Background: Oxytocin (OT) has been suggested as a treatment to improve social behavior in autisti... more Background: Oxytocin (OT) has been suggested as a treatment to improve social behavior in autistic patients. Accordingly, the OT (Oxt Ϫ/Ϫ ) and the OT receptor null mice (Oxtr Ϫ/Ϫ ) display autistic-like deficits in social behavior, increased aggression, and reduced ultrasonic vocalization.
Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal ni... more Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4). The effects of CC4 on nAChRs were investigated using in vitro assays and animal behaviours. When electrophysiologically tested using heterologously expressed human subtypes, CC4 was less efficacious than cytisine on neuronal α4β2, α3β4, α7 and muscle-type receptors, and had no effect on 5-hydroxytryptamine3 receptors. Acting through α4β2 and α6β2 nAChRs, CC4 is a partial agonist of nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal effect on this response. In addition, it had low affinity for, and was less efficacious than nicotine and cytisine on the α3β4 and α7-nAChR subtypes. Like cytisine and nicotine, CC4-induced conditioned place preference (CPP), and its self-administration shows an inverted-U dose-response curve. Pretreatment with non-reinforcing doses of CC4 significantly reduced nicotine-induced self-administration and CPP without affecting motor functions. Our in vitro and in vivo findings reveal that CC4 selectively reduces behaviours associated with nicotine addiction consistent with the partial agonist selectivity of CC4 for β2-nAChRs. The results support the possible development of CC4 or its derivatives as a promising drug for tobacco smoking cessation.
Nicotine is the primary addictive substance in tobacco smoke and electronic cigarette (e-cig) vap... more Nicotine is the primary addictive substance in tobacco smoke and electronic cigarette (e-cig) vapour. Methodological limitations have made it difficult to compare the role of the nicotine and non-nicotine constituents of tobacco smoke. The aim of this study was to compare the effects of traditional cigarette smoke and e-cig vapour containing the same amount of nicotine in male BALB/ c mice exposed to the smoke of 21 cigarettes or e-cig vapour containing 16.8 mg of nicotine delivered by means of a mechanical ventilator for three 30-min sessions/day for seven weeks. One hour after the last session, half of the animals were sacrificed for neurochemical analysis, and the others underwent mecamylamine-precipitated or spontaneous withdrawal for the purposes of behavioural analysis. Chronic intermittent non-contingent, second-hand exposure to cigarette smoke or e-cig vapour led to similar brain cotinine and nicotine levels, similar urine cotinine levels and the similar up-regulation of α4β2 nicotinic acetylcholine receptors in different brain areas, but had different effects on body weight, food intake, and the signs of mecamylamine-precipitated and spontaneous withdrawal episodic memory and emotional responses. The findings of this study demonstrate for the first time that e-cig vapour induces addiction-related neurochemical, 1 3 5 7 Please cite this article as: Ponzoni, L, et al., Different physiological and behavioural effects of e-cigarette vapour and cigarette smoke in mice. European Neuropsychopharmacology (2015), http://dx.Ponzoni et al. 2 Please cite this article as: Ponzoni, L, et al., Different physiological and behavioural effects of e-cigarette vapour and cigarette smoke in mice. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.06.010
Autism Spectrum Disorder (ASD), Attention-deficit Hyperactivity Disorder (ADHD), schizophrenia, A... more Autism Spectrum Disorder (ASD), Attention-deficit Hyperactivity Disorder (ADHD), schizophrenia, Alzheimer's and Parkinson's disease are characterized by attentional deficits. In the present study we first applied the virtual object recognition test (VORT), where 3D objects were replaced with highly discriminated geometrical shapes and presented on two 3.5-inch widescreen displays, in different inbred mice strains (C57BL/6N, DBA/2J, BALB/cJ), in comparison with the standard object recognition test (NOR). In both NOR and VORT, there was a progressive decay of performance in terms of reduced discrimination index from 5min to 72h of inter-trial delay in all strains. However, BALB/cJ inbred mice showed a better long lasting performance than C57BL/6N and DBA/2J, when tested in NOR. In VORT, BALB/cJ showed the best performance. Total exploration time was always higher in BALB/cJ than C57BL/6N and DBA/2J mice. C57BL/6N were less explorative strain than DBA/2J and BALB/cJ mice. When VORT was applied to SNAP-25(+/-) mice, an impairment in both NOR and VORT was shown. However, when moving shapes were applied, these heterozygous mice improved their performance, suggesting that the introduction of motion is a strong cue that makes the task more valuable to study attention deficits. Taken together, these data indicate that VORT provides a useful and rapid tool to identify the attentional deficit in different inbred strains and genetically modified mice, enhancing the value of psychiatric mouse models.
The Journal of pharmacology and experimental therapeutics, 1995
Chronic administration of cocaine produces sensitization to its behavioral effects in humans and ... more Chronic administration of cocaine produces sensitization to its behavioral effects in humans and experimental animals. In the present study, rats treated with cocaine (10 mg/kg, i.p.) once daily for 10 days showed an enhancement in the acute drug stimulation of locomotor activity and stereotypy. Biochemical analysis in the nucleus accumbens of chronic cocaine-treated animals indicated that sensitization of D1 dopamine (DA) receptors had also developed. In fact, stimulation of adenylyl cyclase activity by DA was increased in nucleus accumbens membranes from sensitized rats. Our findings suggest that a novel postsynaptic mechanism, i.e., an increased DA-D1 receptor function, may play a role in the sensitization. A causal relationship between the two events is supported by the observation that neither motor behavioral sensitization nor DA-dependent adenylyl cyclase hyperactivity developed when the opiate antagonist naltrexone (2 mg/kg, s.c.) was given daily for 10 days before cocaine. ...
Synaptosomal-associated protein of 25 kDa (SNAP-25) is involved in different neuropsychiatric dis... more Synaptosomal-associated protein of 25 kDa (SNAP-25) is involved in different neuropsychiatric disorders, including schizophrenia and attention-deficit/hyperactivity disorder. Consistently, SNAP-25 polymorphisms in humans are associated with hyperactivity and/or with low cognitive scores. We analysed five SNAP-25 gene polymorphisms (rs363050, rs363039, rs363043, rs3746544 and rs1051312) in 46 autistic children trying to correlate them with Childhood Autism Rating Scale and electroencephalogram (EEG) abnormalities. The functional effects of rs363050 single-nucleotide polymorphism (SNP) on the gene transcriptional activity, by means of the luciferase reporter gene, were evaluated. To investigate the functional consequences that SNAP-25 reduction may have in children, the behaviour and EEG of SNAP-25 +/ − adolescent mice (SNAP-25 +/+ ) were studied. Significant association of SNAP-25 polymorphism with decreasing cognitive scores was observed. Analysis of transcriptional activity revealed that SNP rs363050 encompasses a regulatory element, leading to protein expression decrease. Reduction of SNAP-25 levels in adolescent mice was associated with hyperactivity, cognitive and social impairment and an abnormal EEG, characterized by the occurrence of frequent spikes. Both EEG abnormalities and behavioural deficits were rescued by repeated exposure for 21 days to sodium salt valproate (VLP). A partial recovery of SNAP-25 expression content in SNAP-25 +/ − hippocampi was also observed by means of western blotting. A reduced expression of SNAP-25 is responsible for the cognitive deficits in children affected by autism spectrum disorders, as presumably occurring in the presence of rs363050(G) allele, and for behavioural and EEG alterations in adolescent mice. VLP treatment could result in novel therapeutic strategies.
antiamnesic effect of a novel anticholinesterase inhibitor (MF268). PHARMACOL BIOCHEM BEHAV 59 (4... more antiamnesic effect of a novel anticholinesterase inhibitor (MF268). PHARMACOL BIOCHEM BEHAV 59 (4) 897-901, 1998.-In the present study a short (120 min) and long-lasting (360 min) antagonism of scopolamine-induced amnesia in rats was investigated in an eight-arm radial maze, by (3a S , 8a R )-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol[8-(cis2,6-dimethyl-morpholin-4-yl)octyl]-carbamate L -bitartrate hydrate (MF268), a new cholinesterase inhibitor. Upon completing the training session, the rats were orally administered increasing doses of MF268 (2, 3, 6, 7, and 8 mg/kg) 60 min prior to SC injection of scopolamine (0.25 mg/kg). Following a further 60 min the rat was placed in the maze. The reversal of scopolamine-induced impairment was characterized by an inverted U-shaped dose-response curve. A significant reduction in the number of errors, and time taken to complete the maze was observed with a dose of 6 mg/kg. The compound improved memory retention without affecting scopolamine-induced hypermotility. When the same dose was administered 360 min prior to the test a significant reduction in the number of amnesic animals was observed, whereas no cognitive improvement was detected when either 1-Benzil-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine hydrochloride (E2020) (0.25 mg/kg) or tacrine (0.5 mg/kg) were administered 360 min prior to the test. The kinetics of whole-brain cholinesterase confirmed the long-lasting activity for MF268. A clinical relevance for the use of MF268 in AD treatment is suggested.
Eptastigmine, a potent and long-lasting cholinesterase inhibitor on age-related memory deficits, ... more Eptastigmine, a potent and long-lasting cholinesterase inhibitor on age-related memory deficits, was studied. Four groups of 3-, 18-, 23-and 27-month-old Wistar rats were first submitted to spontaneous motor activity evaluation and then trained in an eight-arm radial maze until they reached the criterion. The effect of introducing a 2-h delay between the fourth and fifth choices was then evaluated under the influence of acute oral dose of eptastigmine (0.5 mg kg −1 ) 120 min before the test. Eptastigmine reversed the impairment observed in vehicle-treated rats at all the tested ages. Two naive groups of 3-and 18-month-old rats were treated twice a day for 30 days with eptastigmine (0.25 mg kg −1 p.o.) or vehicle and trained daily in the maze. Subchronic administration did not affect the performance in young rats, while in 18-month-old rats, the mean number of days needed to reach the criterion decreased and the percentage of animals reaching the criterion increased when compared to the vehicle group. The 18-month-old rats (ex-eptastigmine and ex-vehicle) were then allowed to age in their home cage without any further treatment for an additional 5 and 9 months, until they reached 23 and 27 months. The ex-eptastigmine rats tested at 23 months, without any treatment, showed better performance than that observed in ex-vehicle rats. When the same rats were tested again at 27 months of age, no difference was seen in comparison with ex-vehicle rats. Eptastigmine might, therefore, be helpful for correcting age-related memory impairment attributed to cholinergic hypofunction.
Given that a number of the techniques used to test drug abuse liability are not free from critici... more Given that a number of the techniques used to test drug abuse liability are not free from criticism, a series of oral free-choice experimental procedures was adopted. When simultaneously offered as alternatives to glucose using the classical polydipsic procedure, no preference for buprenorphine (0.025 mg/ml), morphine (0.5 mg/ml) or fentanyl (0.005 mg/ml) solutions was shown by premedicated rats. The same result was obtained when the two-bottle procedure was used for at least one month to offer etonitazene (10 micrograms/ml), buprenorphine (60 micrograms/ml), cocaine (300 micrograms/ml) and haloperidol (25 micrograms/ml) solutions as simultaneous alternatives to aspartame. This absence of preference was maintained even when the rats showed evident pharmacological effects and, in the case of the opiates, tolerance and withdrawal syndrome. However, when a gustatory marker (quinine) was introduced into one of the two solutions, preference was always shown for the other. Finally, in a conditioned taste aversion (CTA) test, etonitazene (5 or 40 micrograms/kg, i.p.) and haloperidol (0.5 or 2 mg/kg, i.p.) did not induce any reduction in saccharin consumption, while morphine (40 mg/kg) did. Pretreatment with naloxone (120 micrograms/kg, i.c.v.) did not antagonize morphine-induced CTA, while it did antagonize morphine-induced analgesia.
In a previous paper (Sala et el. 1989), rats submitted to a freechoice drinking schedule, were un... more In a previous paper (Sala et el. 1989), rats submitted to a freechoice drinking schedule, were unable to discriminate between plain water and untasted medicated solutions containing either etonitazene HCI (E), a strong synthetic u-opiate, or haloperidol (H), the well known anti-dopaminergic agent, both in concentrations high enough to induce evident neurobehavioral effects. To solve the problem whether animals were able to discriminate the central effects of such drugs, we decided to adopt the conditioned taste aversion (CTA) test, which may be induced not only by emetic agents but also by some psychoactive drugs, known to act as positive reinforcers. According to Garcia and Ervin (1968),male Wistar rats, waterdeprived for 24 h,, were daily trained to a period of 10 min access to water and submitted every third day to a 10 min drinking test with 0.1% saccharin solution in place of water.At the end of every session saccharin intake was measured. Five minutes after the end of each saccharin session , isotonic saline or the drugs .:were Lp, administered at the following dosage: E 5 and 40 llg)kg; H 0.5 and 2mg/kg; Lithium (L) 13mg/kg;apomorphine HCI (A) 7mg/kg and Morphine (M) 10 and 40mg/kg. Such three-days sessions were repeated ten times. Pharmacological effects (behavior, analgesia, catatonia) were evaluated 30' after the administration. As expected L,A and M in d u c e d a significant CTA. On the contrary E (either at low inactive dose or at strong analgesic and catatonic dose) and H (either at weakly catatonic low dose or at strongly catatonic high dose) were unable to modify saccharin intake. The obtained data confirm our previous findings of a substantial inability of the rat to discriminate central effects and are in agreement with the hypothesis that CTA may be induced only by drugs eliciting peripheral effects (Hunt and Amit,1987).
We studied the ability of eptastigmine, a second-generation acetylcholinesterase inhibitor (AChEI... more We studied the ability of eptastigmine, a second-generation acetylcholinesterase inhibitor (AChEI), to reverse the age-related increase of electroencephalogram (EEG) mean cortical spectral power in slow-wave δ activity and decrease in fast-wave α and β activity. The relative basal spectral power profile evaluated for 50 min of the old (27-30 months) in comparison to young (4-6 months) awake rats was consistently different, showing a significant increase in δ (0.2-4.0 Hz) frequency and a significant decrease of α (8.2-13.0 Hz) and β (13.2-25.0) bands. When 0.5, 1, 2, 4 mg kg −1 of eptastigmine were administered orally as single increasing doses for old and young rats 2 h prior to the EEG recordings, lasting 2 h, the relative mean spectral power difference ( %) showed a linear log dose-related decrease in δ activity and a progressive increase in α and β activity in old rats. Compared to vehicle, in young rats, the eptastigmine dose of 0.5 mg kg −1 produced a significant decrease in δ activity and an increase in β activity. The spontaneous motor activity, evaluated through cumulative horizontal and vertical counts for 30 min in old rats was significantly decreased when compared to young rats. Single oral treatment with eptastigmine (0.5 mg kg −1 for young and 2 mg kg −1 for old rats) given 2 h before the test did not significantly change motor activity in comparison to vehicle group of the same age. These results suggest a possible strategy to alleviate the severe slowing of neocortical EEG accompanying the cognitive decline.
Background: Oxytocin (OT) has been suggested as a treatment to improve social behavior in autisti... more Background: Oxytocin (OT) has been suggested as a treatment to improve social behavior in autistic patients. Accordingly, the OT (Oxt Ϫ/Ϫ ) and the OT receptor null mice (Oxtr Ϫ/Ϫ ) display autistic-like deficits in social behavior, increased aggression, and reduced ultrasonic vocalization.
Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal ni... more Many of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4). The effects of CC4 on nAChRs were investigated using in vitro assays and animal behaviours. When electrophysiologically tested using heterologously expressed human subtypes, CC4 was less efficacious than cytisine on neuronal α4β2, α3β4, α7 and muscle-type receptors, and had no effect on 5-hydroxytryptamine3 receptors. Acting through α4β2 and α6β2 nAChRs, CC4 is a partial agonist of nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal effect on this response. In addition, it had low affinity for, and was less efficacious than nicotine and cytisine on the α3β4 and α7-nAChR subtypes. Like cytisine and nicotine, CC4-induced conditioned place preference (CPP), and its self-administration shows an inverted-U dose-response curve. Pretreatment with non-reinforcing doses of CC4 significantly reduced nicotine-induced self-administration and CPP without affecting motor functions. Our in vitro and in vivo findings reveal that CC4 selectively reduces behaviours associated with nicotine addiction consistent with the partial agonist selectivity of CC4 for β2-nAChRs. The results support the possible development of CC4 or its derivatives as a promising drug for tobacco smoking cessation.
Nicotine is the primary addictive substance in tobacco smoke and electronic cigarette (e-cig) vap... more Nicotine is the primary addictive substance in tobacco smoke and electronic cigarette (e-cig) vapour. Methodological limitations have made it difficult to compare the role of the nicotine and non-nicotine constituents of tobacco smoke. The aim of this study was to compare the effects of traditional cigarette smoke and e-cig vapour containing the same amount of nicotine in male BALB/ c mice exposed to the smoke of 21 cigarettes or e-cig vapour containing 16.8 mg of nicotine delivered by means of a mechanical ventilator for three 30-min sessions/day for seven weeks. One hour after the last session, half of the animals were sacrificed for neurochemical analysis, and the others underwent mecamylamine-precipitated or spontaneous withdrawal for the purposes of behavioural analysis. Chronic intermittent non-contingent, second-hand exposure to cigarette smoke or e-cig vapour led to similar brain cotinine and nicotine levels, similar urine cotinine levels and the similar up-regulation of α4β2 nicotinic acetylcholine receptors in different brain areas, but had different effects on body weight, food intake, and the signs of mecamylamine-precipitated and spontaneous withdrawal episodic memory and emotional responses. The findings of this study demonstrate for the first time that e-cig vapour induces addiction-related neurochemical, 1 3 5 7 Please cite this article as: Ponzoni, L, et al., Different physiological and behavioural effects of e-cigarette vapour and cigarette smoke in mice. European Neuropsychopharmacology (2015), http://dx.Ponzoni et al. 2 Please cite this article as: Ponzoni, L, et al., Different physiological and behavioural effects of e-cigarette vapour and cigarette smoke in mice. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.06.010
Autism Spectrum Disorder (ASD), Attention-deficit Hyperactivity Disorder (ADHD), schizophrenia, A... more Autism Spectrum Disorder (ASD), Attention-deficit Hyperactivity Disorder (ADHD), schizophrenia, Alzheimer's and Parkinson's disease are characterized by attentional deficits. In the present study we first applied the virtual object recognition test (VORT), where 3D objects were replaced with highly discriminated geometrical shapes and presented on two 3.5-inch widescreen displays, in different inbred mice strains (C57BL/6N, DBA/2J, BALB/cJ), in comparison with the standard object recognition test (NOR). In both NOR and VORT, there was a progressive decay of performance in terms of reduced discrimination index from 5min to 72h of inter-trial delay in all strains. However, BALB/cJ inbred mice showed a better long lasting performance than C57BL/6N and DBA/2J, when tested in NOR. In VORT, BALB/cJ showed the best performance. Total exploration time was always higher in BALB/cJ than C57BL/6N and DBA/2J mice. C57BL/6N were less explorative strain than DBA/2J and BALB/cJ mice. When VORT was applied to SNAP-25(+/-) mice, an impairment in both NOR and VORT was shown. However, when moving shapes were applied, these heterozygous mice improved their performance, suggesting that the introduction of motion is a strong cue that makes the task more valuable to study attention deficits. Taken together, these data indicate that VORT provides a useful and rapid tool to identify the attentional deficit in different inbred strains and genetically modified mice, enhancing the value of psychiatric mouse models.
The Journal of pharmacology and experimental therapeutics, 1995
Chronic administration of cocaine produces sensitization to its behavioral effects in humans and ... more Chronic administration of cocaine produces sensitization to its behavioral effects in humans and experimental animals. In the present study, rats treated with cocaine (10 mg/kg, i.p.) once daily for 10 days showed an enhancement in the acute drug stimulation of locomotor activity and stereotypy. Biochemical analysis in the nucleus accumbens of chronic cocaine-treated animals indicated that sensitization of D1 dopamine (DA) receptors had also developed. In fact, stimulation of adenylyl cyclase activity by DA was increased in nucleus accumbens membranes from sensitized rats. Our findings suggest that a novel postsynaptic mechanism, i.e., an increased DA-D1 receptor function, may play a role in the sensitization. A causal relationship between the two events is supported by the observation that neither motor behavioral sensitization nor DA-dependent adenylyl cyclase hyperactivity developed when the opiate antagonist naltrexone (2 mg/kg, s.c.) was given daily for 10 days before cocaine. ...
Synaptosomal-associated protein of 25 kDa (SNAP-25) is involved in different neuropsychiatric dis... more Synaptosomal-associated protein of 25 kDa (SNAP-25) is involved in different neuropsychiatric disorders, including schizophrenia and attention-deficit/hyperactivity disorder. Consistently, SNAP-25 polymorphisms in humans are associated with hyperactivity and/or with low cognitive scores. We analysed five SNAP-25 gene polymorphisms (rs363050, rs363039, rs363043, rs3746544 and rs1051312) in 46 autistic children trying to correlate them with Childhood Autism Rating Scale and electroencephalogram (EEG) abnormalities. The functional effects of rs363050 single-nucleotide polymorphism (SNP) on the gene transcriptional activity, by means of the luciferase reporter gene, were evaluated. To investigate the functional consequences that SNAP-25 reduction may have in children, the behaviour and EEG of SNAP-25 +/ − adolescent mice (SNAP-25 +/+ ) were studied. Significant association of SNAP-25 polymorphism with decreasing cognitive scores was observed. Analysis of transcriptional activity revealed that SNP rs363050 encompasses a regulatory element, leading to protein expression decrease. Reduction of SNAP-25 levels in adolescent mice was associated with hyperactivity, cognitive and social impairment and an abnormal EEG, characterized by the occurrence of frequent spikes. Both EEG abnormalities and behavioural deficits were rescued by repeated exposure for 21 days to sodium salt valproate (VLP). A partial recovery of SNAP-25 expression content in SNAP-25 +/ − hippocampi was also observed by means of western blotting. A reduced expression of SNAP-25 is responsible for the cognitive deficits in children affected by autism spectrum disorders, as presumably occurring in the presence of rs363050(G) allele, and for behavioural and EEG alterations in adolescent mice. VLP treatment could result in novel therapeutic strategies.
antiamnesic effect of a novel anticholinesterase inhibitor (MF268). PHARMACOL BIOCHEM BEHAV 59 (4... more antiamnesic effect of a novel anticholinesterase inhibitor (MF268). PHARMACOL BIOCHEM BEHAV 59 (4) 897-901, 1998.-In the present study a short (120 min) and long-lasting (360 min) antagonism of scopolamine-induced amnesia in rats was investigated in an eight-arm radial maze, by (3a S , 8a R )-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol[8-(cis2,6-dimethyl-morpholin-4-yl)octyl]-carbamate L -bitartrate hydrate (MF268), a new cholinesterase inhibitor. Upon completing the training session, the rats were orally administered increasing doses of MF268 (2, 3, 6, 7, and 8 mg/kg) 60 min prior to SC injection of scopolamine (0.25 mg/kg). Following a further 60 min the rat was placed in the maze. The reversal of scopolamine-induced impairment was characterized by an inverted U-shaped dose-response curve. A significant reduction in the number of errors, and time taken to complete the maze was observed with a dose of 6 mg/kg. The compound improved memory retention without affecting scopolamine-induced hypermotility. When the same dose was administered 360 min prior to the test a significant reduction in the number of amnesic animals was observed, whereas no cognitive improvement was detected when either 1-Benzil-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine hydrochloride (E2020) (0.25 mg/kg) or tacrine (0.5 mg/kg) were administered 360 min prior to the test. The kinetics of whole-brain cholinesterase confirmed the long-lasting activity for MF268. A clinical relevance for the use of MF268 in AD treatment is suggested.
Eptastigmine, a potent and long-lasting cholinesterase inhibitor on age-related memory deficits, ... more Eptastigmine, a potent and long-lasting cholinesterase inhibitor on age-related memory deficits, was studied. Four groups of 3-, 18-, 23-and 27-month-old Wistar rats were first submitted to spontaneous motor activity evaluation and then trained in an eight-arm radial maze until they reached the criterion. The effect of introducing a 2-h delay between the fourth and fifth choices was then evaluated under the influence of acute oral dose of eptastigmine (0.5 mg kg −1 ) 120 min before the test. Eptastigmine reversed the impairment observed in vehicle-treated rats at all the tested ages. Two naive groups of 3-and 18-month-old rats were treated twice a day for 30 days with eptastigmine (0.25 mg kg −1 p.o.) or vehicle and trained daily in the maze. Subchronic administration did not affect the performance in young rats, while in 18-month-old rats, the mean number of days needed to reach the criterion decreased and the percentage of animals reaching the criterion increased when compared to the vehicle group. The 18-month-old rats (ex-eptastigmine and ex-vehicle) were then allowed to age in their home cage without any further treatment for an additional 5 and 9 months, until they reached 23 and 27 months. The ex-eptastigmine rats tested at 23 months, without any treatment, showed better performance than that observed in ex-vehicle rats. When the same rats were tested again at 27 months of age, no difference was seen in comparison with ex-vehicle rats. Eptastigmine might, therefore, be helpful for correcting age-related memory impairment attributed to cholinergic hypofunction.
Given that a number of the techniques used to test drug abuse liability are not free from critici... more Given that a number of the techniques used to test drug abuse liability are not free from criticism, a series of oral free-choice experimental procedures was adopted. When simultaneously offered as alternatives to glucose using the classical polydipsic procedure, no preference for buprenorphine (0.025 mg/ml), morphine (0.5 mg/ml) or fentanyl (0.005 mg/ml) solutions was shown by premedicated rats. The same result was obtained when the two-bottle procedure was used for at least one month to offer etonitazene (10 micrograms/ml), buprenorphine (60 micrograms/ml), cocaine (300 micrograms/ml) and haloperidol (25 micrograms/ml) solutions as simultaneous alternatives to aspartame. This absence of preference was maintained even when the rats showed evident pharmacological effects and, in the case of the opiates, tolerance and withdrawal syndrome. However, when a gustatory marker (quinine) was introduced into one of the two solutions, preference was always shown for the other. Finally, in a conditioned taste aversion (CTA) test, etonitazene (5 or 40 micrograms/kg, i.p.) and haloperidol (0.5 or 2 mg/kg, i.p.) did not induce any reduction in saccharin consumption, while morphine (40 mg/kg) did. Pretreatment with naloxone (120 micrograms/kg, i.c.v.) did not antagonize morphine-induced CTA, while it did antagonize morphine-induced analgesia.
In a previous paper (Sala et el. 1989), rats submitted to a freechoice drinking schedule, were un... more In a previous paper (Sala et el. 1989), rats submitted to a freechoice drinking schedule, were unable to discriminate between plain water and untasted medicated solutions containing either etonitazene HCI (E), a strong synthetic u-opiate, or haloperidol (H), the well known anti-dopaminergic agent, both in concentrations high enough to induce evident neurobehavioral effects. To solve the problem whether animals were able to discriminate the central effects of such drugs, we decided to adopt the conditioned taste aversion (CTA) test, which may be induced not only by emetic agents but also by some psychoactive drugs, known to act as positive reinforcers. According to Garcia and Ervin (1968),male Wistar rats, waterdeprived for 24 h,, were daily trained to a period of 10 min access to water and submitted every third day to a 10 min drinking test with 0.1% saccharin solution in place of water.At the end of every session saccharin intake was measured. Five minutes after the end of each saccharin session , isotonic saline or the drugs .:were Lp, administered at the following dosage: E 5 and 40 llg)kg; H 0.5 and 2mg/kg; Lithium (L) 13mg/kg;apomorphine HCI (A) 7mg/kg and Morphine (M) 10 and 40mg/kg. Such three-days sessions were repeated ten times. Pharmacological effects (behavior, analgesia, catatonia) were evaluated 30' after the administration. As expected L,A and M in d u c e d a significant CTA. On the contrary E (either at low inactive dose or at strong analgesic and catatonic dose) and H (either at weakly catatonic low dose or at strongly catatonic high dose) were unable to modify saccharin intake. The obtained data confirm our previous findings of a substantial inability of the rat to discriminate central effects and are in agreement with the hypothesis that CTA may be induced only by drugs eliciting peripheral effects (Hunt and Amit,1987).
We studied the ability of eptastigmine, a second-generation acetylcholinesterase inhibitor (AChEI... more We studied the ability of eptastigmine, a second-generation acetylcholinesterase inhibitor (AChEI), to reverse the age-related increase of electroencephalogram (EEG) mean cortical spectral power in slow-wave δ activity and decrease in fast-wave α and β activity. The relative basal spectral power profile evaluated for 50 min of the old (27-30 months) in comparison to young (4-6 months) awake rats was consistently different, showing a significant increase in δ (0.2-4.0 Hz) frequency and a significant decrease of α (8.2-13.0 Hz) and β (13.2-25.0) bands. When 0.5, 1, 2, 4 mg kg −1 of eptastigmine were administered orally as single increasing doses for old and young rats 2 h prior to the EEG recordings, lasting 2 h, the relative mean spectral power difference ( %) showed a linear log dose-related decrease in δ activity and a progressive increase in α and β activity in old rats. Compared to vehicle, in young rats, the eptastigmine dose of 0.5 mg kg −1 produced a significant decrease in δ activity and an increase in β activity. The spontaneous motor activity, evaluated through cumulative horizontal and vertical counts for 30 min in old rats was significantly decreased when compared to young rats. Single oral treatment with eptastigmine (0.5 mg kg −1 for young and 2 mg kg −1 for old rats) given 2 h before the test did not significantly change motor activity in comparison to vehicle group of the same age. These results suggest a possible strategy to alleviate the severe slowing of neocortical EEG accompanying the cognitive decline.
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