present study investigated the effect of acamprosate on ethanol (EtOH)-induced place preference in mice with EtOH physical dependence. The expression of EtOH (2 g/kg, intraperitoneally)-induced place preference in mice without EtOH treatment before the experiment was dose-dependently suppressed by acamprosate. The levels of protein kinase A (PKA) and phospho-cAMP response element binding protein (p-CREB) in the limbic forebrain after EtOH-conditioning in naïve mice was unchanged. Furthermore, mice on the 4th day of withdrawal from continuous EtOH vapor inhalation for 9 days showed transient and significant enhancement of EtOH (1 g/kg, intraperitoneally)-induced place preference, which was significantly suppressed by acamprosate (300 mg/kg, oral administration; p.o., once a day) administered daily for 3 days after withdrawal from EtOH inhalation and during EtOH-conditioning. PKA and p-CREB proteins in the limbic forebrain of EtOH-conditioned mice on 4th day of withdrawal from continuous EtOH inhalation for 9 days significantly increased, which were completely abolished by acamprosate. These findings suggest that the signal transduction pathway via the PKA-p-CREB pathway in the limbic forebrain may be functionally related to the development of sensitization of EtOH-induced place preference and provide a possible molecular basis for the pharmacological effect of acamprosate to prevent or reduce the relapse of alcohol dependence.

Involvement of sigma 1 receptor in the SSRI-induced suppression of the methamphetamine-induced behavioral sensitization and rewarding effects in mice.

The abuse of methamphetamine causes abnormal behaviors which are indistinguishable from schizophrenia in humans. Recent reports have shown that selective serotonin reuptake inhibitors (SSRIs) have beneficial effects on methamphetamine-related behaviors, including behavioral sensitization and rewarding effects in animals. However, the exact mechanisms by which SSRIs affect methamphetamine-related behaviors are not yet clear. The present study was designed to investigate the effects of SSRIs on the development of methamphetamine-induced behavioral sensitization and rewarding effects in mice. Behavioral sensitization was measured by examining the locomotor activity of mice in a tilting cage after repeated injections of methamphetamine. Repeated administration of methamphetamine significantly induced a behavioral sensitization. Some SSRIs (fluoxetine and fluvoxamine), which have sigma-1 receptor agonistic activity, inhibited the development of methamphetamine-induced behavioral sensitization. Fluoxetine also dose-dependently attenuated the rewarding effects of methamphetamine as measured by the conditioned place preference paradigm. Furthermore, the sigma-1 receptor antagonist NE-100 significantly reversed the inhibitory effects of fluoxetine on methamphetamine-induced behavioral sensitization and rewarding effects. These results suggest that sigma-1 receptor agonistic activity might be involved in the attenuating effects of fluoxetine and fluvoxamine on methamphetamine-induced behavioral sensitization and rewarding effects.

Regulation of type 1 inositol 1,4,5-triphosphate receptor by dopamine receptors in cocaine-induced place conditioning.

Recent study shows that type 1 inositol-1,4,5-triphosohate receptors (IP(3) Rs) may be involved in amphetamine-induced conditioned preference, but little is known about its role in psychological dependence on cocaine. This study investigated the role and regulation of IP(3) R-1 in mice with cocaine-induced place preference. The cocaine-induced place preference was dose-dependently inhibited by intracerebroventricular pretreatment with IP(3) R antagonists, 2-aminophenoxyethane-borate (2-APB), and xestospongin C. The levels of IP(3) R-1 in the frontal cortex and nucleus accumbens of cocaine-conditioned mice significantly increased, which was completely abolished by SCH23390 and sulpiride, selective dopamine D1 and D2 receptor antagonists, respectively. These findings suggest that IP(3) R-1-mediated intracellular signaling pathway may play an important role in the development of cocaine-induced place preference and that the expression of IP(3) R-1 is controlled by both dopamine D1 and D2 receptors in the frontal cortex and nucleus accumbens of mice with cocaine-induced place preference.

Effects of dronabinol on morphine-induced dopamine-related behavioral effects in animals.

The present study examined the effects of dronabinol, a United States FDA-approved synthetic cannabinoid receptor agonist, on morphine (a prototypic µ-opioid receptor agonist)-induced dopamine-related behaviors in animals. Dronabinol suppressed the rewarding effects of morphine in rats and its emetic effects in ferrets. Furthermore, the morphine-induced increase in dopamine release from the nucleus accumbens was significantly attenuated by dronabinol, which indicated that the suppressive effects of dronabinol on morphine-induced behaviors are at least in part mediated by regulation of the dopaminergic system. Since cannabinoid receptor agonists have been shown to enhance the antinociceptive effects of morphine, the use of dronabinol as an adjuvant could be useful for preventing the adverse effects of µ-opioid receptor agonists when used to control pain.

Olanzapine suppresses the rewarding and discriminative stimulus effects induced by morphine.

Atypical antipsychotic medications are effective for treating both the positive and negative symptoms of schizophrenia. Olanzapine is an atypical antipsychotic that blocks dopaminergic, serotonergic, adrenergic, histaminergic, and muscarinic receptors. In this study, we used rodents to investigate whether olanzapine could suppress the hyperlocomotion, rewarding effect, and discriminative stimulus effect induced by the prototypic µ-opioid morphine, which are all considered to reflect the abuse potential or psychoactive effects of µ-opioids. Olanzapine at doses that failed to induce motor coordination produced a dose-dependent reduction in hyperlocomotion induced by morphine in mice. Olanzapine at a dose that did not produce motor dysfunction also inhibited the significant place preference induced by morphine in mice. Furthermore, the discriminative stimulus effect induced by morphine in rats was dose-dependently and significantly attenuated by olanzapine at the dose that did not induce the motor dysfunction. These results suggest that treatment with both µ-opioids and olanzapine at a dose lower than that at which it induces motor dysfunction could be very useful for preventing the abuse potential and/or psychoactive effects of µ-opioids.

Actin dynamics in development of behavioral sensitization after withdrawal from long-term ethanol administration to mice.

BACKGROUND AND METHODS: The present study investigated the role of actin depolymerizing factor (ADF) in the brain of mice after withdrawal from continuous ethanol (EtOH) vapor inhalation for 9 days using C57BL/6J and ADF mutant mice. RESULTS: C57BL/6J mice with withdrawal signs 10 hours after withdrawal from EtOH vapor inhalation showed transient and significant enhancement of locomotor activity by a single injection of EtOH (2 g/kg, i.p.) and of EtOH-induced place preference 3 days after withdrawal from EtOH vapor inhalation, suggesting the development of sensitization of locomotion activity to EtOH and of place preference 3 days after withdrawal from EtOH in C57BL/6J mice with EtOH physical dependence. The levels of ADF and G-actin in the ventral tegmental area, including a little bit of surrounding tissues, increased immediately (0 hours), 10 hours, and 3 days after withdrawal from EtOH vapor. F-actin, synaptic vesicle-associated protein 38, and postsynaptic density 95 increased 0 hours and 3 days after withdrawal with their decreases 10 hours after withdrawal from EtOH vapor. An F-actin stabilizing agent phalloidin (3 nmol/mouse/d, i.c.v., once a day) administered daily for 3 days after withdrawal from continuous EtOH vapor inhalation for 9 days significantly suppressed the increase in both EtOH-induced place preference and locomotor activity by a single injection of EtOH 3 days after withdrawal from long-term EtOH vapor inhalation for 9 days. In addition, the changes in behavioral sensitization in ADF mutant mice were significantly weaker than those observed in C57BL/6J mice (wild-type mice for ADF mutant mice). CONCLUSIONS: The findings presented here suggest that withdrawal from EtOH physical dependence causes behavioral sensitization to EtOH, which may be, at least in part, mediated by alternation of actin dynamics.

Discriminative stimulus effects of hallucinogenic drugs: a possible relation to reinforcing and aversive effects.

The subjective effects of drugs are related to the kinds of feelings they produce, such as euphoria or dysphoria. One of the methods that can be used to study these effects is the drug discrimination procedure. Many researchers are trying to elucidate the mechanisms that underlie the discriminative stimulus effects of abused drugs (e.g., alcohol, psychostimulants, and opioids). Over the past two decades, the patterns of drug abuse have changed, so that club/recreational drugs such as phencyclidine (PCP), 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD), and ketamine, which induce perceptual distortions, like hallucinations, are now more commonly abused, especially in younger generations. However, the mechanisms of the discriminative stimulus effects of hallucinogenic drugs are not yet fully clear. This review will briefly focus on the recent findings regarding hallucinogenic/psychotomimetic drug-induced discriminative stimulus effects in animals. In summary, recent research has demonstrated that there are at least two plausible mechanisms that can explain the cue of the discriminative stimulus effects of hallucinogenic drugs; one is mediated mainly by 5-HT(2) receptors, and the other is mediated through sigma-1 (σ(1))-receptor chaperone regulated by endogenous hallucinogenic ligand.