[Show abstract][Hide abstract] ABSTRACT: The superior colliculus is a hub for multisensory integration necessary for visuo-spatial orientation, control of gaze movements and attention. The multiple functions of the superior colliculus have prompted hypotheses about its involvement in neuropsychiatric conditions, but to date, this topic has not been addressed experimentally. We describe experiments on genetically modified mice, the Isl2-EphA3 knock-in line, that show a well-characterized duplication of the retino-collicular and cortico-collicular axonal projections leading to hyperstimulation of the superior colliculus. To explore the functional impact of collicular hyperstimulation, we compared the performance of homozygous knock-in, heterozygous knock-in and wild-type mice in several behavioral tasks requiring collicular activity. The light/dark box test and Go/No-Go conditioning task revealed that homozygous mutant mice exhibit defective response inhibition, a form of impulsivity. This defect was specific to attention as other tests showed no differences in visually driven behavior, motivation, visuo-spatial learning and sensorimotor abilities among the different groups of mice. Monoamine quantification and gene expression profiling demonstrated a specific enrichment of noradrenaline only in the superficial layers of the superior colliculus of Isl2-EphA3 knock-in mice, where the retinotopy is duplicated, whereas transcript levels of receptors, transporters and metabolic enzymes of the monoaminergic pathway were not affected. We demonstrate that the defect in response inhibition is a consequence of noradrenaline imbalance in the superficial layers of the superior colliculus caused by retinotopic map duplication. Our results suggest that structural abnormalities in the superior colliculus can cause defective response inhibition, a key feature of attention-deficit disorders.
Brain Structure and Function 03/2014; · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The lateral habenula (LHb) is an epithalamic structure connected with both the basal ganglia and the limbic system and which exerts a major influence on midbrain monoaminergic nuclei. The current view is that the LHb receives and processes cortical information in order to select proper strategies in a variety of behavior. Recent evidence indicates that the LHb might also be implicated in hippocampus-dependent memory processes. However, if and how the LHb functionally interacts with the dorsal hippocampus (dHPC) is still unknown. We therefore performed simultaneous recordings within the LHb and the dHPC in both anesthetized and freely-moving rats. We first showed that a subset of LHb cells were phase-locked to hippocampal theta oscillations. Furthermore, the LHb generated spontaneous theta oscillatory activity which was highly coherent with hippocampal theta oscillations. Using reversible LHb inactivation, we found that the LHb might regulate dHPC theta oscillations. In addition, we showed that LHb silencing altered performance in a hippocampus-dependent spatial recognition task. Finally, increased coherence between the LHb and the dHPC was positively correlated to the memory performance in this test. Collectively, these results suggest that the LHb functionally interacts with the hippocampus and is involved in hippocampus-dependent spatial information processing.Neuropsychopharmacology accepted article preview online, 5 June 2013; doi:10.1038/npp.2013.142.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2013; · 8.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mild cognitive impairment (MCI) is a clinical condition that often precedes Alzheimer disease (AD). Compared with apolipoprotein E-ε3 (APOE3), the apolipoprotein E-ε4 (APOE4) allele is associated with an increased risk of developing MCI and spatial navigation impairments. In MCI, the entorhinal cortex (EC), which is the main innervation source of the dentate gyrus, displays partial neuronal loss. We show that bilateral partial EC lesions lead to marked spatial memory deficits and reduced synaptic density in the dentate gyrus of APOE4 mice compared with APOE3 mice. Genotype and lesion status did not affect the performance in non-navigational tasks. Thus, partial EC lesions in APOE4 mice were sufficient to induce severe spatial memory impairments and synaptic loss in the dentate gyrus. In addition, lesioned APOE4 mice showed no evidence of reactional increase in cholinergic terminals density as opposed to APOE3 mice, suggesting that APOE4 interferes with the ability of the cholinergic system to respond to EC input loss. These findings provide a possible mechanism underlying the aggravating effect of APOE4 on the cognitive outcome of MCI patients.
Neurobiology of aging 05/2013; · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Electrophysiological and neuroanatomical evidence for reciprocal connections with the medial prefrontal cortex (mPFC) and the hippocampus make the reuniens and rhomboid (ReRh) thalamic nuclei a putatively major functional link for regulations of cortico-hippocampal interactions. In a first experiment using a new water escape device for rodents, the double-H maze, we demonstrated in rats that a bilateral muscimol (MSCI) inactivation (0.70 vs 0.26 and 0 nmol) of the mPFC or dorsal hippocampus (dHip) induces major deficits in a strategy shifting/spatial memory retrieval task. By way of comparison, only dHip inactivation impaired recall in a classical spatial memory task in the Morris water maze. In the second experiment, we showed that ReRh inactivation using 0.70 nmol of MSCI, which reduced performance without obliterating memory retrieval in the water maze, produces an as large strategy shifting/memory retrieval deficit as mPFC or dHip inactivation in the double-H maze. Thus, behavioral adaptations to task contingency modifications requiring a shift toward the use of a memory for place might operate in a distributed circuit encompassing the mPFC (as the potential set-shifting structure), the hippocampus (as the spatial memory substrate), and the ventral midline thalamus, and therein the ReRh (as the coordinator of this processing). The results of the current experiments provide a significant extension of our understanding of the involvement of ventral midline thalamic nuclei in cognitive processes: they point to a role of the ReRh in strategy shifting in a memory task requiring cortical and hippocampal functions and further elucidate the functional system underlying behavioral flexibility.
Journal of Neuroscience 05/2013; 33(20):8772-83. · 6.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The APOE-ɛ4 allele is associated with increased cognitive decline during normal aging and Alzheimer's disease. However, several studies intriguingly found a beneficial effect on cognition in young adult human APOE-ɛ4 carriers. Here, we show that 3-month old bigenic hAPP-Yac/apoE4-TR mice outperformed their hAPP-Yac/apoE3-TR counterparts on learning and memory performances in the highly hippocampus-dependent, hidden-platform version of the Morris water maze task. The two mouse lines did not differ in a non-spatial visible-platform version of the task. This hAPP-Yac/apoE-TR model may thus provide a useful tool to study the mechanisms involved in the antagonistic pleiotropic effects of APOE-ɛ4 on cognitive functions.
Behavioural brain research 01/2013; · 3.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Electrophysiological and neuroanatomical evidence for reciprocal connections with the medial prefrontal cortex (mPFC) and the hip-pocampus make the reuniens and rhomboid (ReRh) thalamic nuclei a putatively major functional link for regulations of cortico-hippocampal interactions. In a first experiment using a new water escape device for rodents, the double-H maze, we demonstrated in rats that a bilateral muscimol (MSCI) inactivation (0.70 vs 0.26 and 0 nmol) of the mPFC or dorsal hippocampus (dHip) induces major deficits in a strategy shifting/spatial memory retrieval task. By way of comparison, only dHip inactivation impaired recall in a classical spatial memory task in the Morris water maze. In the second experiment, we showed that ReRh inactivation using 0.70 nmol of MSCI, which reduced performance without obliterating memory retrieval in the water maze, produces an as large strategy shifting/memory retrieval deficit as mPFC or dHip inactivation in the double-H maze. Thus, behavioral adaptations to task contingency modifications requiring a shift toward the use of a memory for place might operate in a distributed circuit encompassing the mPFC (as the potential set-shifting structure), the hippocampus (as the spatial memory substrate), and the ventral midline thalamus, and therein the ReRh (as the coordi-nator of this processing). The results of the current experiments provide a significant extension of our understanding of the involvement of ventral midline thalamic nuclei in cognitive processes: they point to a role of the ReRh in strategy shifting in a memory task requiring cortical and hippocampal functions and further elucidate the functional system underlying behavioral flexibility.
[Show abstract][Hide abstract] ABSTRACT: The formation of enduring declarative-like memories engages a dialog between the hippocampus and the prefrontal cortex (PFC). Electrophysiological and neuroanatomical evidence for reciprocal connections with both of these structures makes the reuniens and rhomboid nuclei (ReRh) of the thalamus a major functional link between the PFC and hippocampus. Using immediate early gene imaging (c-Fos), fiber-sparing excitotoxic lesion, and reversible inactivation in rats, we provide evidence demonstrating a contribution of the ReRh to the persistence of a spatial memory. Intact rats trained in a Morris water maze showed increased c-Fos expression (vs home cage and visible platform groups: >500%) in the ReRh when tested in a probe trial at a 25 d delay, against no change at a 5 d delay; behavioral performance was comparable at both delays. In rats subjected to excitotoxic fiber-sparing NMDA lesions circumscribed to the ReRh, we found normal acquisition of the water-maze task (vs sham-operated controls) and normal probe trial performance at the 5 d delay, but there was no evidence for memory retrieval at the 25 d delay. In rats having learned the water-maze task, lidocaine-induced inactivation of the ReRh right before the probe trial did not alter memory retrieval tested at the 5 d or 25 d delay. Together, these data suggest an implication of the ReRh in the long-term consolidation of a spatial memory at the system level. These nuclei could then be a key structure contributing to the transformation of a new hippocampal-dependent spatial memory into a remote one also depending on cortical networks.
Journal of Neuroscience 07/2012; 32(29):9947-59. · 6.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We assessed lifelong environmental enrichment effects on possible age-related modifications in emotional behaviors, spatial memory acquisition, retrieval of recent and remote spatial memory, and cholinergic forebrain systems. At the age of 1 month, Long-Evans female rats were placed in standard or enriched rearing conditions and tested after 3 (young), 12 (middle-aged), or 24 (aged) months. Environmental enrichment decreased the reactivity to stressful situations regardless of age. In the water maze test, it delayed the onset of learning deficits and prevented age-dependent spatial learning and recent memory retrieval alterations. Remote memory retrieval, which was altered independently of age under standard rearing conditions, was rescued by enrichment in young and middle-aged, but unfortunately not aged rats. A protected basal forebrain cholinergic system, which could well be one out of several neuronal manifestations of lifelong environmental enrichment, might have contributed to the behavioral benefits of this enrichment.
[Show abstract][Hide abstract] ABSTRACT: Animals can perform goal-directed tasks by using response cues or place cues. The underlying memory systems are occasionally presented as competing. Using the double-H maze test (Pol-Bodetto et al.), we trained rats for response learning and, 24 h later, tested their memory in a 60-s probe trial using a new start place. A modest shift of the start place (translation: 60-cm to the left) provided a high misleading potential, whereas a marked shift (180° rotation; shift to the opposite) provided a low misleading potential. We analyzed each rat's first arm choice (to assess response vs. place memory retrieval) and its subsequent search for the former platform location (to assess the persistence in place memory or the shift from response to place memory). After the translation, response memory-based behavior was found in more than 90% rats (24/26). After the rotation, place memory-based behavior was observed in 50% rats, the others showing response memory or failing. Rats starting to use response cues were nevertheless able to subsequently shift to place ones. A posteriori behavioral analyses showed more and longer stops in rats starting their probe trial on the basis of place (vs. response) cues. These observations qualify the idea of competing memory systems for responses and places and are compatible with that of a cooperation between both systems according to principles of match/mismatch computation (at the start of a probe trial) and of error-driven adjustment (during the ongoing probe trial).
Behavioural brain research 02/2012; 230(2):333-42. · 3.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Current views posit the dorsal hippocampus (DHipp) as contributing to spatial memory processes. Conversely, the ventral hippocampus (VHipp) modulates stress, emotions and affects. Arguments supporting this segregation include differences in (i) connectivity: the DHipp is connected with the entorhinal cortex which receives visuospatial neocortical inputs; the VHipp is connected with both the amygdala and hypothalamus, (ii) electrophysiological characteristics: there is a larger proportion of place cells in the DHipp than in the VHipp, and an increasing dorsoventral gradient in the size of place fields, suggesting less refined spatial coding in the VHipp, and (iii) consequences of lesions: spatial memory is altered after DHipp lesions, less dramatically, sometimes not, after VHipp lesions. Using reversible inactivation, we report in rats, that lidocaine infusions into the DHipp or VHipp right before a probe trial impair retrieval performance in a water-maze task. This impairment was found at two post-acquisition delays compatible with recent memory (1 and 5 days). Pre-training blockade of the VHipp did not prevent task acquisition and drug-free retrieval, on the contrary to pre-training blockade of DHipp, which altered performance in a subsequent drug-free probe trial. Complementary experiments excluded possible locomotor, sensorimotor, motivational or anxiety-related biases from data interpretation. Our conclusion is that a spatial memory can be acquired with the DHipp, less efficiently with the VHipp, and that the retrieval of such a memory and/or the expression of its representation engages the dorsoventral axis of the hippocampus when the task has been learnt with an entirely functional hippocampus.
Brain Structure and Function 06/2011; 217(1):93-106. · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: According to systems consolidation, as hippocampal-dependent memories mature over time, they become additionally (or exclusively) dependent on extra-hippocampal structures. We assessed the recruitment of hippocampal and cortical structures on remote memory retrieval in a performance-degradation resistant (PDR; no performance degradation with time) versus performance-degradation prone (PDP; performance degraded with time) context. Using a water-maze task in two contexts with a hidden platform and three control conditions (home cage, visible platform with or without access to distal cues), we compared neuronal activation (c-Fos imaging) patterns in the dorsal hippocampus and the medial prefrontal cortex (mPFC) after the retrieval of recent (5 days) versus remote (25 days) spatial memory. In the PDR context, the hippocampus exhibited greater c-Fos protein expression on remote than recent memory retrieval, be it in the visible or hidden platform group. In the PDP context, hippocampal activation increased at the remote time point and only in the hidden platform group. In the anterior cingulate cortex, c-Fos expression was greater for remote than for recent memory retrieval and only in the PDR context. The necessity of the mPFC for remote memory retrieval in the PDR context was confirmed using region-specific lidocaine inactivation, which had no impact on recent memory. Conversely, inactivation of the dorsal hippocampus impaired both recent and remote memory in the PDR context, and only recent memory in the PDP context, in which remote memory performance was degraded. While confirming that neuronal circuits supporting spatial memory consolidation are reorganized in a time-dependent manner, our findings further indicate that mPFC and hippocampus recruitment (i) depends on the content and perhaps the strength of the memory and (ii) may be influenced by the environmental conditions (e.g., cue saliency, complexity) in which memories are initially formed and subsequently recalled.
[Show abstract][Hide abstract] ABSTRACT: Aged rodents exhibit memory and attention dysfunctions. Environmental enrichment (EE) attenuates memory impairments. Whether it may reduce attention deficits is not known. At the age of 1 month, Long-Evans female rats were placed in standard or EE conditions and tested after 3 (young), 12 (middle-aged) or 24 (aged) months of differential housing. Spatial reference memory was assessed in a water-maze task. Attention performance was evaluated in the five-choice serial reaction time (5-CSRT) task. EE improved spatial memory at all ages, but did not ameliorate 5-CSRT performance in young and middle-aged rats; it prevented, however, the degradation of attention performances detected in aged rats. The number of ChAT (+30 to +64%)- and p75(NTR)-positive (+35 to +44%) neurons was higher in the basal forebrain of aged enriched vs. standard rats, suggesting their EE-mediated protection. The weaker deficit of attention found in aged EE rats might be linked to a better survival in the very long term of neurons in the basalo-cortical system.
Neurobiology of aging 05/2009; 32(4):718-36. · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The club drug ecstasy (3,4-methylenedioxymethylamphetamine or MDMA) is often taken recreationally with ethanol (EtOH). We have shown previously that EtOH potentiates the psychomotor effects of MDMA in rats. More recently, we demonstrated in striatal slices that MDMA produced preferential release of serotonin, but when combined with EtOH, the preferential release shifted to dopamine, raising the possibility that administration of EtOH may increase the reward effect of MDMA. To address this possibility, adult male Long-Evans rats were tested for conditioned place preference following treatment with saline, EtOH (0.75 g/kg), MDMA (6.6 mg/kg) or the combination. The only condition that produced a preference for the compartment associated with the drug was that of the drug combination. The current data are in line with anecdotal reports and one study in humans, indicating that EtOH alters the pharmacological effects of MDMA including self reports of enhanced or prolonged euphoria. Thus, administration of EtOH might increase the risk for compulsive use of MDMA, an issue that warrants further study.
Journal of Psychopharmacology 04/2009; 24(2):275-9. · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ecstasy (3,4-methylenedioxymethylamphetamine; MDMA) is a popular club drug often taken with ethanol (EtOH). We recently found EtOH potentiated the psychomotor effects of MDMA in rats. This potentiation could reflect pharmacodynamic or/and pharmacokinetic processes. To test the latter hypothesis, rats were injected i.p. with 6.6 or 10 mg/kg MDMA with or without 1.5 g/kg EtOH, and were killed at 5, 15 or 60 min after injection. MDMA, its primary metabolite, 3,4-methylenedioxyamphetamine (MDA), and EtOH concentrations were determined in the plasma and the hippocampus, frontal cortex and striatum at each time-point. EtOH potentiated MDMA-induced hyperactivity mainly during the first 60 min post-administration. Fifteen and 60 min after treatment with MDMA and EtOH, MDMA concentrations were greater than after MDMA alone in the blood and the three brain regions examined. EtOH, however, did not increase the fraction of MDMA converted to MDA, as shown by unaltered MDA/MDMA ratios at either MDMA dose. Interestingly, when combined with EtOH, the distribution of MDMA and MDA in the brain was not homogeneous. Concentrations of both were much higher in the striatum and cortex, than in the hippocampus. Thus, at least part of the potentiation of the MDMA-induced hyperlocomotion by EtOH might be the result of a higher concentration of MDMA and metabolites in the blood and brain. Our results present clear evidence that EtOH increases brain and blood concentrations of MDMA and leads to the possibility of both enhanced MDMA-based neurotoxicity and increased liability for abuse.
The International Journal of Neuropsychopharmacology 01/2009; 12(6):749-59. · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: New amphiphilic derivatives of sodium alginate were prepared by covalent attachment of dodecylamine onto the polysaccharide via amide linkages at different substitution ratios, using 2-chloro-1-methylpyridinium iodide (CMPI) as coupling reagent. The aim was to limit the progressive loss of associative behaviour which occurs in the case of previously described dodecyl ester alginate derivatives due to hydrolysis of ester bonds. A series of hydrogels was obtained which differed by the amount of attached dodecyl tails. The stability and viscoelastic properties were evaluated and compared to those of hydrogels obtained with alginate esters. The observed differences were discussed in relation to the synthesis procedures. The advantages of amide links are underlined, especially with regard to long-term stability of hydrogels.
Carbohydrate research 12/2008; 344(2):223-8. · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Apolipoprotein (apo) E4, one of three human apoE (h-apoE) isoforms, has been identified as a major genetic risk factor for Alzheimer's disease and for cognitive deficits associated with aging. However, the biological mechanisms involving apoE in learning and memory processes are unclear. A potential isoform-dependent role of apoE in cognitive processes was studied in human apoE targeted-replacement (TR) mice. These mice express either the human apoE3 or apoE4 gene under the control of endogenous murine apoE regulatory sequences, resulting in physiological expression of h-apoE in both a temporal and spatial pattern similar to humans. Male and female apoE3-TR, apoE4-TR, apoE-knockout and C57BL/6J mice (15-18 months) were tested with spatial memory and avoidance conditioning tasks. Compared to apoE3-TR mice, spatial memory in female apoE4-TR mice was impaired based on their poor performances in; (i) the probe test of the water-maze reference memory task, (ii) the water-maze working memory task and (iii) an active avoidance Y-maze task. Retention performance on a passive avoidance task was also impaired in apoE4-TR mice, but not in other genotypes. These deficits in both spatial and avoidance memory tasks may be related to the anatomical and functional abnormalities previously reported in the hippocampus and the amygdala of apoE4-TR mice. We conclude that the apoE4-TR mice provide an excellent model for understanding the mechanisms underlying apoE4-dependent susceptibility to cognitive decline.
Behavioural Brain Research 06/2008; 193(2):174-82. · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study investigated if sub-populations of rats characterized by their basal level of impulsivity (BLI) in a delayed-reinforcement task, displayed differences in the functioning of neurotransmitter systems modulating impulsive choice behavior. For this, the effects of various doses of caffeine and d-amphetamine were investigated in three sub-populations of rats displaying pronounced differences in their impulsive choice behavior and their post-mortem serotonergic and dopaminergic functions were assessed. Caffeine and d-amphetamine reduce impulsive choice behavior only in the Medium BLI sub-population. Dopamine utilization was similar in the three sub-populations, but serotonin utilization was lower in the prefrontal cortex of the Medium and Very high BLI sub-populations as compared to the low BLI one. These results suggest that anti-impulsive effects of caffeine and d-amphetamine are dependent on the BLI of rats and that a low serotonergic function in the prefrontal cortex may be a trait marker of impulsivity evaluated by impulsive choice behavior.
Behavioural Brain Research 04/2008; 187(2):273-83. · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: (+/-)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is often taken recreationally with ethanol (EtOH). In rats, EtOH may potentiate MDMA-induced hyperactivity, but attenuate hyperthermia.
Experiment 1 compared the interactions between EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) with EtOH + cocaine (COCA; 10 mg/kg) and EtOH + amphetamine (AMPH; 1 mg/kg) on locomotor activity and thermoregulation. Experiment 2 used a weaker dose of MDMA (3.3 mg/kg) and larger doses of COCA (20 mg/kg) and AMPH (2 mg/kg).
Drug treatments were administered on four occasions (2, 5, and 2 days apart, respectively; experiment 1) or two (2 days apart; experiment 2).
All psychostimulants increased activity, and EtOH markedly increased the effect of MDMA. AMPH alone-related hyperactivity showed modest sensitization across treatment days, while MDMA + EtOH activity showed marked sensitization. AMPH, COCA, and MDMA induced hyperthermia of comparable amplitude (+1 to +1.5 degrees C). Co-treatment with EtOH and AMPH (1 mg/kg) or COCA (10 mg/kg) produced hypothermia greater than that produced by EtOH alone. Conversely, EtOH attenuated MDMA-related hyperthermia, an effect increasing across treatment days. These results demonstrate that the interaction between MDMA and EtOH may be different from the interaction between EtOH and AMPH or COCA.
Because of potential health-related consequences of such polydrug misuse, it is worth identifying the mechanisms underlying these interactions, especially between EtOH and MDMA. Given the different affinity profiles of the three drugs for serotonin, dopamine, and norepinephrine transporters, our results appear compatible with the possibility of an important role of serotonin in at least the EtOH-induced potentiation of MDMA-induced hyperlocomotion.
[Show abstract][Hide abstract] ABSTRACT: To assess a possible role for serotonin in the mediation of the behavioral changes induced by enriched housing conditions (EC), adult female Long-Evans rats sustaining a serotonin depletion (150 microg of 5,7-dihydroxytryptamine, icv) and sham-operated rats were housed postoperatively for 30 days in enriched (12 rats/large cage containing various objects) or standard housing conditions (2 rats/standard laboratory cage). Thereafter, anxiety responses (elevated plus-maze), locomotor activity (in the home-cage), sensori-motor capabilities (beam-walking task), and spatial memory (eight-arm radial maze) were assessed. Monoamine levels were subsequently measured in the frontoparietal cortex and the hippocampus. Overall, EC reduced anxiety-related responses, enhanced sensori-motor performance and improved the memory span in the initial stage of the spatial memory task. Despite a substantial reduction of serotonergic markers in the hippocampus (82%) and the cortex (74%), these positive effects of EC were not altered by the lesion. EC reduced the serotonin levels in the ventral hippocampus (particularly in unlesioned rats: -23%), increased serotonin turnover in the entire hippocampus (particularly in lesioned rats: +36%) and augmented the norepinephrine levels in the dorsal hippocampus (+68% in unlesioned and +49% in lesioned rats); no such alterations were found in the frontoparietal cortex. Our data suggest that an intact serotonergic system is not a prerequisite for the induction of positive behavioral effects by EC. The neurochemical changes found in the hippocampus of EC rats, however, show that the monoaminergic innervation of the hippocampus is a target of EC.
Neurobiology of Learning and Memory 08/2007; 88(1):1-10. · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In our previous work, we showed that ethanol (EtOH) potentiates 3,4-methylenedioxymethamphetamine (MDMA)-induced hyperlocomotion while protecting against its hyperthermic effects. Whereas the effect on activity were found on all days (although declining over the three first days), the protection against hyperthermia completely disappeared on the second day. The latter effect was previously thought to reflect tolerance to ethanol or the combination, per se.
In the present study, we changed the treatment regimen to irregular and longer intervals between treatments (48, 120, and again 48 h) to check if tolerance was still observed.
We found progressive sensitization of locomotor activity to EtOH (1.5 g/kg, i.p.)+MDMA (6.6 mg/kg, i.p.), and a partial EtOH protection against MDMA-induced hyperthermia that persisted after the first drug challenge day. When the monoamine neurotransmitters, dopamine, and serotonin were assessed 2 weeks after treatment, we found no consistent effect on the concentration of any of these neurotransmitters, whatever the treatment. Similarly, we found that regional brain concentrations of MDMA were not significantly affected by EtOH at a 45-min post-treatment delay; however, the overall ratio of the metabolite 3,4-methylenedioxyamphetamine (MDA) to MDMA was lower (overall, -16%) in animals treated with the combination compared to MDMA alone, indicating possible contribution of pharmacokinetic factors. This difference was especially marked in the striatum (-25%).
These findings shed new light on the consequences of EtOH-MDMA, taken together at a nearly normal ambient temperature, both in terms of motivation and potential risks for recreational drug users.