Assessment of aversive effects of methylone in male and female Sprague-Dawley rats: Conditioned taste avoidance, body temperature and activity/stereotypies.

Methylone's rewarding effects have been well characterized; however, little is known about its aversive effects and how such effects may be impacted by sex. In this context, the present study investigated the aversive effects of methylone (vehicle, 5.6, 10 or 18 mg/kg, IP) in 35 male and 31 female Sprague-Dawley rats assessed by conditioned taste avoidance and changes in body temperature and activity/stereotypies. Methylone induced significant taste avoidance, changes in temperature and increased activity and stereotypies in both males and females. Similar to work with other synthetic cathinones, methylone has aversive effects as indexed by significant taste avoidance and changes in temperature and activity (two characteristics of methylone overdose in humans). The only endpoint for which there were significant sex differences was in general activity with males displaying a faster onset and females displaying a longer duration. Although sex was not a factor with taste avoidance and temperature, separate analyses for males and females revealed different patterns, e.g., males displayed a more rapid acquisition of taste avoidance and females displayed changes in temperature at lower doses. Males displayed a faster onset and females displayed a longer duration of activity (consistent with the analyses considering sex as a factor), while time- and dose-dependent stereotypies did not show consistent pattern differences. Although sex differences were relatively limited when sex was specifically assessed as a factor (or only evident when sex comparisons were made in the patterns of effects), sex as a biological variable in the study of drugs should be made to determine if differences exist and, if evident, the basis for these differences.

Comparative assessment of 6-[18 F]fluoro-L-m-tyrosine and 6-[18 F]fluoro-L-dopa to evaluate dopaminergic presynaptic integrity in a Parkinson's disease rat model.

Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson's disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical importance in the preclinical evaluation of highly awaited disease-modifying therapies. Among existing methods, the high sensitivity of positron emission tomography (PET) is attractive to achieve that goal. The aim of this study was to perform a quantitative comparison of brain images obtained in 6-hydroxydopamine (6-OHDA) lesioned rats using two dopaminergic PET radiotracers, namely [18 F]fluoro-3,4-dihydroxyphenyl-L-alanine ([18 F]FDOPA) and 6-[18 F]fluoro-L-m-tyrosine ([18 F]FMT). Because the imaging signal is theoretically less contaminated by metabolites, we hypothesized that the latter would show stronger relationship with behavioural and post-mortem measures of striatal dopaminergic deficiency. We used a within-subject design to measure striatal [18 F]FMT and [18 F]FDOPA uptake in eight partially lesioned, eight fully lesioned and ten sham-treated rats. Animals were pretreated with an L-aromatic amino acid decarboxylase inhibitor. A catechol-O-methyl transferase inhibitor was also given before [18 F]FDOPA PET. Quantitative estimates of striatal uptake were computed using conventional graphical Patlak method. Striatal dopaminergic deficiencies were measured with apomorphine-induced rotations and post-mortem striatal DA content. We observed a strong relationship between [18 F]FMT and [18 F]FDOPA estimates of decreased uptake in the denervated striatum using the tissue-derived uptake rate constant Kc . However, only [18 F]FMT Kc succeeded to discriminate between the partial and the full 6-OHDA lesion and correlated well with the post-mortem striatal DA content. This study indicates that the [18 F]FMT could be more sensitive, with respect of [18 F]FDOPA, to investigate DA terminals loss in 6-OHDA rats, and open the way to in vivo L-aromatic amino acid decarboxylase activity targeting in future investigations on progressive PD models.

[Assessment of hyper- and hypodopaminergic behaviors in Parkinson's disease]. / Evaluation des troubles comportementaux hyper- et hypodopaminergiques dans la maladie de Parkinson.

The common perception that Parkinson's disease patients tend to be depressed, anxious, apathetic and harm-avoiding has currently been challenged by the recognition that they can also exhibit a hedonistic, novelty-seeking personality. Thus, Parkinson's disease patients may indulge in their passions in an irresponsible and disinhibited manner, and engage in repetitive, compulsive behaviors that may be harmful and destructive to their social or professional lives. The dopamine dysregulation syndrome includes hypersexuality, pathological gambling, and compulsive shopping; it is associated with addiction to dopaminergic medication. However, not all behavioral changes are necessarily accompanied by a dopaminergic addiction. After antiparkinson treatment is initiated, patients enter a 'honeymoon period' during which changes in mood and behavior reflect a return to the patients' premorbid personality. The increased motivation and higher level of activity in professional as well as leisure activities are considered positive changes by both the patients and their relatives. With prolonged and increased dopaminergic treatment, these positive behavioral changes can become excessive and evolve into nocturnal hyperactivity and stereotyped, repetitive and time consuming behaviors which ultimately disorganize the patient's everyday routine and herald behavioral addictions. These drug-induced behavioral changes are under-appreciated by neurologists and under-reported by the patients who neither complain about the behaviors nor understand the relationship between motivated behavior and dopaminergic medication. For these reasons, we propose a new scale for the assessment of behavior and mood to quantify and track changes related to Parkinson's disease, to dopaminergic medication, and to non-motor fluctuations. This scale is based on the concept of hypo- and hyperdopaminergic mood and behavior. The scale consists of 18 items addressing non-motor symptoms, grouped in four parts: general psychological evaluation, apathy, non-motor fluctuations and hyperdopaminergic behaviors. The rating in five points (0-4 from absent to severe) is carried out during a semi-structured interview. Open-ended questions introduce each item, allowing patients to express themselves as freely as possible. Close-ended questions permit the rating of severity and intensity. This new instrument can be used by psychologists, psychiatrists or neurologists familiar with Parkinson's disease. Designed to detect changes in mood and behavior of Parkinson's disease patients resulting either from the disease or its treatment, this tool can be used in conjunction with the neurocognitive evaluation, to help tailor the treatment of motor and non-motor symptoms to each individual's needs.

A pharmacological MRI assessment of dizocilpine (MK-801) in the 3-nitroproprionic acid-lesioned rat.

The NMDA-antagonist dizocilpine (MK-801) is known to have dissociative, neurotoxic and neuroprotective properties. Although its neuroprotective properties are well documented, at present only ex vivo autoradiography has demonstrated its activity in lesioned brains. We report here the use of pharmacological magnetic resonance imaging (phMRI) to visualise the neural substrates of MK-801 in normal control rats and in animals that received systemic 3-nitroproprionic acid (3-NPA) 2 weeks earlier. In control animals, this NMDA-antagonist resulted in activity in the hippocampus, retrospinal (RS) cortex, anterior cingulate and the medial prefrontal cortex (MPFC). Activity in the MPFC has been associated with the dissociative properties of this agent and has been suggested to be the neurological substrate of positive psychotic symptoms, whereas RS and hippocampus have been the main sites of neurotoxic actions of MK-801. In contrast, in animals with 3-NPA-lesions affecting the striatum, no activity in the MPFC was observed, but a positive BOLD signal in the striatum was apparent. Lesioned animals injected with saline did not show this pattern of activity indicating that it is not merely an artefact of the ongoing neurodegeneration. This striatal activity could therefore be a site of MK-801-mediated neuroprotection. phMRI therefore sheds further light on the in vivo activity of MK-801 which, in turn, may allow us to more fully understand the different actions of NMDA-antagonists.

Effects of rimonabant, a cannabinoid CB1 receptor ligand, on energy expenditure in lean rats.

OBJECTIVE: To determine the effect of rimonabant on energy expenditure (O2 consumption) in rats at different metabolic states and in cannabinoid CB1 receptor-deficient (CB1R-/-) mice. DESIGN: Animals were exposed to light-dark cycles and fed only during dark cycles. Rimonabant or vehicle was administered together with food (absorptive), following overnight feeding (postabsorptive) or following a whole day of no food (fasting). Indirect calorimetric measurements, physical activity and food intake were measured continuously. RESULTS: Compared with vehicle-treated rats, rats administered 3 and 10 mg kg(-1) rimonabant showed an 18 and 49% increase in O2 consumption, respectively after 3 h. A second dose of rimonabant administered 9-14.5 h after the first one failed to affect O2 consumption, suggesting the development of tolerance. Similarly, stereotypic behaviors and ambulatory activity increased following the first dose but these effects were not observed after the second dose. Respiratory quotients revealed no effect of rimonabant on rates of carbohydrate and fat oxidation. Analysis of the correlation between O2 consumption and physical activity indicated that factors other than increased physical activity may contribute to the increase in O2 consumption. Similar studies in mice demonstrated that wild type but not CB1R-/- mice showed a change in O2 consumption and physical activity following rimonabant administration, suggesting that these effects are mediated by the cannabinoid CB1 receptor. CONCLUSION: Previous studies suggested that reduced food intake alone may not explain the weight reduction observed with rimonabant. Our studies suggest that rimonabant stimulates significant acute energy expenditure in non-obese rodents, which could not be completely accounted for by an increase in physical activity. However, with the observation that there is rapid development of tolerance, these results suggest that there may be additional mechanism(s) that lead to weight loss in these rodents.

The influence of cost manipulation on water contrafreeloading induced by repeated exposure to quinpirole in the rat.

RATIONALE: Quinpirole (QNP), a D2/D3 dopaminergic receptor agonist, was found to elicit an apparently antieconomical drinking behavior called contrafreeloading (CFL). The perseverative operant responding observed may represent a compulsive-like behavior prompted by sensitization to the effects of QNP. OBJECTIVES: In the present study, we investigated the effect of different response costs on instrumental behavior and CFL in rats repeatedly treated with QNP (0.5 mg/kg i.p.). Moreover, we studied the consummatory components of ingestive behavior in no-choice paradigms and the role of learned operant conditioning in free drinking. MATERIALS AND METHODS: In experiment 1, rats were trained to perform under three different fixed ratio schedules of reinforcement (FR1, FR3, and FR10) and were given a choice between operant and free access to water. In experiment 2, rats were divided into four groups, each one resembling experiment 1 in one or more features, with no choice available and water consumption measured at an interval of 0-60 min. RESULTS: (a) Increasing FR significantly reduced CFL % in saline -- but not in QNP-injected groups; (b) under free-drinking conditions, QNP caused a progressive hypodipsic effect which was, however, contrasted by maintaining cues formerly contingent on operant access to water; and (c) under CFL conditions QNP-treated rats drank more than under free access conditions. CONCLUSIONS: QNP confers rigidity in responding for water, impeding adaptation to different contingencies for access to the resource. In QNP-treated rats, CFL behavior appears adaptive as far as it allows animals to partially circumvent the hypodipsic effect of the drug.

Amphetamine induced rotation in the assessment of lesions and grafts in the unilateral rat model of Parkinson's disease.

In the unilateral rat model of Parkinson's disease (PD), amphetamine induced rotation is widely used as an index of both lesion deficits and of graft-derived recovery. We have analysed the time course of the rotational response in lesioned rats, and in rats with lesions and dopamine grafts. In lesioned rats, the rotation exhibited a typical dose-dependent response, with low rates of rotation in the first 10 min after injection, rising gradually to a maximum after 20-30 min. Grafted rats exhibited a peak of rotation in the first 10 min after injection, which then fell to a minimum after 30 min. We demonstrate that the response seen in grafted rats is both drug and dose-dependent and show that the rotational profile results from interaction of the grafted and intact striata which exhibit differential temporal responses to the amphetamine.

Specific symptomatic changes following donepezil treatment of Alzheimer's disease: a multi-centre, primary care, open-label study.

BACKGROUND: Standard measurement scales used in anti-dementia trials may not capture symptomatic changes recognized by clinicians and caregivers. We studied a symptom checklist, completed separately by caregivers and by clinicians, to identify patterns of change associated with donepezil treatment. METHODS: In a multi-centre, 6-month, open-label study of 101 primary care patients, changes in a 19-symptom checklist were assessed in relation to changes in standardized scales of cognition, activities of daily living, behavior, and caregiver burden. RESULTS: Three symptoms were reported in more than 80% of patients by both clinicians and caregivers: problems in remembering, (97%), temporal orientation (89%), and repetitiveness (85%). Five others overlapped on each of the clinician and caregiver 'top ten', including cognitive activation, spatial orientation, leisure, attention, and apathy. Clinicians reported that symptoms did not improve in 38 patients, whereas there was some improvement in 43, and improvement in most symptoms in 20. Caregivers reported that symptoms did not improve in 55 patients, whereas 27 and 19 patients showed some and most symptoms improving respectively. Patients with the greatest symptomatic improvement also improved most on the ADAS-Cog and the other standardized measures, whereas no improvement (or decline) in each standardized measure was observed in people whose symptoms worsened or did not improve. CONCLUSION: A symptom checklist allowed clinically meaningful profiles to be identified, but revealed different estimates of response between clinicians and caregivers. Both agreed that improved executive function was the most common response. A symptom checklist can help translate between standard measures and everyday practice.

Neurobehavioral assessment of children and adolescents attending a developmental disabilities clinic.

Although the risk of the eventual development of tardive dyskinesia and other persistent adverse effects of neuroleptics is high, among adults with mental retardation and other developmental disabilities, neuroleptics may ameliorate dyskinesias, aggression, and inattention. The effects of traditional neuroleptics on a comparable population of children and adolescents with mental retardation and other developmental disabilities are unknown. The objective of this study was to develop an assessment battery to describe the effects of traditional neuroleptics on the behavior and movements of a small sample of children and adolescents with mental retardation and other developmental disabilities. 13 children and adolescents aged 6 to 16 years attending a developmental disabilities clinic were evaluated utilizing a Movement Assessment Battery to measure behavior and motions. Five subjects took traditional neuroleptic medications. Trained raters can reliably assess the movements and behaviors of children and adolescents with multiple handicaps. Children and adolescents with developmental disabilities may be vulnerable to experience functional impairment and akathisia, tics, and other dyskinesias when administered traditional neuroleptic medications.

Topographical Assessment of Ethological and Dopamine Receptor Agonist-Induced Behavioral Phenotype in Mutants with Congenic DARPP-32 'Knockout'.

Congenic (10 backcrosses into C57BL/6J) mutants with targeted gene deletion of DARPP-32, a neuronal phosphoprotein regarded as an essential mediator of the biological effects of dopamine (DA), were assessed phenotypically using an ethologically based approach that resolves all topographies of behavior in the mouse repertoire. Over initial exploration, female, but not male, DARPP-32 mutants evidenced increased locomotion and decreased grooming, while a decrease in rearing seated was evident in mutants of both genders; continuing assessment over several hours did not reveal additional phenotypic effects. Following challenge with the nonselective DA receptor agonist apomorphine, low doses were associated with reduced levels of sniffing, grooming, total rearing, and rearing seated in DARPP-32 mutants relative to wildtypes; this would suggest some role for DARPP-32 in mediating the biological effects of presynaptic D(2)-like autoreceptor or inhibitory postsynaptic D(2)-like receptor activation. Following challenge with higher doses, while stereotyped sniffing and locomotion with chewing was largely unaltered, the additional murine response of Straub tail was essentially abolished in DARPP-32 mutants, indicating some specific involvement of DARPP-32 in mediating this topography of behavior; additionally, there were overall reductions in levels of sniffing, total rearing, rearing seated, and grooming in DARPP-32 mutants that were unrelated to the dose of apomorphine administered, indicating broader topographical effects following the stress of the injection procedure relative to more naturalistic conditions. The developmental absence of DARPP-32 following targeted gene deletion appears to be associated with compensatory processes that maintain certain topographies of spontaneous and agonist-induced DAergic function, while other topographies remain impaired.

Assessment of neuroleptic-like properties of progesterone.

There is considerable evidence from epidemiological studies that the onset of psychiatric disorders may be related to changes in the secretion of gonadal hormones. For example, the postpartum period appears to be a vulnerable phase for the occurrence of psychiatric disturbances such as dysphoric mood and even severe psychotic disturbances. It has been suggested that a sudden drop in progesterone concentrations may contribute to the development of such disorders. Because the administration of this steroid might be of therapeutic value in psychiatric disturbances, we investigated the behavioral properties of progesterone in the rat to assess putative neuroleptic-like properties of this steroid. Progesterone administration dose-dependently increased the EEG activity during wakefulness in the 10- to 30-Hz frequency bands and decreased locomotor activity. While no anxiolytic activity could be detected in the plus maze, the highest dose of progesterone (90 mg/kg) exerted an inhibitory effect on the conditioned avoidance response. In contrast to haloperidol (0.5 mg/kg), progesterone neither produced catalepsy nor antagonized amphetamine-induced stereotypy. However, both progesterone (10, 30 and 90 mg/kg) and haloperidol (0.1 mg/kg) effectively restored the disruption of the prepulse inhibition (PPI) of the acoustic startle response (ASR) that was evoked by apomorphine (2 mg/kg). In contrast, allopregnanolone (10 mg/kg), one of the main metabolites of progesterone, did not significantly antagonize the effect of apomorphine on the PPI. This behavioral profile of progesterone is compatible with the sedative properties of its metabolite allopregnanolone via the GABAA receptor, but also with the possibility that progesterone itself shares some properties with atypical antipsychotics, which may be relevant for the development and treatment of psychotic disturbances.

A new video path analyzer to monitor travel distance, rearing, and stereotypic movement of rats.

A new video path analyzer, described herein, monitors travel distance, rearing, stereotypic movement, rotation, and speed of rats simultaneously. The video path analyzer was equipped with a cage (black background, 50 cm long x 50 cm wide x 50 cm high), camera, television screen, computer, and printer. A detailed description of this equipment is included. While studying the known activating effects of d-amphetamine on rats' behavior, we also evaluated the equipment for its maximum and accurate contribution to this study. Results indicate that this equipment compared to photocell equipment produced reliable data and offered the advantages of lower cost. It is expected to gain more popularity in the near future.

Effects of rating parameters on assessment of neuroleptic-induced vacuous chewing movements.

Long-term administration of neuroleptics to rats produces a syndrome of vacuous chewing movements (VCMs). The validity of the VCM syndrome as a model for tardive dyskinesia (TD) in humans is unclear. This is due, in part, to inconsistencies between studies. Methods for rating VCMs have varied markedly and could account for the inconsistencies. The purpose of this study was to evaluate the importance of the different methods on VCM scores. The effects of habituation and length of rating sessions were examined in rats habituated for 2 min, 1 h, or several hours over 4 days, compared to unhabituated rats. Ratings with and without habituation were highly correlated, as were ratings from 2- and 5-min observation periods. Ratings from neuroleptic-treated rats in restraining tubes, however, were significantly correlated with unrestrained ratings only following several hours of habituation. Locomotor activity was not correlated with VCM scores. These results suggest that habituation to open cages is not an important factor in assessing VCMs. Use of restraining tubes, however, may alter scores. The lack of an habituation effect or of a relationship between activity and VCMs suggests that locomotor and oral behaviors are not necessarily in competition. Restraining rats to rate VCMs does not appear to be necessary and could alter the neurobiology of VCMs.

Behavioural assessment in rats of the antipsychotic potential of the potent dopamine D2 receptor antagonist, (-)eticlopride.

The effects of the selective D2 DA receptor antagonist, (-)eticlopride, a drug belonging to the benzamide class, were investigated on the D2 DA agonist SND 919- and CQP 201-403-induced stereotyped behaviour and on CQP 201-403-induced shaking, in rats, and on isolation-induced aggression, in mice. (-)Eticlopride was also tested over a wide dose range (5-1200 micrograms kg-1, s.c.) for sedative and cataleptic activity, in rats. For comparison, some experiments were performed with (-)sulpiride (10 and 40 mg kg-1, s.c.) The data obtained show that (-)eticlopride differs from (-)sulpiride and potentially modifies animal behaviour, whether spontaneous or induced; moreover, they suggest a potential clinical use for this neuroleptic in the management of psychotic states.

Behavioural assessment of pinealectomy and foetal pineal gland transplantation in rats: Part II.

Pineal gland is an endocrine organ which exerts regulatory effects on the activity of various organs and systems. The present study was undertaken to highlight in experimental animals the possible integrative function of this endocrine organ on a behavioural pattern. Pinealectomy and foetal pineal gland transplantation to a subpial cortical area close to the pinealectomized region was performed. Behaviour was defined through motor activity induced by low (2 mg/kg) and high (10 mg/kg) doses of amphetamine in rats. It was shown that pinealectomy produced significant different patterns of behaviour induced by low and high doses of amphetamine. In sham operated animals low dose amphetamine induced a significant locomotor stimulation but without stereotyped activity. High dose amphetamine induced stereotyped activity. After pinealectomy even low dose amphetamine produced the behavioural pattern of stereotyped activity resembling a high dose amphetamine-induced behaviour. This differential effect of amphetamine, seen in pinealectomized rats, was completely restored after transplantation. On the other hand, melatonin treatment did not generate a significant alteration of behavioural profile either in the control or pinealectomized group of rats. Results are discussed with regard to the general regulatory function of the pineal gland.

Opponent-process theory and drug conditioning: an assessment for conditioned stimulant-induced movement.

Opponent-process theory occupies an important place in drug conditioning because it accounts for conditioned drug effects which are opposite to those induced by the drug itself. It has not been established, however, whether there is an opponent-process component to stimulant drug induced conditioned effects. In the present study the unilateral 6-hydroxydopamine (6-OHDA) rat model was used to examine this issue. Two groups of Sprague-Dawley rats with equivalent 6-OHDA lesions were administered five apomorphine treatments (0.05 mg/kg s.c.) either paired or unpaired to a 10-min test chamber placement. Apomorphine induced vigorous contralateral rotation and suppressed all ipsilateral rotation. While the apomorphine-induced contralateral rotation response can be conditioned to the test environment cues, the critical test of opponent-process theory in the present study was whether the opposite response of ipsilateral rotation would also become conditioned as a latent opponent-process response to the exteroceptive test environment cues associated with the apomorphine drug state. The postacquisition saline test for conditioning showed that the paired group exhibited higher rates of contralateral and ipsilateral rotation compared to the unpaired group. In addition, when the animals were subsequently tested with the dopaminergic receptor antagonist, haloperidol (0.5 mg/kg), unexpectedly, contralateral rotation was enhanced in the paired group, whereas, ipsilateral rotation was suppressed in both groups. While these findings are, in part, compatible with an opponent-process mechanism, the data supported a simpler explanation; namely, the mechanism of differential habituation in the two groups due to a blocking effect of apomorphine on habituation selectively in the paired group.(ABSTRACT TRUNCATED AT 250 WORDS)

[Behavioral assessment of neuroleptics (2)--stereotypy].

This paper describes the definition of stereotypy and the different methods available for measuring both the form and the invariance of stereotyped behavior. With respect to the use of stereotypy for screening antipsychotic drugs, commonly used techniques for observing dopamine agonist-induced oral stereotypy in rats and the relevant points to analyze in the results are discussed. Apart from the ways of visually analyzing stereotyped behavior, some approaches for quantifying the intensity of stereotypy by using automated systems are also discussed.

An automated method for the assessment of spontaneous and stereotyped climbing behavior in mice. Effects of the selective D1- and D2-dopamine receptor agonists SKF-38393 and RU-24926 and their association.

A video-tracking technique has been used for the evaluation of climbing behavior in mice. An automated image analysis system, the Videotrack 512 (Electronique Lyonnaise), was adapted for this specific application. This allowed distinguishing between spontaneous climbing and stereotyped climbing. The activity duration of mice was simultaneously measured. In order to validate this method, in the present study the ability of apomorphine to induce climbing in mice, and the effects of the D1-dopamine receptor agonist SKF-38393 and the D2-dopamine agonist RU-24926 and their association were investigated.