Age-dependent loss of NMDA receptors in hippocampus,striatum, and frontal cortex of the rat: Prevention by acetyl-l-carnitine

Acute i.p. administration of Acetyl-L-Carnitine (ALCAR), a component of several biological systems, has been found to modify spontaneous and evoked electrocortical activity in young rats, and, in the old rats, to improve learning ability and to increase the number of NMDA receptors in the whole brain. The present study was aimed at ascertaining the effect of chronic treatment with ALCAR added to drinking water on age-related changes in the different brain areas of rats. In twenty-four-month-old rats, ALCAR treatment for six months significantly impeded the decline in the number of NMDA receptors within the hippocampus, the frontal cortex and the striatum compared to the adult animal. This finding thus confirms the previously reported positive effect of ALCAR on the brain NMDA receptor system.     

Correlation of spike intervals and amplitudes in hypersynchronous EEG episodes in rat with cobalt focus.

EEG activity was recorded from rats with chronic cobalt foci and implanted electrodes. Within this activity, hypersynchronous rhythmic spike episodes (and those of waves) of mean frequency of 8-9/sec were studied. The spike amplitude-interval relationship was assessed, using correlation analysis method. A positive correlation of an exponential nature was found to be growing in line with temporal development of episode.     

Post-radiation effect on the interhemispheric asymmetry in EEG and thermography characteristics

Complex analysis of EEG and thermographic parameters carried out in 10 healthy subjects and 34 patients, Chernobyl clean-up participants revealed a correlation between EEG and brain temperature changes in the baseline state and during mental arithmetic. During cognitive activity the maximal increase in the average EEG coherence and temperature shifts in healthy subjects were observed in the left frontotemporal and right parietotemporal areas. In patients changes in both parameters under study were most pronounced, the interhemispheric relations were impaired. The visual analysis revealed "flat" and "hypersynchronous" EEG types in patients. The dominant pathologic activity in the betal range indicative of mediobasal and oral brainstem lesions was characteristic of the flat EEG. This type of activity was observed in 60% of patients. In these cases, a general decrease in EEG coherence and temperature was most pronounced in the left hemisphere. The hypersynchronou EEG type (40% patients) was characterized by paroxysmal activity in the theta and alpha ranges suggesting diencephalic brain lesions. In these cases, EEG coherence and temperature were more variable; changes in the right hemisphere were significant, be it increase or decrease. Our complex approach to investigation of brain activity in different aspects seems to be promising in estimation of the brain functional state both in healthy persons and patients in remote terms after exposure to radiation. The specific hemispheric temperature changes revealed in Chernobyl patients especially during cognitive activity can be the sequels of postradiation disorders of vascular neuro-circulation. The EEG findings suggest subcortical disorders at different levels (diencephalic or brainstem) and functional failure of the right or left hemispheres in remote terms after exposure to radiation.     

Steroid anaesthesia: alphadione depresses multiunit activity in the mesencephalic reticular formation

Cortical EEG and multiunit activity (MUA) of the mesencephalic reticular formation (MRF), area hypothalami anterior (AH) and the nucleus amygdalae basalis (AMY) were studied before and after different doses of alphadione (Althesin) and hexobarbitone (Evipan-Natrium) given to cats with chronically implanted electrodes. Non-anaesthetic doses of alphadione (0.15 ml/kg; 0.3 ml/kg; 0.6 ml/kg and 1.2 ml/kg i.p.) had sedative effects decreasing selectively the MUA in the MRF. In doses of 2.0 ml/kg, 2.4 ml/kg and 3.0 ml/kg i.p., alphadione induced anaesthesia which was associated with a rapid decrease of MUA in the MRF and by a gradual decrease of activity in the AH and AMY. The i.p. dose of 3.0 ml/kg abolished MUA responses of the reticular formation to acoustic, visual and somatic stimulation but failed to block responses to pain. Deep anaesthesia with lasting analgesia could be maintained by i.v. infusion (0.075 ml/kg/min). This procedure blocked the responsiveness to painful stimulation while pharyngeal and laryngeal reflexes were maintained. Hexobarbitone in a dose of 20.0 mg/kg i.p. did not produce anaesthesia in the cat. Administration of 40.0 mg/kg i.p. resulted in a rapid decrease of MUA in the MRF, AH and AMY, MUA responses to each stimulation were abolished and the pharyngeal reflex was blocked.     

The effect of self-stimulation of the lateral hypothalamus on the sleep-waking cycle in rats during alcoholization]

Directed activation of a system of positive emotional reinforcement induces regulatory effect on limbic-neocortical mechanisms of the sleep-waking cycle organization in rats after chronic alcoholization carried out in periods of decreased and increased circadian rhythms of emotional activity. In animals with high level of positive emotional drive after the alcoholization self-stimulation of the lateral hypothalamus suppresses hypersynchronous paroxysmal activity in waking EEG, decreases the content of waking in the sleep-waking cycle, restores the paradoxical phase of sleep. In animals with inhibition of positive emotional drive in consequence of alcoholization self-stimulation of the lateral hypothalamus has no essential effect on the mechanisms of regulation of the sleep-waking cycle.     

Tonic facilitatory influences of dorsal pontine reticular structures on the response gain of limb extensors to sinusoidal labyrinth and neck stimulations

Experiments were performed to find out whether changes in resting discharge of the inhibitory reticulospinal (RS) neurons of the medulla, produced either by selective destruction or by cholinergic activation of a pontine tegmental reticular system, may modify the response gain of limb extensor muscles to given parameters of roll tilt of the animal or neck rotation. In precollicular decerebrate cats, an electrolytic lesion of the dorsal aspect of the pontine tegmentum, which slightly increased the tonic contraction of limb extensors, greatly decreased the amplitude of the multiunit EMG response of forelimb extensor muscles, i.e. of the medial head of the triceps brachii, to roll tilt of the animal and neck rotation (at 0.15 Hz, +/- 10 degrees), leading to selective stimulation of labyrinth or neck receptors. Correspondingly, the response gain of the forelimb extensors to labyrinth and neck stimulation decreased, but no change in the phase angle of the responses was observed. These findings did not depend on the increased postural activity, since they were still observed in the absence of any change in spontaneous EMG activity of the triceps brachii following the lesion. The changes in posture as well as in response gain of the forelimb extensors to labyrinth and neck stimulation produced by the pontine lesion appeared suddenly, and persisted for several hours throughout the survival period. Moreover, these changes involved mainly, but not exclusively, the limbs ipsilateral to the side of the lesion. Histological controls indicated that the structure responsible for the postural and reflex changes described above corresponded to the dorsal aspect of the pontine tegmentum located immediately ventral to the locus coeruleus (LC); this area corresponded to the peri-LC region as well as the surrounding pontine reticular formation (RF), including the dorsal aspect of the central tegmental field. This region closely corresponds to the area from which a tegmentoreticular tract, ending on the medullary inhibitory area, originates. It was previously shown that unilateral or bilateral lesion of the LC, which decreased the extensor tonus in the ipsilateral limbs, greatly enhanced the response gain of the triceps brachii to sinusoidal stimulation of labyrinth and neck receptors. These findings were attributed to suppression of an inhibitory influence that the LC exerts on the dorsal pontine reticular structures described above.(ABSTRACT TRUNCATED AT 400 WORDS)     

The benzodiazepine recognition site inverse agonists Ro 15-4513 and FG 7142 both antagonize the EEG effects of ethanol in the rat

The aim of the present study was to compare the ability of Ro 15-4513 and FG 7142, two inverse agonists for benzodiazepine recognition sites, to antagonize the EEG effects of ethanol in freely moving rats. Ethanol (2.5 g/kg, p.o.) induced sedation and ataxia associated with a progressive suppression of the fast cortical activities and an enhancement of low frequencies in both cortical and hippocampal tracings. In contrast, Ro 15-4513 (2 mg/kg, i.p.) and FG 7142 (10 mg/kg, i.p.) both caused a state of alertness associated with desynchronized cortical activity and theta hippocampal rhythm as well as spiking activity which was predominantly observed in the cortical tracings. When rats were treated with FG 7142 or RO 15-4513 either before or after ethanol, a reciprocal antagonism of the behavioral and EEG effects of ethanol and of the partial inverse agonists was observed. These data support the view that the anti-ethanol effects of Ro 15-4513 may be related to its partial inverse agonist properties.     

Modifications of acoustic habituation by interruption of visual input in quipazine treated cats

The influence of interruption of the visual input on acoustic habituation was studied in cats before and following the administration of quipazine, 3 mg/kg iv. The characteristics of acoustic habituation were analyzed through the magnitude and temporal course of multiunit activity (MUA) responses elicited in the mesencephalic reticular formation (MRF) by repetitive acoustic stimuli (70 db, 50 Hz trains of 2 sec duration) in 6 freely moving cats with cortical electrodes over the parietal cortex and bipolar electrodes chronically implanted in MRF and basolateral amygdala (AMN). The cats were submitted to repetitive acoustic stimulation during one 30 min period before, and three 30 min periods after drug administration in the following conditions: a) with unmasked eyes; b) with masked eyes by means of dark contact lenses. Persistent attentive behavior, catatonic attitudes, hypersynchronous (6 Hz, 100-150 microV) EEG activity and significant increase of spontaneous MUA in FRM and AMN were induced by quipazine both in the cats tested with unmasked and with masked eyes. This increase of MUA was higher immediately following drug administration and progressively decreased, although MUA values remained significantly higher than controls 110 min after quipazine administration. Acoustic habituation, evidenced through the progressive decrease of MUA responses of MRF to acoustic stimuli, was observed before quipazine administration when the cats were tested with unmasked and with masked eyes; as well as in cats tested with unmasked eyes following drug administration. However, the MUA responses to acoustic stimuli did not decrease in cats with masked eyes during acoustic stimulation periods 0-30 min and 40-70 min after quipazine administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of anticholinergic drugs alone and in combination with nembutal on burst theta-neurons of the rabbit septum

Activity of neurones with rhythmic theta-bursts was recorded in the medial septum--diagonal band complex of the waking rabbits with intact and deafferented septum. Effects of anticholinergic (scopolamine, atropine) and cholinomimetic (physostigmine) drugs were investigated after i.v. injection. Cholinoblocking drugs in doses, suppressing the theta-rhythm in the hippocampal EEG, eliminated rhythmic activity in some cells with weak theta-modulation. Theta-bursts persisted in cells with stable continuous rhythmicity, though its regularity decreased in some of them. Strong reticular or sensory stimulation evoked an increase of burst frequency, involvement of additional septal cells into rhythmic activity and appearance of the theta-rhythm in the hippocampal EEG. Neither anticholinergic, nor cholinomimetic drugs influenced the frequency and basic characteristics of theta-bursts in any condition tested. The anticholinergic drugs have no selective effect upon low-frequency theta-bursts. The septohippocampal connections contain a significant non-cholinergic component. The theoretical concept of the septum as a sole source of the whole frequency band of the theta-rhythm is proposed.     

Triangular Relationship between Sleep Spindle Activity,General Cognitive Ability and the Efficiency of Declarative Learning

EEG sleep spindle activity (SpA) during non-rapid eye movement (NREM) sleep has been reported to be associated with measures of intelligence and overnight performance improvements. The reticular nucleus of the thalamus is generating sleep spindles in interaction with thalamocortical connections. The same system enables efficient encoding and processing during wakefulness. Thus, we examined if the triangular relationship between SpA, measures of intelligence and declarative learning reflect the efficiency of the thalamocortical system. As expected, SpA was associated with general cognitive ability, e.g. information processing speed. SpA was also associated with learning efficiency, however, not with overnight performance improvement in a declarative memory task. SpA might therefore reflect the efficiency of the thalamocortical network and can be seen as a marker for learning during encoding in wakefulness, i.e. learning efficiency.     

Acetyl-L-carnitine prevents total body hydroxyl free radical and uric acid production induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the rat

Acetyl-L-carnitine (ALCAR) is intimately involved in the transport of long chain fatty acids across the inner mitochondrial membrane during oxidative phosphorylation. ALCAR also has been reported to attenuate the occurrence of parkinsonian symptoms associated with 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) in vivo, and protects in vitro against the toxicity of the neurotoxic 1-methyl-4-phenylpyridinium (MPP+) metabolite of MPTP. The mechanism for these protective effects remains unclear. ALCAR may attenuate hydroxyl (HO*) free radical production in the MPTP/MPP+ neurotoxic pathway through several mechanisms. Most studies on MPTP/MPP+ toxicity and protection by ALCAR have focused on in vivo brain chemistry and in vitro neuronal culture studies. The present study investigates the attenuative effects of ALCAR on whole body oxidative stress markers in the urine of rats treated with MPTP. In a first study, ALCAR totally prevented the MPTP-induced formation of HO* measured by salicylate radical trapping. In a second study, the production of uric acid after MPTP administration-a measure of oxidative stress mediated through xanthine oxidase-was also prevented by ALCAR. Because ALCAR is unlikely to be a potent radical scavenger, these studies suggest that ALCAR protects against MPTP/MPP+-mediated oxidative stress through other mechanisms. We speculate that ALCAR may operate through interference with organic cation transporters such as OCTN2 and/or carnitine-acylcarnitine translocase (CACT), based partly on the above findings and on semi-empirical electronic similarity calculations on ALCAR, MPP+, and two other substrates for these transporters.     

Reduction of rapid eye movement (REM) sleep by glucose alone or glucose and insulin in rats

Administration of a high dose of glucose (2.5 g/kg, i.p.) that is known to produce severe hyperglycemia in euglycemic rats suppressed rapid eye movement (REM) sleep time significantly during the first three hours of 8 hr total electroencephalogram (EEG) recording period. Co-administration of glucose (2.5 g/kg, i.p.) and a non-convulsive dose of insulin (1.0 I.U./kg, i.p.) produced a significant reduction in REM sleep time during 1st through 5th hour and an increase in slow-wave sleep (NREM) time in the 3rd and 4th hour of 8 hr total EEG recording period. However, awake, NREM and REM sleep time in the 8 hr total EEG recording period were unaffected by either glucose alone or glucose plus insulin treatments. These results strongly suggest that the insulin's effects on the sleep-awake cycle i.e. reduction in REM and a slight increase in NREM sleep times of rats is not due to indirect effects of insulin on the central nervous system via hypoglycemia as reported by us previously, but could possibly be due to its direct effects on brain chemistry of neurotransmitters such as serotonin, catecholamines and acetylcholine which are believed to modulate the sleep-awake cycle pattern in rats.     

Dopamine-dependent responses to cocaine depend on corticotropin-releasing factor receptor subtypes

The effects on locomotor response to cocaine challenge, acquisition of cocaine conditioned place preference and cocaine-induced dopamine (DA) release in nucleus accumbens and ventral tegmental area by the non-specific corticotropin-releasing factor (CRF) receptors antagonist alpha-helical CRF, the selective CRF receptor subtype 1 antagonist CP-154,526 and the selective CRF receptor subtype 2 antagonist anti-sauvagine-30 (AS-30) were investigated in rats. Both alpha-helical CRF (10 microg, i.c.v.) and CP-154,526 (3 microg, i.c.v.) decreased the cocaine-induced distance travelled, whereas AS-30 (3 microg, i.c.v.) did not show such an effect. The CRF receptor antagonists also have significant effects on stereotype counts induced by cocaine injection, in which the alpha-helical CRF or CP-154,526 but not AS-30 did significantly reduce the stereotype counts. alpha-Helical CRF (10 microg) prior to each injection of cocaine blocked cocaine conditioned place preference with no significant difference observed in the time spent in the drug-paired side between post- and pre-training and both 1 and 3 microg CP-154,526 also had significant inhibitory effects on cocaine-induced place preference. However, pre-treatment with an i.c.v. infusion of AS-30 (1 or 3 microg) prior to each injection of cocaine did not affect the acquisition of conditioned place preference. The alpha-helical CRF and CP-154,526 reduced extracellular DA levels of nucleus accumbens and ventral tegmental area in response to the injection of cocaine. However, both alpha-helical CRF and CP-154,526 did not modify extracellular DA levels under basal conditions. In contrast, the i.c.v. infusion of AS-30 had no effects on either the basal DA or the cocaine-induced increase in DA release in nucleus accumbens and ventral tegmental area. These findings demonstrate that activation of the CRF receptor is involved in behavioral and neurochemical effects of cocaine challenge and cocaine reward and that the role of CRF receptor subtypes 1 and 2 in cocaine-induced locomotion, reward and DA release is not identical. The CRF receptor subtype 1 is largely responsible for the action of the CRF system on cocaine locomotion and reward. These results suggest that the CRF receptor antagonist, particularly the CRF receptor subtype 1 antagonist, might be of some value in the treatment of cocaine addiction and cocaine-related behavioral disorders.     

Electroencephalographic effects of the intracentral administration of antibodies to brain-specific antigen S-100]

The EEG method with the assessment of the rhythm power on analogue computers was used to examine the effects of intracentral administration of antibodies to the brain-specific antigen S-100 (S-100 protein). Intracerebral injections of antibodies to S-100 protein caused an increase of the EEG basic rhythm power in the hippocampus, caudate nucleus and the mesenphalic reticular formation, with the subsequent development of epileptiform activity in these structures.     

Impairment of space-frequency parameters of EEG coherence during cognitive performance (consequences of Chernobyl accident)

Changes in frequency and space parameters of the EEG coherence evoked by cognitive performance were analyzed in 13 healthy subjects and participants of the Chemobyl clean-up. In healthy subjects, the EEG coherences in the alpha and beta frequency bands were significantly increased during arithmetic count and during visuospatial performance. Each test was characterized by regionally-specific features. Chemobyl patients demonstrated a global decrease in the EEG coherence predominantly in the alpha and beta frequency bands, especially in the frontal cortical areas. Patients with various pathological EEG patterns demonstrated specific impairment of EEG parameters. In patients with a "flat" EEG pattern, the EEG coherence predominantly decreased in the frontal associative areas, especially during arithmetic calculation. In patients with a "hypersynchronous" EEG pattern, the decrease in the EEG coherence was most pronounced in the parietal associative areas, especially during the visuospatial performance. The revealed impairments of the EEG coherence reactivity may be a reflection of disorders of the intracortical and corticosubcortical interaction and can result from the remote postradiation brain atrophy, especially, of cortical structures.     

Selective discharge of pontine neurons during the postural atonia produced by an anticholinesterase in the decerebrate cat.

I. Episodes of postural atonia associated with bursts of REM similar to those which occur spontaneously either in the intact preparation during desynchronized sleep, or in the chronic decorticate or decerebrate preparations, can be elicited in acute decerebrate cats following intravenous injection of small doses of an anticholinesterase. The present experiments were performed in precollicular decerebrate animals in order to identify the pontine neurons which show increases in their firing rate related in time with the appearance of the cataplectic episodes. In particular long-term recordings of single units were obtained before, during and after the episodes of postural atonia produced by i.v. injection of 0.03-0.1 mg/kg of eserine sulphate. Spontaneous discharge rates were used to measure the selectivity of each individual unit, i.e., the tendency of the unit to discharge more during the cataplectic episode than during the postural rigidity. The physiological data obtained from neurons histologically localized in different nuclear groups were then averaged. 2. Neurons localized in the pontine reticular formation as well as in the region of the locus coeruleus and the raphe system showed low rates of discharge when rigidity was present. The same units, however, showed a remarkable increase in firing rate which preceded by several tenths of seconds the onset of postural atonia and lasted throughout the cataplectic episodes. 3. The neurons of the pontine reticular formation had a selectivity which was higher than that of the neurons located in the locus coeruleus-raphe system; moreover the cells of the gigantocellular tegmental field (FTG) had the highest selectivity of all pontine reticular structures studied. 4. The relation of the discharge rate curves to the occurrence of the cataplectic episodes suggests that these neurons constitute output elements of a generator system for postural atonia. It is postulated that these pontine reticular neurons are directly involved in the activation of the bulbospinal inhibitory system, which is finally responsible for the abolition of the decerebrate rigidity. 5. During cataplectic episodes these pontine neurons showed some clustered discharges which appeared in association with bursts of eye movements. In most instances, however, there was no constant relationship of the unit activity to individual eye movements. Moreover large phasic increases in firing rate appeared also during the intervals between successive bursts of REM. 6. The striking increase in firing rate of the FTG neurons observed during the cataplectic episodes cannot be attributed to an increased excitatory input to these neurons. In fact excitatory influences following intense somatic stimulation are unlikely to occur during the cataplectic episodes; moreover the response of these neurons to intense somatosensory stimulations did not reach rates comparable with those occurring spontaneously during the induced cataplectic episodes...     

Analysis of the electroencephalographic activity associated with thalamic tumors

A physiologically based model of corticothalamic dynamics is used to investigate the electroencephalographic (EEG) activity associated with tumors of the thalamus. Tumor activity is modeled by introducing localized two-dimensional spatial non-uniformities into the model parameters, and calculating the resulting activity via the coupling of spatial eigenmodes. The model is able to reproduce various qualitative features typical of waking eyes-closed EEGs in the presence of a thalamic tumor, such as the appearance of abnormal peaks at theta ( approximately 3Hz) and spindle ( approximately 12Hz) frequencies, the attenuation of normal eyes-closed background rhythms, and the onset of epileptic activity, as well as the relatively normal EEGs often observed. The results indicate that the abnormal activity at theta and spindle frequencies arises when a small portion of the brain is forced into an over-inhibited state due to the tumor, in which there is an increase in the firing of (inhibitory) thalamic reticular neurons. The effect is heightened when there is a concurrent decrease in the firing of (excitatory) thalamic relay neurons, which are in any case inhibited by the reticular ones. This is likely due to a decrease in the responsiveness of the peritumoral region to cholinergic inputs from the brainstem, and a corresponding depolarization of thalamic reticular neurons, and hyperpolarization of thalamic relay neurons, similar to the mechanism active during slow-wave sleep. The results indicate that disruption of normal thalamic activity is essential to generate these spectral peaks. Furthermore, the present work indicates that high-voltage and epileptiform EEGs are caused by a tumor-induced local over-excitation of the thalamus, which propagates to the cortex. Experimental findings relating to local over-inhibition and over-excitation are discussed. It is also confirmed that increasing the size of the tumor leads to greater abnormalities in the observable EEG. The usefulness of EEG for localizing the tumor is investigated.     

Changes in electrical brain activity in patients with panic disorders

Brain electrical activity was recorded in 38 patients with typical and in 42 patients with atypical panic disorders, also in 30 normal controls. Compared to controls, patients both with typical and with atypical panic disorders differed significantly in reduced spectral power of the EEG alpha band in the right hemisphere. Moreover, in patients with typical panic disorders, the spectral power of the EEG beta1 band was increased in the frontal, temporal, central, and parietal areas of the right hemisphere. In patients with atypical panic disorders, the spectral power of the theta band was increased in the temporal areas of the right hemisphere. The changes in the EEG activity in patients with typical panic disorders are supposed to reflect an increase in activity of non-specific systems of the mesencephalic reticular formation, and the EEG changes in patients with atypical panic attacks may be associated with increased activity of the temporolimbic brain structures.     

Effects of Acetyl-l-Carnitine and Myo-Inositol on High-Energy Phosphate and Membrane Phospholipid Metabolism in Zebra Fish: A 31P-NMR-Spectroscopy Study

Acetyl-l-carnitine (ALCAR) and myo-inositol are reported to enhance motor activity in animal models; modulate membrane phospholipid metabolism (ALCAR and myo-inositol) and high-energy phosphate metabolism (ALCAR) back to normal; and be effective treatments of major depression in humans. Fish in general and zebra fish in particular present unique animal models for the in vivo study of high-energy phosphate and membrane phospholipid metabolism by noninvasive in vivo ^31P NMR. This ^31P NMR study of free-swimming zebra fish showed that both ALCAR and myo-inositol decreased levels of phosphodiesters and inorganic orthophosphate and increased levels of PCr in the fish. These findings demonstrate both ALCAR and myo-inositol modulate membrane phospholipid and high-energy phosphate metabolism in free-swimming zebra fish.     

The Acetylcholinesterase Inhibitors Competitively Inhibited an Acetyl l-Carnitine Transport Through the Blood–Brain Barrier

We investigated the interaction of acetylcholinesterase (AChE) inhibitors with acetyl-L-carnitine (ALCAR) transporter at the blood-brain barrier (BBB). ALCAR uptake by conditionally immortalized rat brain capillary endothelial cell lines (TR-BBB cells), as an in vitro model of BBB, were characterized by cellular uptake study using [(3)H]ALCAR. In vivo brain uptake of [(3)H]ALCAR was determined by brain uptake index after carotid artery injection in rats. In results, the transport properties for [(3)H]ALCAR by TR-BBB cell were consistent with those of ALCAR transport by the organic cation/carnitine transporter 2 (OCTN2). Also, OCTN2 was confirmed to be expressed in the cells. The uptake of [(3)H]ALCAR by TR-BBB cells was inhibited by AChE inhibitors such as donepezil, tacrine, galantamine and rivastigmine, which IC(50) values are 45.3, 74.0, 459 and 800 μM, respectively. Especially, donepezil and galantamine inhibited the uptake of [(3)H]ALCAR competitively, but tacrine and rivastigmine inhibited noncompetitively. Furthermore, [(3)H]ALCAR uptake by the rat brain was found to be significantly decreased by quinidine, donepezil and galantamine. Our results suggest that transport of AChE inhibitors such as donepezil and galantamine through the BBB is at least partly mediated by OCTN2 which is involved in transport of ALCAR.