"It Works for Me": Pseudotherapy Use is Associated With Trust in Their Efficacy Rather Than Belief in Their Scientific Validity.

Objectives: To identify how perceptions, attitudes, and beliefs towards pseudotherapies, health, medicine, and the public health system influence the pseudotherapy use in Spain. Methods: We carried out a cross-sectional study using the Survey of Social Perception of Science and Technology-2018 (5,200 interviews). Dependent variable: ever use of pseudotherapies. Covariables: attitude towards medicine, health and public health system; perceived health; assessment of the scientific character of homeopathy/acupuncture. The association was estimated using prevalence ratios obtained by Poisson regression models. The model was adjusted for age and socioeconomic variables. Results: Pseudotherapy use was higher in women (24.9%) than in men (14.2%) (p < 0.001). The probability of use in men (p < 0.001) and women (p < 0.001) increases with the belief in pseudotherapies' usefulness. Among men, a proactive attitude (reference: passive) towards medicine and health (RP:1.3), and a negative (reference: positive) assessment of the quality of the public health system increased use-probability (RP:1.2). For women, poor health perceived (referencie: good) increased likelihood of use (RP:1.2). Conclusion: Pseudotherapy use in Spain was associated with confidence in its usefulness irrespective of users' assessment of its scientific validity.

Enhanced noradrenergic activity in the amygdala contributes to hyperarousal in an animal model of PTSD.

Increased activity of the noradrenergic system in the amygdala has been suggested to contribute to the hyperarousal symptoms associated with post-traumatic stress disorder (PTSD). However, only two studies have examined the content of noradrenaline or its metabolites in the amygdala of rats previously exposed to traumatic stress showing inconsistent results. The aim of this study was to investigate the effects of an inescapable foot shock (IFS) procedure (1) on reactivity to novelty in an open-field (as an index of hyperarousal), and (2) on noradrenaline release in the amygdala during an acute stress. To test the role of noradrenaline in amygdala, we also investigated the effects of microinjections of propranolol, a ß-adrenoreceptor antagonist, and clenbuterol, a ß-adrenoreceptor agonist, into the amygdala of IFS and control animals. Finally, we evaluated the expression of mRNA levels of ß-adrenoreceptors (ß1 and ß2) in the amygdala, the hippocampus and the prefrontal cortex. Male Wistar rats (3 months) were stereotaxically implanted with bilateral guide cannulae. After recovering from surgery, animals were exposed to IFS (10 shocks, 0.86mA, and 6s per shock) and seven days later either microdialysis or microinjections were performed in amygdala. Animals exposed to IFS showed a reduced locomotion compared to non-shocked animals during the first 5min in the open-field. In the amygdala, IFS animals showed an enhanced increase of noradrenaline induced by stress compared to control animals. Bilateral microinjections of propranolol (0.5µg) into the amygdala one hour before testing in the open-field normalized the decreased locomotion observed in IFS animals. On the other hand, bilateral microinjections of clenbuterol (30ng) into the amygdala of control animals did not change the exploratory activity induced by novelty in the open field. IFS modified the mRNA expression of ß1 and ß2 adrenoreceptors in the prefrontal cortex and the hippocampus. These results suggest that an increased noradrenergic activity in the amygdala contributes to the expression of hyperarousal in an animal model of PTSD.

Infralimbic cortex controls the activity of the hypothalamus-pituitary-adrenal axis and the formation of aversive memory: Effects of environmental enrichment.

The aim of the present study was to investigate the effects of the stimulation and inhibition of the ventral part of the medial prefrontal cortex (infralimbic cortex) on basal and stress-induced plasma levels of corticosterone and on the acquisition of aversive memory in animals maintained in control and environmental enrichment (EE) conditions. Intracortical microinjections of the GABAA antagonist picrotoxin and agonist muscimol were performed in male Wistar rats to stimulate and inhibit, respectively, the activity of the infralimbic cortex. Injections were performed 60 min before foot shock stress and training in the inhibitory avoidance task. Picrotoxin injections into the infralimbic cortex increased basal plasma levels of corticosterone. These increases were higher in EE rats which suggest that EE enhances the control exerted by infralimbic cortex over the hypothalamus-pituitary-adrenal (HPA) axis and corticosterone release. Muscimol injections into the infralimbic cortex reduced the stress-induced plasma levels of corticosterone and the retention latency 24h after training in the inhibitory avoidance performance in control and EE animals, respectively. These results further suggest that the infralimbic cortex is required for the activation of the HPA axis during stress and for the acquisition of contextual aversive memories.

Stress, neurotransmitters, corticosterone and body-brain integration.

Stress can be defined as a brain-body reaction towards stimuli arising from the environment or from internal cues that are interpreted as a disruption of homeostasis. The organization of the response to a stressful situation involves not only the activity of different types of neurotransmitter systems in several areas of the limbic system, but also the response of neurons in these areas to several other chemicals and hormones, chiefly glucocorticoids, released from peripheral organs and glands. Thus, stress is probably the process through which body-brain integration plays a major role. Here we review first the responses to an acute stress in terms of neurotransmitters such as dopamine, acetylcholine, glutamate and GABA in areas of the brain involved in the regulation of stress responses. These areas include the prefrontal cortex, amygdala, hippocampus and nucleus accumbens and the interaction among those areas. Then, we consider the role of glucocorticoids and review some recent data about the interaction of these steroids with several neurotransmitters in those same areas of the brain. Also the actions of other substances (neuromodulators) released from peripheral organs such as the pancreas, liver or gonads (insulin, IGF-1, estrogens) are reviewed. The role of an environmental enrichment on these same responses is also discussed. Finally a section is devoted to put into perspective all these environmental-brain-body-brain interactions during stress and their consequences on aging. It is concluded that the integrative perspective framed in this review is relevant for better understanding of how the organism responds to stressful challenges and how this can be modified through different environmental conditions during the process of aging. This article is part of a Special Issue entitled: Brain Integration.

Aging increases basal but not stress-induced levels of corticosterone in the brain of the awake rat.

The main purpose of this study was to evaluate the effect of aging on plasma and free corticosterone (CORT) levels in the brain in basal conditions and in response to an acute stressor. Microdialysis experiments were performed in the hippocampus (HC) and the prefrontal cortex (PFC) of young adult (6 months) and aged (24 months) male Wistar rats. Basal free levels of CORT in the HC and the PFC were higher in aged animals. Restraint stress increased plasma CORT and free CORT levels in the HC and the PFC both in young and aged animals. However, while the increase of plasma CORT was higher in aged rats compared with young rats, the increases of free CORT in the HC and the PFC were not different between these two groups of rats. These results suggest that the changes produced by aging in the brain may be related to the enhanced basal levels of free CORT and not to the CORT increases in response to stress.

Prefrontal cortex, caloric restriction and stress during aging: studies on dopamine and acetylcholine release, BDNF and working memory.

This study was designed to investigate whether long-term caloric restriction during the life span of the rat changes the effects of an acute mild stress on the release of dopamine and acetylcholine in the prefrontal cortex (PFC) and on working memory performance. Spontaneous motor activity was also monitored and levels of BDNF measured in the prefrontal cortex, amygdala and hippocampus. Male Wistar rats (3 months of age) were housed during 3, 12, 21 and 27 months (6, 15, 24 and 30 months of age at the end of housing) in caloric restriction (CR; 40% food intake restriction) or control conditions. After behavioural testing, animals were further subdivided into two other groups. In one of the groups BDNF protein levels were determined. In the other group rats were implanted with guide cannulas into the PFC to perform microdialysis experiments. In CR rats the release of dopamine produced by handling stress did not differ from the response found in control rats of 6, 15 and 24 months of age. The release of acetylcholine was not changed at the ages of 6 and 15 months but reduced at the age of 24 months. Stress did not change dopamine or acetylcholine release in CR and control rats of 30 months of age. BDNF levels were increased in the hippocampus and amygdala, but not in the PFC, of 6 and 15 months CR rats. Spontaneous motor activity was increased in all groups of CR rats. Age, however, decreased motor activity in CR and control rats. Both experimental groups showed similar working memory performance in a delayed alternation task in basal conditions and after a situation of acute stress. These results suggest that CR does not modify the function of the PFC in response to an acute stress nor the changes found as a result of the normal process of aging.

Environmental enrichment increases the in vivo extracellular concentration of dopamine in the nucleus accumbens: a microdialysis study.

The present study was designed to elucidate the effects of environmental enrichment in adulthood (EE) on the in vivo basal and stimulated extracellular concentration of dopamine in the nucleus accumbens of awake rats. The effects of EE on novelty-induced motor activity in an open field and on the levels of brain-derived neurotrophic factor (BDNF) in the nucleus accumbens and striatum were also analysed. Male Wistar rats (3 months of age) were housed in enriched or control conditions during 12 months. After behavioural testing, animals were subdivided in two groups. In one of the groups, BDNF protein levels were determined. In the second group of rats, microdialysis experiments were performed to monitor dialysate concentrations of dopamine in the nucleus accumbens after the perfusion of the glutamatergic agonist α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA; 100 µM) or potassium (100 mM). Both basal and potassium stimulated dialysate concentrations of dopamine were higher in EE than in control rats (basal: 80%; potassium: 210%). EE did not significantly change the increases of dialysate concentrations of dopamine induced by AMPA although there was a trend towards an enhancement of the effects of AMPA. EE decreased novelty-induced locomotor activity but did not modify the levels of BDNF in the nucleus accumbens or in the striatum. These results suggest that the in vivo activity of the mesolimbic dopamine system is enhanced by housing rats in an enriched environment and that this effect is not mediated by BDNF. These findings may be relevant for the understanding of the effects of EE on motor behaviour.

Environmental enrichment, prefrontal cortex, stress, and aging of the brain.

As a result of living in an enriched environment, the brain of animals undergoes molecular and morphological changes leading to improvements in learning and memory. These improvements correlate well with increase in neurogenesis, synaptic density, or neurotrophic factors. We review here, in the context of the literature, the experiments performed in our own laboratory on the effects of environmental enrichment on the dynamics of dopamine and acetylcholine in the prefrontal cortex under a situation of acute mild stress. In these last studies we found that the release of dopamine and acetylcholine under stress is reduced in animals housed in an enriched environment. We also reported that the stress-induced release of dopamine but not acetylcholine is lower in aged rats compared with young rats. These results suggest that environmental enrichment reduces the reactivity to stress of the prefrontal dopaminergic and cholinergic systems in the rat. We further hypothesize that the positive effects on stress coping behaviors of housing animals in an enriched environment are associated with reductions, rather than increases, in the release of dopamine and acetylcholine in the prefrontal cortex. Finally we propose that a reduction in the stress-induced release of dopamine observed during aging in control animals might be an index of a better adaptation to stressful stimuli.

Blockade of NMDA receptors in the prefrontal cortex increases dopamine and acetylcholine release in the nucleus accumbens and motor activity.

OBJECTIVES: The present study investigates the effects of injections of a specific N-methyl-D-aspartic acid (NMDA) antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phophonic acid (CPP) into the prefrontal cortex (PFC) on the extracellular concentrations of dopamine and acetylcholine in the nucleus accumbens (NAc) and on motor activity in the freely moving rat. MATERIALS AND METHODS: Sprague-Dawley male rats were implanted with guide cannulas into the medial PFC and NAc to perform bilateral microinjections and microdialysis experiments. Spontaneous motor activity was monitored in the open field. RESULTS: Injections of CPP (1 microg/0.5 microL) into the PFC produced a significant increase of the baseline extracellular concentrations of dopamine (up to 130%), dihydroxyphenylacetic acid (DOPAC; up to 120%), homovanillic acid (HVA; up to 130%), and acetylcholine (up to 190%) in the NAc as well as motor hyperactivity. In the NAc, perfusion of the NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate antagonists CPP (50 microM)+6,7-dinitroquinoxaline-2,3-dione (DNQX; 50 microM) through the microdialysis probe blocked acetylcholine release, but not DOPAC and HVA increases produced by CPP injections into the PFC. Also, increases in motor activity produced by prefrontal injections of CPP were significantly reduced by bilateral injections into the NAc of a mixed D1/D2 antagonist, flupenthixol (5 and 25 microg/0.5 microL). Injections into the NAc of the muscarinic antagonist scopolamine (1 and 10 microg/0.5 microL) further increased, and of the nicotinic antagonist mecamylamine (1 and 10 microg/0.5 microL) did not change, the increases in motor activity produced by prefrontal CPP injections. CONCLUSIONS: These results suggest that the dysfunction of NMDA receptors in the PFC could be a key factor in the neurochemical and motor effects associated with corticolimbic hyperactivity.

Environmental enrichment reduces the response to stress of the cholinergic system in the prefrontal cortex during aging.

The present study was designed to evaluate the release of acetylcholine in the prefrontal cortex (PFC) induced by handling stress during aging and also to investigate whether this response changed as a result of the animals living in an enriched environment. Male Wistar rats of 3 months of age were housed in control and enriched conditions during the entire period of their adult life and experiments were performed at 6, 15 and 24 months of age. Spontaneous motor activity was first monitored in an open field arena. Then, rats were stereotaxically implanted with guide cannula to perform microdialysis experiments in the PFC and to evaluate the effects of stress on extracellular concentrations of acetylcholine. Handling stress increased the extracellular concentrations of acetylcholine in the PFC of control and enriched rats. These increases were not modified by aging in control rats. However, environmental enrichment (EE) reduced the effects of stress on acetylcholine concentrations in all groups of age. Spontaneous motor activity in the open field was reduced by aging. EE also decreased motor activity in all groups of age. These results suggest that EE reduces the reactivity to stress of the cholinergic system in the prefrontal cortex during aging.

Effects of an enriched environment on the release of dopamine in the prefrontal cortex produced by stress and on working memory during aging in the awake rat.

The present study was designed to investigate the effects of a mild acute stress on the in vivo release of dopamine in the prefrontal cortex (PFC) during aging and whether housing animals in an enriched environment changes these effects. Behavioural parameters such as spontaneous motor activity (open-field) and working memory performance in a delayed alternation task (water T-maze) were also studied. Male Wistar rats (3 months of age) were housed during 3, 12, and 21 months (6, 15 and 24 months of age at the end of housing) in enriched or control conditions. After behavioural testing, animals were subdivided in two groups. In one of the groups BDNF protein levels were determined in PFC, hippocampus and amygdala. Rats of the second group were implanted with guide cannula in the PFC to perform microdialysis experiments and to monitor extracellular concentrations of dopamine. The release of dopamine in the PFC produced by handling stress (40 min) was significantly reduced in both enriched and control 24 months animals. However, the increases of dopamine produced by stress were significantly lower in enriched animals when compared to controls. Similarly, the increases of dopamine produced by perfusing K(+) 100 mM into the PFC were also reduced by aging and environmental enrichment. Both spontaneous motor activity and working memory performance were significantly reduced by aging. Moreover, animals housed in an enriched environment did show a lower spontaneous motor activity at all ages studied, though they did not show any change in performing the working memory task, either in basal conditions or after an acute stress. The BDNF protein levels were increased by environmental enrichment in the hippocampus and amygdala, but not in the PFC. These results suggest that both environmental enrichment and aging reduces the activity of the mesocortical dopamine system.

Glutamate-dopamine-GABA interactions in the aging basal ganglia.

The study of neurotransmitter interactions gives a better understanding of the physiology of specific circuits in the brain. In this review we focus mostly on our own results on the interaction of the neurotransmitters glutamate, dopamine and GABA in the basal ganglia during the normal process of aging. We review first the studies on the action of endogenous glutamate on the extracellular concentrations of dopamine and GABA in the neostriatum and nucleus accumbens during aging. It was found that there exists an age-related change in the interaction of glutamate, dopamine and GABA and that these effects of aging exhibit a dorsal-to-ventral pattern of effects with no changes in the dorsal parts (dorsal striatum) and changes in the most ventral parts (nucleus accumbens). Second we reviewed the data on the effects of different ionotropic and metabotropic glutamate receptor agonists on the extracellular concentrations of dopamine and GABA in the nucleus accumbens. The results obtained clearly show the different contribution of each glutamate receptor subtype in the age-related changes produced on the interaction of glutamate, dopamine and GABA in this area of the brain. Third the effects of an enriched environment on the action of AMPA and NMDA-receptor agonists in the nucleus accumbens of rats during aging are also evaluated. Finally, and since the nucleus accumbens has been suggested to play a role in emotion and motivation and also motor behaviour, we speculated on the possibility of a specific contribution for the different glutamatergic pathways terminating in the nucleus accumbens and their interaction with a decreased dopamine playing a relevant role in motor behaviour during aging.

Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain.

Cajal was probably the first neurobiologist to suggest that plasticity of nerve cells almost completely disappeared during aging. However, we know today that neural plasticity is still present in the brain during aging. In this review we suggest that aging is a physiological process that occurs asynchronously in different areas of the brain and that the rate of that process is modulated by environmental factors and related to the neuronal-synaptic-molecular substrates of each area. We review here some of the most recent results on aging of the brain in relation to the plastic changes that occur in young and aged animals as a result of living in an enriched environment. We highlight the results from our own laboratory on the dynamics of neurotransmitters in different areas of the brain. Specifically we review first the effects of aging on neurons, dendrites, synapses, and also on molecular and functional plasticity. Second, the effects of environmental enrichment on the brain of young and aged animals. And third the effects of an enriched environment on the age-related changes in neurogenesis and in the extracellular concentrations of glutamate and GABA in hippocampus, and on dopamine, acetylcholine, glutamate and GABA under a situation of acute mild stress in the prefrontal cortex.

Stress, prefrontal cortex and environmental enrichment: studies on dopamine and acetylcholine release and working memory performance in rats.

The aim of the present study was to investigate whether environmental enrichment changes the effects of acute stress on both the release of dopamine and acetylcholine in the prefrontal cortex (PFC) and working memory performance. Male Wistar rats (3 months of age) were housed in enriched or control conditions during 12 months. Behavioural testing was carried out to assess working memory performance in a delayed alternation task (water escape T-maze). Horizontal and vertical motor activity were also monitored in the open field. After behavioural testing (open field and water T-maze), animals were implanted with guide cannula in the PFC to perform microdialysis experiments and to monitor dopamine and acetylcholine extracellular concentrations. Handling stress (40min) produced similar increases of extracellular concentrations of dopamine in the PFC of both enriched and control animals. In contrast, handling stress increased significantly the extracellular concentrations of acetylcholine in the PFC of control, but not enriched, animals. Exposing animals to a lit open field during 10min significantly reduced working memory performance assessed immediately in the water T-maze just in control animals, though these effects were not significantly different between both groups of animals. Spontaneous motor activity in the open field was lower in enriched compared to control animals. These results suggest that environmental enrichment changes acetylcholine, but not dopamine, reactivity to stress in the PFC.

Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged rats.

The aim of the present study was to investigate the effects of environmental enrichment on the neurogenesis and the extracellular concentrations of glutamate and GABA in the hippocampus of freely moving young and aged rats. Male Wistar rats of 2 (young) and 25 (old) months of age were housed during 8 weeks in an enriched environment; control rats were kept in individual plastic cages during that same period of time. Rats were injected intraperitoneally with bromodeoxyuridine (BrdU; 40 mg/kg; 7 days) during the fourth week of the housing period to detect neurogenesis in the dentate gyrus (DG) of the hippocampus. Rats were sacrified 6 weeks after the last injection of BrdU. During the last week of housing, rats were tested in the water maze for the evaluation of spatial learning. After the housing period, rats were stereotaxically implanted with guide-cannulas to accommodate microdialysis probes in the CA3 area of the hippocampus and the extracellular concentrations of glutamate and GABA were determined. Aged rats showed a decrease in the number of BrdU positive cells in the dentate gyrus compared to young rats. However, neurogenesis in the dentate gyrus of both young and old rats was increased in animals housed in an enriched environment. Microdialysis experiments in the CA3 area of the hippocampus showed that enriched housing conditions increased basal extracellular concentrations of glutamate in aged rats. Perfusion of KCl 100 mM produced a higher increase of extracellular glutamate and GABA in aged rats but not in young rats housed in an enriched environment compared to control rats. These results suggest that enriched housing conditions change both neurogenesis in the dentate gyrus and glutamate and GABA levels in the CA3 area of the hippocampus of aged rats.

Effects of the metabotropic glutamate receptor agonist, ACPD, on the extracellular concentrations of GABA and acetylcholine in the prefrontal cortex of the rat during the normal process of aging.

The aim of the present study was to investigate the effects of activation of metabotropic glutamate receptors (mGluR) on the extracellular concentrations of GABA and acetylcholine in the prefrontal cortex of freely moving rats of different groups of age. Perfusion, through the microdialysis probe, of the agonist of mGluR, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD; 100, 500 and 1000 microM), in the prefrontal cortex of young rats produced a dose-related increase of the dialysate concentrations of GABA. The effects of perfusion of ACPD on the concentrations of GABA were attenuated in middle-aged rats. In the prefrontal cortex of aged rats, perfusion of ACPD produced no changes in dialysate concentrations of GABA at any of the doses used. Conversely, perfusion of ACPD (100, 500 and 1000 microM) in the prefrontal cortex of young, middle-aged and aged rats did not modify the dialysate concentrations of acetylcholine. Basal concentrations of acetylcholine in the prefrontal cortex of middle-aged and aged rats were significantly lower than those in young rats. In contrast, basal dialysate concentrations of GABA were not significantly different in young, middle-aged and aged rats. These results suggest that the interaction GABA-glutamate in the prefrontal cortex, mediated by mGluRs, changes with age.

Dopamine and GABA increases produced by activation of glutamate receptors in the nucleus accumbens are decreased during aging.

The aim of the present study was to investigate the effects of aging on the increases of dopamine and GABA induced by activation of ionotropic and metabotropic glutamate receptors in the nucleus accumbens of the freely moving rat. The effects of local perfusion of the agonists NMDA (10, 100 and 500 microM), AMPA (1, 20 and 100 microM) and ACPD (100, 500 and 1000 microM) on extracellular concentration of dopamine and GABA in the nucleus accumbens of young (2-4 months), middle-aged (10-14 months) and aged (24-32 months) male Wistar rats were studied using microdialysis. In young rats, perfusion of the agonists NMDA and AMPA, but not ACPD, produced an increase of dialysate concentrations of dopamine. Perfusion of the three glutamate agonists (NMDA, AMPA and ACPD) produced an increase of dialysate GABA. This increase was delayed in time compared with the increase of dopamine. In the nucleus accumbens of middle-aged and aged rats, the increases of dopamine induced by NMDA were significantly lower than those in young rats. Also the increases of dopamine induced by AMPA were lower in aged rats than those in young rats. The effects of AMPA, NMDA and ACPD on dialysate GABA were significantly lower in aged rats than in young rats. These findings suggest that aging changes the interaction between the neurotransmitters glutamate and dopamine and glutamate and GABA in the nucleus accumbens of the freely moving rat.

Effects of CB1 cannabinoid receptor modulating compounds on the hyperkinesia induced by high-dose levodopa in the reserpine-treated rat model of Parkinson's disease.

The present study was designed to determine the potential of CB1 cannabinoid receptor modulating compounds in the treatment of L-3,4-dihydroxyphenylalanine (L-dopa)-induced dyskinesia in Parkinson's disease. In the reserpine-treated rat model of parkinsonism, administration of a high dose of L-dopa (150 mg/kg) but not of Cl-APB (0.5 mg/kg) or quinpirole (0.5 mg/kg) produced a hyperkinetic state characterised by an increase in horizontal and vertical activity, which likely represent correlates of antiparkinsonian and dyskinetic activity, respectively. Injection of the CB1 cannabinoid receptor antagonist SR141716 (0.1-3 mg/kg) reduced the increase in vertical activity elicited by L-dopa without affecting the increase in horizontal activity. Injection of the CB1 cannabinoid receptor agonist WIN55,212-2 (0.1-3 mg/kg) reduced the L-dopa-induced increase in vertical activity and, at the highest dose only (3 mg/kg), also reduced horizontal activity elicited by L-dopa. WIN55,212-2 (1 mg/kg) reduced motor activity induced by both the D1 receptor agonist Cl-APB (0.5 mg/kg) and the D2 receptor agonist quinpirole (0.5 mg/kg) in the reserpine-treated rat. SR141716 (1 mg/kg) had no effects on motor activity induced by Cl-APB (0.5 mg/kg) nor quinpirole (0.5 mg/kg) in the reserpine-treated rat. Injection of the inhibitor of endocannabinoid transport AM404 (0.1-1 mg/kg) did not affect the increase in horizontal or vertical activity elicited by L-dopa (150 mg/kg) in the reserpine-treated rat. The data suggest that both CB1 cannabinoid receptor antagonists and agonists can modulate the behavioural effects of L-dopa and may be useful for the treatment of the dyskinesia associated with long-term L-dopa treatment of Parkinson's disease.