Ethological analysis of morphine withdrawal with different dependence programs in male mice

This work was performed to clarify the differences between a long or short development of morphine dependence as well as between a recently installed or a long-term dependence. Morphine withdrawal in rats is a well-characterized phenomenon but this is not so in mice. A study of the principal withdrawal signs have been performed in mice, evaluating their specificity and particular profile of appearance in each type of dependence. Mice were divided into two groups that received increasing doses of morphine every 24 h, three groups that received increasing doses of morphine twice a day for 3 days, and a control group that received saline. Naloxone-induced opiate withdrawal was evaluated following short-term exposition to morphine [Test 1 (T1)--saline and Test 2 (T2)--naloxone] and long-term exposition to morphine [Test 3 (T3)--naloxone and Test 4 (T4)--saline]. Morphine administration twice a day is more effective in inducing opiate dependence than once a day, and with the latter, the duration of morphine exposure increases the intensity of withdrawal signs. Weight loss, diarrhea, body shakes, jumping, paw tremor, ptosis, piloerection, and the modified Gellert-Holtzman scale for mice are specific patterns of naloxone-induced withdrawal. The first four signs allow the discrimination between different levels of opiate dependence. Body care, piloerection, and the modified Gellert-Holtzman scale could be useful to detect conditioned withdrawal.     

Role of CB2 Cannabinoid Receptors in the Rewarding,Reinforcing, and Physical Effects of Nicotine

This study was aimed to evaluate the involvement of CB2 cannabinoid receptors (CB2r) in the rewarding, reinforcing and motivational effects of nicotine. Conditioned place preference (CPP) and intravenous self-administration experiments were carried out in knockout mice lacking CB2r (CB2KO) and wild-type (WT) littermates treated with the CB2r antagonist AM630 (1 and 3 mg/kg). Gene expression analyses of tyrosine hydroxylase (TH) and α3- and α4-nicotinic acetylcholine receptor subunits (nAChRs) in the ventral tegmental area (VTA) and immunohistochemical studies to elucidate whether CB2r colocalized with α3- and α4-nAChRs in the nucleus accumbens and VTA were performed. Mecamylamine-precipitated withdrawal syndrome after chronic nicotine exposure was evaluated in CB2KO mice and WT mice treated with AM630 (1 and 3 mg/kg). CB2KO mice did not show nicotine-induced place conditioning and self-administered significantly less nicotine. In addition, AM630 was able to block (3 mg/kg) nicotine-induced CPP and reduce (1 and 3 mg/kg) nicotine self-administration. Under baseline conditions, TH, α3-nAChR, and α4-nAChR mRNA levels in the VTA of CB2KO mice were significantly lower compared with WT mice. Confocal microscopy images revealed that CB2r colocalized with α3- and α4-nAChRs. Somatic signs of nicotine withdrawal (rearings, groomings, scratches, teeth chattering, and body tremors) increased significantly in WT but were absent in CB2KO mice. Interestingly, the administration of AM630 blocked the nicotine withdrawal syndrome and failed to alter basal behavior in saline-treated WT mice. These results suggest that CB2r play a relevant role in the rewarding, reinforcing, and motivational effects of nicotine. Pharmacological manipulation of this receptor deserves further consideration as a potential new valuable target for the treatment of nicotine dependence.     

GHB ameliorates naloxone-induced conditioned place aversion and physical aspects of morphine withdrawal in mice

Rationale Gamma-hydroxybutyric acid (GHB) is a naturally occurring substance in the brain, the administration of which has proved useful in the treatment of the opiate withdrawal symptoms in humans.Objectives The aim of the present work was to validate this beneficial effect on the physical and motivational aspects of morphine withdrawal in mice.Methods In a first experiment, animals rendered morphine-dependent were conditioned to develop a place aversion (CPA) to the compartment paired with naloxone administration in a two-chamber apparatus. The conditioning phase consisted of three pairings of either naloxone (0.250 mg/kg) or vehicle in one compartment, both with similar time allotments during the preconditioning test. During the testing phase, mice were again allowed to explore the entire apparatus. GHB (6, 12.5, 25, and 50 mg/kg) was administered during either the acquisition or expression phase of this conditioning. In a second experiment, the capacity of GHB to ameliorate the intensity of physical signs of morphine withdrawal was evaluated.Results GHB blocked CPA in both phases: administered during acquisition (from 12.5 mg/kg and higher) as well as in the expression phase (from 6 mg/kg, except for 25 mg/kg). It also decreased the intensity of physical signs of morphine withdrawal to near control levels measured by the modified Gellert–Holtzman scale (25 mg/kg and higher). Decreases in jumping, body shakes, and paw tremor were also observed.Conclusions Our results support the idea that GHB ameliorates both aspects of morphine withdrawal, physical as well as motivational signs.     

Necrotizing Aspergillosis of large airways: CT findings in eight patients

PURPOSE: The aim of this study was to evaluate the CT findings of pathologically proven necrotizing aspergillosis of the large airways (necrotizing Aspergillus bronchitis). METHOD: Medical records and imaging studies from two tertiary medical centers were reviewed for pathologically proven cases of necrotizing aspergillosis of the large airways. Fiberoptic bronchoscopic examination and CT scans of the chest were available in all cases. Two thoracic radiologists who were blinded to the clinical and pathologic data reviewed the thoracic CT scans retrospectively and reached a final decision. The CT images were evaluated for the presence, distribution, and extent of CT findings. RESULTS: The study included eight patients, seven men and one woman, ranging in age from 28 to 67 years (mean age 46 years). All patients had histopathologically proved necrotizing Aspergillus of the large airways and no other superimposed infections. Six patients had leukemia, one had chronic liver disease, and one had chronic obstructive lung disease. All patients had bronchial wall thickening and focal bronchial narrowing involving a lobar or segmental bronchus. The bronchial narrowing was irregular or nodular in seven patients and smooth in one. Atelectasis distal to a narrowed bronchus was present in five patients. CONCLUSION: The CT findings of necrotizing bronchial aspergillosis include bronchial wall thickening, which is often nodular, and narrowing of the bronchial lumen, which is often associated with distal atelectasis.     

Naloxone-induced opiate withdrawal produces long-lasting and context-independent changes in aggressive and social behaviors of postdependent male mice

The purpose of this study was to determine whether an environment associated with naloxone-induced morphine withdrawal affects aggressive or social behaviors in postdependent mice. Morphine-dependent or saline-treated mice received 3 naloxone injections in 1 of 2 different environments (A or B); 15 days afterward, when the mice were completely drug free, an aggression test was carried out in Environment A. All the mice suffering morphine withdrawal showed a significant increase in aggression, irrespective of the environment in which the withdrawal took place. In these conditions, the impact of morphine dependence and the 3 induced withdrawals was so profound that the environment could not be discriminative. In addition, modifications in the behavioral profile of postdependent mice that suffered only spontaneous withdrawal were long-lasting, with the mice carrying out more attacks during social investigation without presenting threat postures.     

Social behavioural profile of cocaine in isolated and grouped male mice

Studies concerning the relationship between cocaine and aggression in humans as well as in animals have discrepant outcomes. Increases, decreases, or no changes, have been reported after single or chronic cocaine administration in animal models. To clarify, at least in part, the complex behavioural actions of cocaine, the present study evaluated cocaine effects on social behaviours of mice exposed to different situations (isolated or group housed) using confrontations between two male mice in a neutral area. Different doses of cocaine (6, 25 and 50 mg/kg) were administered in a single or binge pattern (three doses in 24 h) and the behavioural test was performed 20 min after the last injection. No increases in aggression were observed in any situation tested. Instead, cocaine at the two higher doses employed (either in single or binge administration), decreased aggressive behaviours in isolated mice, with no changes being observed in grouped animals. In both types of animals, cocaine increased defensive elements (avoidance/flee) and abolishes social contacts. In conclusion, cocaine presents an anti-aggressive action and may be interpreted as having an anxiogenic-like effect.     

Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness

Rationale

Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade.

Objectives

The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs.

Methods

Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA).

Results

Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine.

Conclusions

These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence.

Highlights

? Topiramate increases the rewarding properties of cocaine in CPP? Topiramate alters dopaminergic signaling in the mesolimbic circuit? Topiramate delays the extinction of cocaine-induced CPP? TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine? Results show that it should limit the use of topiramate in cocaine-dependent subjects

     

Effect of adolescent exposure to MDMA and cocaine on acquisition and reinstatement of morphine-induce CPP

It is well known that an elevated percentage of ecstasy users also consume cocaine. Recently, it has been reported that a high frequency of heroin smokers first consumed heroin under the effects of ecstasy with the hope of reducing the stimulant effects of the latter drug. The aim of the present study was to evaluate the effect of exposure to MDMA and cocaine during adolescence on morphine-induced conditioned place preference (CPP) and reinstatement in adulthood. In the first experiment, adolescent mice were exposed to six injections of MDMA and three weeks later their response to the reinforcing properties of 40 mg/kg of morphine was evaluated using the CPP paradigm. All the treatment groups developed the same magnitude of morphine-induced preference and, after CPP was extinguished, it was restored in all the groups with a priming dose of 10 mg/kg of morphine. Only mice that had been treated with 10 or 20 mg/kg of MDMA had their morphine-induced preference reinstated after receiving only 5 mg/kg of morphine. In the second experiment, adolescent mice were similarly treated with six administrations of cocaine (25 mg/kg) or cocaine plus MDMA (5, 10 or 20 mg/kg), and their response to morphine-induce CPP was evaluated three weeks later. Similarly to the first experiment, all the groups developed a preference for the morphine-paired compartment, but this preference was not reinstated with a priming dose of 10 mg/kg of morphine following extinction, as was the case among the control animals. These results lead us to hypothesize that periadolescent MDMA exposure alters responsiveness to the rewarding properties of morphine, highlighting MDMA as a gateway drug whose use may increase the likelihood of dependence on other drugs.     

Subcutaneous sarcoidosis associated with vitiligo, pernicious anaemia and autoimmune thyroiditis

We report a patient with pernicious anaemia, primary autoimmune hypothyroidism and vitiligo, who presented with subcutaneous nodules. Histopathology of the nodules revealed noncaseating granulomas, consistent with a diagnosis of sarcoidosis. Mild pulmonary sarcoid was also detected. Although an association between sarcoidosis and other autoimmune diseases is well-recognized, the presence of the particular autoimmune diseases in our patient and the involvement of subcutaneous fat in the sarcoidal inflammation, appears to represent a most unusual clinicopathological combination.     

The dopamine D3 antagonist U-99194A maleate increases social behaviors of isolation-induced aggressive male mice

Rationale: Blockade of D₁/D₂ dopamine receptors produce an antiaggressive action commonly associated with an impairment of other motor behaviors. The D₃ receptor seems to present opposite actions to the D₁ and D₂, since the blockade of this receptor produces stimulation of motor activity which has been associated with an increase in dopamine neurotransmission. Objective: In this work, the action of the dopamine D₃ antagonist U-99194a maleate on locomotor activity and in a social interaction test in male mice was evaluated. Methods: Animals isolated during 30 days were treated with U-99194a maleate (20–40 mg/kg) or saline and locomotor activity was measured 20 min after drug administration. The behavioral interaction test was performed afterwards, between the experimental isolated animal and a standard opponent. Results: The higher dose used produces a significant decrease in spontaneous motor activity and presents an antiaggressive action without impairment of other behaviors, such as non-social exploration or immobility. At all doses tested, U-99194a maleate significantly increases social investigation. Conclusions: Our results give support to the hypothesis that the D₃ receptor could play a role in emotional behaviors. Received: 4 January 1999/Final version: 12 January 1999