Nicotine suppresses energy storage through activation of sympathetic outflow to brown adipose tissue via corticotropin-releasing factor type 1 receptor

Nicotine is known to stimulate energy expenditure, although the precise mechanism is unclear. To clarify the involvement of corticotropin-releasing factor (CRF) in the mechanism by which nicotine increases energy expenditure, the effect of intraperitoneal injection of nicotine (0.1 or 0.5 mg/kg) on the release of noradrenaline (NA), a stimulator of thermogenesis, in brown adipose tissue (BAT) important for energy expenditure was examined in rats. We also examined the effects of CRF receptor subtype antagonists on the nicotine-induced change in BAT NA release. Nicotine significantly increased BAT NA release at a dose of 0.5 mg/kg, and the increase was completely blocked by antalarmin, a CRF type 1 receptor antagonist, but not by antisauvagine-30, a CRF type 2 receptor antagonist. These results suggest that nicotine increases energy expenditure by activating BAT function, and that CRF type 1 receptors are involved in the mechanism by which nicotine affects energy balance.     

Minocycline affects cocaine sensitization in mice

Growing evidence has pointed to an interaction between the tetracycline antibiotic minocycline and drugs with abuse liability such as opioids and amphetamines. In this work, we tested the hypothesis that similar to its effects on methamphetamine-induced locomotor sensitization, minocycline may influence the behavioral effects of cocaine. Experiments were performed in male C57BL/6J mice using an automated system to measure locomotor activity. We found that 80 mg/kg minocycline significantly reduced locomotor activity when administered either alone or injected 30 min prior to cocaine, which increased locomotor activity. To investigate whether minocycline selectively affects the development of locomotor sensitization induced by four daily injections of 10 mg/kg cocaine, we sought a schedule of minocycline administration that does not per se affect locomotor activity. Thus, we selected 40 mg/kg minocycline administered 3 h prior to cocaine; minocycline did not affect cocaine-stimulated locomotor activity on the first day of administration but prevented the development of cocaine sensitization. We also tested whether minocycline would affect an already established cocaine sensitization. After establishing the sensitization effect by four daily injections, cocaine treatment was discontinued and mice were treated with minocycline daily (days 5–11) or on day 11 only. There was no effect of minocycline treatment on the response of cocaine-sensitized mice to the challenge dose of cocaine on day 11. The mechanisms by which minocycline interferes with the development of cocaine sensitization need to be characterized.     

The suppression of endogenous adrenalin in the prolongation of ketamine anesthesia

This study investigated whether or not the anesthetic effect of ketamine in rats is dependent on adrenal gland hormones. The study was performed on two main rat groups, intact and adrenalectomized. Rat were divided into subgroups and given appropriate doses of ketamine, metyrapone or metyrosine. Durations of anesthesia in the groups were then recorded. Endogenous catecholamine levels were measured in samples taken from peripheral blood. This experimental results showed that ketamine did not induce anesthesia in intact rats at doses of 15 or 30 mg/kg, and that at 60 mg/kg anesthesia was established for only 11 min. However, ketamine induced significant anesthesia even at a dose of 30 mg/kg in animals in which production of endogenous catecholamine (adrenalin, noradrenalin dopamine) was inhibited with metyrosine at a level of 45–47%. Ketamine at 60 mg/kg in animals in which endogenous catecholamine was inhibited at a level of 45–47% established anesthesia for 47.6 min. However, ketamine at 30 and 60 mg/kg induced longer anesthesia in adrenalectomized rats with higher noradrenalin and dopamine levels but suppressed adrenalin production. Adrenalin plays an important role in the control of duration of ketamine anesthesia, while noradrenalin, dopamine and corticosterone have no such function. If endogenous adrenalin is suppressed, ketamine can even provide sufficient anesthesia at a 2-fold lower dose. This makes it possible for ketamine to be used in lengthy surgical procedures.     

Studies on the influence of nicotine infusions on mesolimbic dopamine and locomotor responses to nicotine

The present study examined the effects of constant nicotine infusions on dopamine overflow in the nucleus accumbens and on locomotor activity and compared them with the changes evoked by repeated daily injections (one injection per day for 5 days) of the drug. The putative anxiolytic properties of nicotine have also been examined using the elevated plus-maze test of anxiety. Repetitive daily subcutaneous injections of nicotine (0.4 mg/kg) enhanced (P < 0.01) the overflow of dopamine evoked by a challenge dose of the drug (0.4 mg/kg) and increased (P < 0.01) its stimulatory effects on locomotor activity. The constant infusion of nicotine, at doses of 1 and 4 mg/kg per day, abolished (P < 0.05) the effects of a bolus injection of nicotine on extracellular dopamine and attenuated (P < 0.01) the enhanced locomotor response evoked by daily pretreatment with nicotine boli. The mesolimbic dopamine response to a bolus injection of nicotine was not significantly attenuated by nicotine infusions when the dose was reduced to 0.25 mg/kg per day. The locomotor responses in these rats were significantly (P < 0.05) less than those seen in the animals pretreated with nicotine injections alone but were also higher (P < 0.05) than those seen in saline-treated control rats given a bolus injection of nicotine. Neither the constant infusion (4 mg/kg per day) nor the injection of nicotine (0.4 mg/kg) evoked an anxiolytic or anxiogenic effect in the elevated plus-maze test. However, the nicotine infusions did abolish the locomotor stimulant effects of the drug in this apparatus. They also abolished the plasma corticosterone response to nicotine and attenuated the plasma corticosterone response to the maze. The data suggest that constant infusions of nicotine, at doses of 1 mg/kg per day or more, may cause desensitisation of the nicotinic receptors which mediate the stimulatory effects of the drug on mesolimbic dopamine release and locomotor activity. The data also suggest that the receptors which mediate the increase in plasma corticosterone, seen in animals given nicotine boli, may also be desensitised by nicotine infusions, and that these receptors may be implicated in the adrenocortical response to anxiogenic stimuli.Abbreviations DA dopamine - NAcc nucleus accumbens Correspondence to: M.E.M. Benwell     

Nicotinic acetylcholine receptors of the dorsal hippocampus and the basolateral amygdala are involved in ethanol-induced conditioned place preference

The purpose of this study was to evaluate whether nicotinic acetylcholine receptors of the dorsal hippocampus and the basolateral amygdala (BLA) can potentiate ethanol response in the conditioned place preference (CPP) paradigm. I.p. administration of different doses of ethanol (0.25–1 g/kg) did not induce CPP. However, the higher dose of the drug (1.5 g/kg i.p.) induced place aversion. Furthermore, microinjection of nicotine (0.5–1 μg/rat) into both CA1 regions (intra-CA1) and the BLA (intra-BLA) did not produce a significant CPP. Interestingly, intra-CA1 or -BLA administration of nicotine plus ethanol (0.5 g/kg) during conditioning phase significantly induced a strong CPP. Microinjection of mecamylamine, the nicotinic acetylcholine receptor antagonist, into the CA1 regions or into the BLA did not alter CPP. However, intra-CA1 or -BLA microinjection of mecamylamine (1–4 μg/rat) reversed the response induced by the microinjection of nicotine (1 μg/rat, intra-CA1 or -BLA) plus ethanol (0.5 g/kg i.p.) in the CPP paradigm. On the other hand, the microinjection of nicotine (0.5–1.5 μg/rat) into the BLA, but not into the CA1 regions before the testing phase potentiated the response of ethanol on the expression of conditioned place preference. Moreover, intra-CA1 administration of nicotine plus ethanol increased the locomotor activity on the test day which was reversed by pretreatment with mecamylamine, while other treatments had no effect on locomotor activity. It can be concluded that the activation of nicotinic acetylcholine receptors of the dorsal hippocampus and the basolateral amygdala can potentiate the ethanol response in the CPP paradigm.     

Lateralization of response to social stimuli in fishes: a comparison between different methods and species

An increasing body of research has focused on isolating factors that predict or alter individual differences in the behavioral and neural processes mediating the effects of abused drugs. Within this framework, the current report assessed individual differences and the locomotor effect of nicotine. Rats were screened for activity induced by a novel environment. Rats, which were more active to initial environment exposure, remained more active even after seven additional 30-min exposures to the same environment. Treatment with nicotine-di-D tartrate (1 mg/kg, sc) disrupted this effect. This nicotine disruption of individual differences occurred whether nicotine suppressed locomotor activity (initial administration) or stimulated locomotor activity (seventh and eighth administration). Mecamylamine (1 mg/kg), but not hexamethonium (10 mg/kg), completely blocked the suppressant and stimulant effects of nicotine. Further, mecamylamine restored the nicotine-induced disruption of individual differences; hexamethonium had no effect. This data pattern suggests that the disruptive effects of acute and chronic nicotine on individual differences were mediated by neural nicotinic acetylcholine (nACh) receptors.     

Wistar Kyoto and Wistar rats differ in the affective and locomotor effects of nicotine

Anhedonia is a characteristic of clinical depression and has been associated with dysfunction of the mesolimbic dopaminergic system, a system also involved in mediating nicotine reward. To further examine the relationship between anhedonia, clinical depression and nicotine reward, the present experiment determined if Wistar Kyoto (WKY) rats, an animal model of clinical depression, differed from Wistar rats in nicotine conditioned place preference (CPP). Strain differences in nicotine-induced changes in locomotor activity also were determined simultaneously. To determine if strain differences were specific to reward-based learning, nicotine or lithium chloride (LiCl) conditioned taste avoidance (CTA) experiments were conducted. Rats received vehicle or nicotine (0.4 or 0.8 mg/kg) during a multi-trial, biased CPP training procedure or received vehicle, nicotine (0.2, 0.4 or 0.8 mg/kg) or lithium chloride (LiCl; 0.0375, 0.075 or 0.15 M) during a multi-trial CTA training procedure. Whereas both nicotine doses (0.4 and 0.8 mg/kg) initially induced hypoactivity, only the moderate nicotine dose (0.4 mg/kg) induced hyperactivity with repeated administration and produced a CPP in Wistar rats. Both nicotine doses failed to alter locomotor activity or produce a CPP in WKY rats. WKY rats also acquired a LiCl CTA more slowly and less robustly compared to Wistar rats. In contrast, nicotine dose-dependently produced a CTA in both strains and WKY rats were more sensitive to the avoidance effects of nicotine compared to Wistar rats. Collectively, these results suggest that WKY rats show deficits in nicotine reward and specific aversive drug stimuli compared to Wistar rats.     

Testosterone is essential for cocaine sensitization in male rats

Most studies agree that males and females respond differently to drugs of abuse. In females, estradiol enhances the behavioral response to cocaine. However, studies on the role of testosterone and the locomotor response to psychostimulants in the male rat are inconclusive. Our study was designed to determine the behavioral effects of testosterone on the development and persistence of cocaine sensitization in male rats. We tested different doses of cocaine (10, 15 and 30 mg/kg) to determine which dose induced locomotor sensitization in intact (INT) and gonadectomized (GDX) animals. We also investigated if GDX males with testosterone replacement (GDX-T) showed a similar locomotor response to cocaine as INT males.Our data showed that gonadectomy enhanced the locomotor response to a single cocaine injection. This effect was not observed in gonadectomized rats that received testosterone replacement. However, GDX rats did not show a progressive increase in their locomotor response to repeated cocaine administration (15 and 30 mg/kg) (sensitization) as did INT and GDX-T animals. It is possible that in GDX males, the initial high locomotor response to cocaine creates a ceiling effect that limits further increase in cocaine-induced hyperactivity. These findings indicate that testosterone not only modulates the behavioral response to a single and to repeated cocaine injections, but is also essential for male rats to become sensitized to cocaine.     

Tapentadol,but not morphine,selectively inhibits disease-related thermal hyperalgesia in a mouse model of diabetic neuropathic pain

Neuropathic pain in diabetic patients is a common distressing symptom and remains a challenge for analgesic treatment. Selective inhibition of pathological pain sensation without modification of normal sensory function is a primary aim of analgesic treatment in chronic neuropathic pain. Tapentadol is a novel analgesic with two modes of action, μ-opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition. Mice were rendered diabetic by means of streptozotocin, and neuropathic hyperalgesia was assessed in a 50 °C hot plate test. Normal nociception was determined in control mice. Tapentadol (0.1–1 mg/kg i.v.) and morphine (0.1–3.16 mg/kg i.v.) dose-dependently attenuated heat-induced nociception in diabetic animals with full efficacy, reaching >80% at the highest doses tested. Tapentadol was more potent than morphine against heat hyperalgesia, with ED₅₀ (minimal effective dose) values of 0.32 (0.316) and 0.65 (1) mg/kg, respectively. Non-diabetic controls did not show significant anti-nociception with tapentadol up to the highest dose tested (1 mg/kg). In contrast, 3.16 mg/kg morphine, the dose that resulted in full anti-hyperalgesic efficacy under diabetic conditions, produced significant anti-nociception in non-diabetic controls. Selective inhibition of disease-related hyperalgesia by tapentadol suggests a possible advantage in the treatment of chronic neuropathic pain when compared with classical opioids, such as morphine. It is hypothesized that this superior efficacy profile of tapentadol is due to simultaneous activation of MOR and inhibition of NA reuptake.     

The effects of sodium butyrate,an inhibitor of histone deacetylase,on the cocaine- and sucrose-maintained self-administration in rats

In order to substantiate the concept that cocaine behavioral effects may be influenced by histone modification, rats were trained to self-administer cocaine intravenously (0.75 mg/(kg injection)), and were systemically pretreated with sodium butyrate (NaBu), a potent histone deacetylase inhibitor, before the test session during the maintenance phase. The effect of NaBu on a control reinforcer (sucrose)-induced self-administration was also assessed. NaBu (100–200 mg/kg) was inactive in altering the cocaine (0.75 mg/(kg injection))-maintained responding and at the highest dose (400 mg/kg) it did increase cocaine-induced lever presses during the maintenance phase. On the other hand, sucrose-reinforcing potential was not altered when NaBu was given at the highest dose (400 mg/kg). These findings extend previous observations that changes in histone acetylation are relevant to cocaine-induced behavioral effects. Given that histone acetylase inhibitor enhances cocaine-induced behavioral plasticity, the therapeutic benefits of histone acetyltransferase inhibitors warrant further investigation in the experimental models of cocaine abuse.     

Deletion of the GluR5 subunit of kainate receptors affects cocaine sensitivity and preference

We have demonstrated previously that mice expressing a constitutive deletion of the kainate receptor subunit GluR5 (GluR5 KO) do not differ from wildtype (WT) littermates of a congenic C57BL/6 background with regard to both the development of morphine physical dependence as measured by naloxone-precipitated withdrawal signs and to morphine reward as revealed by the expression of conditioned place preference (CPP). However, unlike WT, GluR5 KO mice fail to develop antinociceptive tolerance following repeated systemic morphine administration. In this report, we examined the impact of GluR5 deletion on cocaine-mediated CPP and locomotor sensitization. Expression of CPP was evident in WT mice following repeated daily administration of 20 mg/kg (but not 10 mg/kg) i.p. cocaine. Interestingly, GluR5 KO mice exhibited enhanced cocaine preference as compared with WT mice at both 10 and 20 mg/kg doses. In addition, while GluR5 KO mice did not differ from WT with respect to baseline locomotor activity, mutant mice demonstrated increased locomotor hyperactivity versus WT mice after repeated injection of 15 mg/kg i.p. cocaine. Collectively, these data indicate that GluR5 appears to negatively modulate some psychostimulant and rewarding properties of cocaine, as demonstrated by heightened sensitization and salience in mutant mice.     

The effects of dopaminergic drugs in the ventral hippocampus of rats in the nicotine-induced anxiogenic-like response

Nicotine an active alkaloid of tobacco has dopaminergic properties. The drug alters anxiety-like behavior in rodents. Ventral hippocampus (VHC) may be a site for modulation of anxiety-like behaviors. The possible involvement of ventral hippocampal dopaminergic receptor mechanism in the nicotine influence on anxiogenic-like response has been investigated in the present study. The effects of apomorphine, sulpiride and SCH23390 on nicotine response in elevated plus maze in rats have been investigated. Intraperitoneal administration of nicotine (0.6 mg/kg) decreased percentage of open arm time (%OAT) but not percentage of open arm entries (%OAE) and locomotor activity, indicating an anxiogenic-like response. Intra-hippocampal injection (intra-VHC) of apomorphine, a D₁/D₂ dopamine receptor agonist (0.1 and 0.2 μg/rat) also caused anxiogenic-like effects, but the drug blocked that of nicotine. Intra-VHC administration of the D₂ receptor antagonist, sulpiride (1, 2.5 and 5 μg/rat) or the D₁ receptor antagonist, SCH23390 (0.01, 0.1 and 1 μg/rat) did not elicit any response. However, pretreatment with sulpiride (1 μg/rat) or SCH23390 (0.1 μg/rat) decreased nicotine's effect. The results may indicate a modulatory effect for the D₁ and D₂ dopamine receptors of VHC in the anxiogenic-like response induced by nicotine.     

Antidepressant-like effect of genipin in mice

The present study aimed to investigate the antidepressant potential of genipin and its possible mechanisms. Mouse models of depression including the forced swimming test (FST) and the tail suspension test (TST) were used to evaluate the effects of genipin. A possible mechanism was explored in the test of antagonism of reserpine-induced ptosis and hypothermia in mice. The contents of monoamine neurotransmitters and their metabolites including epinephrine (NE), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in mice hippocampi were determined by HPLC–ECD. The results showed that intra-gastric administration of genipin at 50, 100, 200 mg/kg or fluoxetine at 7.5 mg/kg for 7 days significantly reduced the duration of immobility in FST and TST, while it did not affect the locomotor activity in the open field test (OFT). However, the effect was not dose-dependent. When the mice were treated with genipin or fluoxetine for 7 days, both of them could antagonize reserpine-induced ptosis and hypothermia. The 5-HT and NE contents in mice hippocampi were decreased after the peritoneal injection of reserpine at 2.0 mg/kg. The pre-treatment with genipin at 50, 100, 200 mg/kg or fluoxetine at 7.5 mg/kg for 7 days could elevate the contents of NE and 5-HT in mice hippocampi significantly. The results suggest that compared with fluoxetine, genipin exerts antidepressant-like effects significantly. A possible mechanism, at least in part, is the regulation of the 5-HT and NE levels in the hippocampus.     

The FAAH inhibitor URB-597 interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus (house musk shrew)

Considerable evidence implicates the endocannabinoid system as a neuromodulator of nausea and vomiting. The action of anandamide (AEA) can be prolonged by inhibiting its degradation, through the use of URB597 (URB), a Fatty Acid Amide Hydrolase (FAAH) enzyme inhibitor. Here we present evidence that the FAAH inhibitor, URB, interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus. In Experiment 1, shrews were injected with URB (0.9 mg/kg) or vehicle 120 min prior to the behavioral testing. They received a second injection of AEA (5 mg/kg) or vehicle 15 min prior to being injected with cisplatin (20 mg/kg) or saline and the number of vomiting episodes were counted for 60 min. In Experiment 2, shrews were injected with vehicle or URB (0.9 mg/kg) 120 min prior to receiving an injection of nicotine (5 mg/kg) or saline and the number of vomiting episodes were counted for 15 min. Experiment 3 evaluated the potential of the CB₁ antagonist, SR141716, to reverse the effect of URB on nicotine-induced vomiting. URB attenuated vomiting produced by cisplatin and nicotine and the combination of URB + AEA suppressed vomiting produced by cisplatin. The effect of URB on nicotine-induced vomiting was reversed by SR141716. These data suggest that the EC system plays a tonic role in the regulation of toxin-induced vomiting.     

Pre-treatment with high doses of cocaine decreases the reinforcing effects of cocaine in the conditioned place preference paradigm

The aim of the present study was to determine if pre-exposure to high doses of cocaine can subsequently alter the rewarding effects of this drug. Adult male mice received a pretreatment of physiological saline, or 12.5 or 25 mg/kg of cocaine (one injection a day for five days). After an interval of six days without injections, the rewarding effects of low doses of cocaine (0.5, 1 or 1.5 mg/kg) were evaluated in the conditioned place preference (CPP) paradigm. Doses of 1 and 1.5 mg/kg induced a clear CPP in animals pre-treated with saline but were ineffective in those pre-treated with 25 mg/kg of cocaine. Only the dose of 1.5 mg/kg induced CPP in mice pre-treated with 12.5 mg/kg of cocaine. Our results, which reveal a decrease in the conditioned rewarding effects of threshold doses of cocaine, demonstrate that exposure to high doses of this drug can alter the reward system.     

Neuroprotective effect of alpha-lipoic acid on hydrostatic pressure-induced damage of retinal ganglion cells in vitro

Cholecystokinin octapeptide (CCK-8) is the most potent endogenous anti-opioid peptide and regulates a variety of physiological processes. In our previous study, we found that exogenous CCK-8 attenuated naloxone-induced withdrawal symptoms, but the possible regulative effects of CCK-8 on the rewarding effects of morphine were not examined. In the present study, we aimed to determine the exact effects of exogenous CCK-8 at various doses on the rewarding action of morphine by utilizing the unbiased conditioned place preference (CPP) paradigm. We therefore examined the effects of CCK-8 on the acquisition, expression and extinction of morphine-induced CPP and on locomotor activity. The results showed that CCK-8 (0.01-1 μg, i.c.v.), administered alone, induced neither CPP nor place aversion, but blocked the acquisition of CPP when administered with 10 mg/kg morphine. The highest dose of CCK-8 (1 μg) administered before CPP testing increased CPP and, along with lower doses (0.1 μg), reduced its extinction. In addition, the highest dose (1 μg) of CCK-8 suppressed locomotor activity. Our study provides the first behavioral evidence for the inhibitory effects of exogenous CCK-8 on rewarding activity and reveals significant effects of exogenous CCK-8 on various stages of place preference and the development of opioid dependence.     

Involvement of GABA(B) receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats

In the present study, effects of intra-hippocampal CA1 (intra-CA1) injections of GABA(B) receptor agonist and antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. Subcutaneous administration of different doses of morphine sulphate (0.5-6 mg/kg) produced a dose-dependent conditioned place preference (CPP). Using a 3-day schedule of conditioning, it was found that the GABA(B) receptor agonist, baclofen (0.5-2 microg/rat; intra-CA1), or the GABA(B) receptor antagonist, phaclofen (1-3 microg/rat; intra-CA1), did not produce a significant place preference or place aversion. Intra-CA1 administration of baclofen (1 and 2 microg/rat; intra-CA1) decreased the acquisition of CPP induced by morphine (3 mg/kg; s.c.). On the other hand, intra-CA1 injection of phaclofen (1 and 2 microg/rat; intra-CA1) in combination with a lower dose of morphine (1 mg/kg) elicited a significant CPP. The response of baclofen (2 microg/rat; intra-CA1) was reversed by phaclofen (4 and 6 microg/rat; intra-CA1). Furthermore, intra-CA1 administration of baclofen but not phaclofen before testing significantly decreased the expression of morphine (3 mg/kg; s.c.)-induced place preference. Baclofen or phaclofen injections had no effects on locomotor activity on the testing sessions. It is concluded that the GABA(B) receptors in dorsal hippocampus may play an active role in morphine reward.     

Role for GABA agonists in the nucleus accumbens in regulating morphine self-administration

In the present study, functional roles of GABA receptors in the nucleus accumbens on morphine self-administration behavior were investigated. Male Sprague–Dawley rats were trained to press lever for morphine (0.1 mg/kg per infusion) during daily 1-h self-administration session. After establishing stable baseline responses, rats were given microinjections of the GABA_A receptor agonist muscimol (0, 250 and 500 ng/μl, bilateral) or the GABA_B receptor agonist baclofen (0, 100 and 250 ng/μl, bilateral) into the nucleus accumbens immediately before the morphine self-administration. Microinjection of muscimol (250 and 500 ng/μl) into the nucleus accumbens, but not baclofen, decreased morphine self-administration responses. These results suggest that activation of GABA_A receptors, but not GABA_B receptors, in the nucleus accumbens plays a critical role in modulating the reinforcing effects of morphine.     

Tramadol induces conditioned place preference in rats: Interactions with morphine and buprenorphine

Surveys and drug surveillance have demonstrated that the abuse liability of tramadol is considerably low in the general population but appears to be higher in opiate addicts, and this difference could attribute to the poly-drug abuse of opioid addicts, although this hypothesis has not been tested in the laboratory. The present study examined the interactions between tramadol and a full μ opioid receptor agonist morphine or a partial μ opioid receptor agonist buprenorphine in a conditioned place preference (CPP) paradigm in rats. Rats were conditioned with tramadol (2–54 mg/kg, i.p.), morphine (0.125–8 mg/kg, s.c.), buprenorphine (0.01–0.316 mg/kg, s.c.) or a combination of a subeffective dose of tramadol (2 mg/kg) with a subeffective dose of morphine or buprenorphine and the CPP effect was measured. The retention of CPP effect was also examined. Tramadol, morphine and buprenorphine all produced a dose-dependent and significant CPP. A smaller dose of tramadol (2 mg/kg) enhanced morphine- and buprenorphine-induced CPP and shifted the dose-effect curves of both drugs leftward. In addition, the combination of tramadol with morphine or buprenorphine prolonged the retention of CPP. These findings indicate that tramadol potentiates the rewarding effects of morphine or buprenorphine largely in an additive manner and support the general contention that tramadol has relatively low abuse liability.     

Therapeutic potential of α2 adrenoceptor antagonism for antipsychotic-induced extrapyramidal motor disorders

We examined the effects of JP-1302 (a selective α_2C antagonist), BRL-44408 (a selective α_2A antagonist) and yohimbine (a non-selective α₂ antagonist) on haloperidol-induced bradykinesia and catalepsy in mice to elucidate the role of α₂ adrenoceptor subtypes in modifying extrapyramidal motor disorders. JP-1302 (0.1–1 mg/kg, s.c.) dose-dependently ameliorated haloperidol-induced bradykinesia in the pole-test and reversed the catalepsy time increased by haloperidol. Antibradykinetic and anticataleptic actions of JP-1302 were statistically significant at 0.3 and 1 mg/kg, and these doses did not alter the ambulatory distance, rearing or center–perimeter residence time in the open-field test. BRL-44408 (1–10 mg/kg, s.c.) and yohimbine (0.3–3 mg/kg, i.p.) also ameliorated haloperidol-induced bradykinesia and catalepsy. However, both agents significantly decreased ambulatory distance and rearing in the open-field test, possibly reflecting their anxiogenic actions associated with α_2A antagonism. The present study shows for the first time that blockade of α_2C receptors can alleviate antipsychotic-induced extrapyramidal motor disorders without affecting gross behaviors.