Glucocorticoids involvement in the control of CNS excitability

The effect of dexamethasone (DEX) and its interaction with psychostimulants agents (morphine, cocaine and amphetamine) has been studied on locomotor activity and straub reaction in mice: a) Morphine administration, (30-75-150 mg/kg,ip) induced a dose-related increase of the locomotor activity of mice, whereas DEX per se (0.1-1.0-10 mg/kg,ip) did not modify the activity of control mice. Pretreatment of mice with DEX 0.1 mg did not alter the hyperactivity produced by the three doses of morphine. In contrast, DEX administered at 1.0 mg reduced the morphine effects on locomotor activity, whereas DEX at 10 mg potentiated the morphine hypermotility. b) Cocaine (10 mg/kg/i.p.) and amphetamine (5 mg/kg/i.p.) increased markedly locomotor activity of mice whereas DEX per se (0.1-1.0-10 mg/kg/i.p.) did not modify the activity of control mice. DEX pretreatment decreased the stimulating effects induced by cocaine and amphetamine. DEX pretreatment 0, 15, 30, 60 and 120 min before amphetamine or cocaine strongly decreased both amphetamine and cocaine effects, but no dose-related effect was observed. The time-course study performed with DEX revealed differences in its reducing effect on cocaine and amphetamine hypermotility when the groups of animals treated with the steroid immediately before the cocaine (or amphetamine) injection when compared to those treated with the steroid later (15, 30, 60 and 120 min). Furthermore, actinomycin D was able to block the reducing effect of DEX on both amphetamine and cocaine hypermotility. c) When morphine was administered in doses of 7.5, 15 and 30 mg/kg/i.p, a dose-dependent straub reaction was produced. DEX per se (0.1-1.0-10 mg /kg,i.p.) did not modify the tail of control mice. Pre-treatment with DEX 120 min before morphine injection caused a dose-dependent reduction of straub reaction. Cycloheximide (15 mg/kg,i.p.) administered 2h before morphine did not change morphine-induced straub reaction, but was able to prevent the effects of DEX on morphine-induced straub reaction. The glucocorticoid receptor antagonist RU-38486 (15 mg/kg,i.p.) did not affect morphine-induced straub reaction, whereas it was able to block the effects of dexamethasone on morphine-induced straub reaction. Our results suggest that DEX may play an important regulatory role on the central effects of morphine, cocaine and amphetamine through a differential modulation of brain excitability systems indicating that DEX may play an important role on the stimulating effects of morphine, cocaine and amphetamine and that it may be of some utility in the clinical management of psychastimuants abuse. The ability of actinomicyn D and/or cycloheximide as well as of RU-38486 to block dexamethasone's effects indicates that the steroid's interference with psychostimulants-mediated effects involve a protein-synthesis-dependent mechanism via glucocorticoid receptors. The patents related to psychostimulant agent and glucocorticoids are also discussed in this article.     

The mitochondrial toxin 3-nitropropionic acid aggravates reserpine-induced oral dyskinesia in rats

The effects of a previous long-term administration of the mitochondrial toxin 3-nitropropionic acid were studied on an animal model of tardive dyskinesia, i.e., the frequency of spontaneous tongue protrusions in rats repeatedly treated with reserpine. 3-Nitropropionic acid (10 or 15 mg/kg i.p., every other day for 17 days) potentiated the increase in tongue-protrusion frequency induced by reserpine (1 mg/kg, s.c., every other day for 3 days) but did not modify reserpine-induced increase in immobility duration and decrease in locomotion frequency. These results support the notion that neurotoxic events are associated with the development of tardive dyskinesia.     

Evidence for presynaptic dopamine mechanisms underlying amphetamine-conditioned locomotion.

Rats with a history of receiving (+)-amphetamine in a specific environment exhibit a conditioned psychomotor response when subsequently placed in that environment without drug treatment. Previous work has shown that while the unconditioned effects of amphetamine can be blocked by dopamine D1 or D2 receptor antagonists or with alpha-methyl-p-tyrosine, conditioned locomotion is not influenced by these treatments. In the present experiment, alpha-methyl-p-tyrosine (50 mg/kg, s.c.) was given in conjunction with amphetamine (1.5 mg/kg, s.c.) for 8 days before testing for conditioned locomotion. alpha-Methyl-p-tyrosine completely blocked amphetamine-induced locomotion but only attenuated amphetamine-conditioned locomotion. Reserpine (reduced over the 8 days from 2.5 to 1.25 mg/kg, i.p.) did not block amphetamine-induced locomotion; indeed, potentiation of amphetamine-induced locomotor activity was observed on the last 3 days of treatment. Reserpine treatment in conjunction with alpha-methyl-p-tyrosine treatment blocked amphetamine-induced locomotion for the first 4 days only, with full recovery of amphetamine-induced unconditioned locomotion by the last treatment day. Reserpine alone had no effect on amphetamine-conditioned locomotion, but completely blocked amphetamine-conditioned locomotion when given with alpha-methyl-p-tyrosine. It is concluded that the alpha-methyl-p-tyrosine-sensitive pool of dopamine mediates the immediate psychomotor effects of amphetamine, but that both the alpha-methyl-p-tyrosine- and reserpine-sensitive pools of dopamine are involved in the establishment of amphetamine-conditioned locomotion. In addition, the occurrence of amphetamine-conditioned locomotion is independent of the direct effects of amphetamine on locomotion.     

Caffeine and amphetamine produce cross-sensitization to nicotine-induced locomotor activity in mice

Sensitization development is linked to the addictive potential of the drugs. The same mechanisms might play a role in sensitization development to the different addictive drugs. The aim of the study was to investigate the development of cross-sensitization to caffeine and amphetamine in nicotine-induced locomotor sensitization in mice. Caffeine (2.5-20 mg/kg), amphetamine (1-16 mg/kg) or saline were injected to Swiss-Webster mice and locomotor activity was recorded for 30 min. Nicotine (0.5-2 mg/kg) or saline were injected to mice and locomotor activity was recorded for 30 min. Process was applied for 19 days, every other day (10 sessions). Caffeine (5 mg/kg), amphetamine (4 mg/kg) or saline were challenged to the different groups of nicotine-sensitized mice 2 days later on the last nicotine injection, and locomotor activity was recorded. Repetitive injections of nicotine (0.5-2 mg) produced locomotor sensitization in mice. After caffeine and amphetamine challenge injections, locomotor activity of the nicotine-sensitized mice was found to be significantly higher than saline-pretreated mice. Saline challenge did not produce any significant effect in nicotine- or saline-pretreated mice. Our results suggest that a cross-sensitization developed to both caffeine and amphetamine in nicotine-sensitized mice. In conclusion, similar central mechanisms may be responsible for the development of addiction to these substances.     

Amphetamine and pentylenetetrazole given post-trial 1 enhance one-trial tolerance to the anxiolytic effect of diazepam in the elevated plus-maze in mice

There are several hypotheses to explain the lack of an anxiolytic effect on animals with previous maze experience (one-trial tolerance). Some of these hypotheses are related to learning and memory, so the reduction of trial 1 duration to 1 min or amnesic drug administration before trial 1 prevents the lack of an anxiolytic effect in trial 2. Amphetamine and pentylenetetrazole have been shown to enhance memory consolidation when administered immediately after training. Thus, the aim of the present study was to evaluate the effect of amphetamine (1.0–3.0 mg/kg) or pentylenetetrazole (30.0 mg/kg), at putative memory-enhancing doses, on the effect of diazepam (2.5 mg/kg) in the elevated plus-maze trial 2 on mice exposed to a 1-min long trial 1. Mice were submitted to 1-min trial 1 in the elevated plus-maze immediately followed by drug treatment (saline, amphetamine, or pentylenetetrazole) and to elevated plus-maze trial 2 after 48 h. Animals were treated with vehicle or diazepam 30 min before trial 2. The results showed that post-trial 1 saline and 1.0 mg/kg amphetamine did not induce one-trial tolerance. On the other hand, 2.0 and 3.0 mg/kg amphetamine and 30 mg/kg pentylenetetrazole induced a lack of anxiolytic effect of diazepam on trial 2 even with 1-min trial 1 length. Furthermore, these data were not due to novelty exposure in trial 1 or to amphetamine treatment so that mice exposed to an activity chamber instead of the plus-maze (trial 1) and then immediately submitted to amphetamine treatment (2.0 mg/kg) did not show one-trial tolerance 48 h after trial 1. Taken as a whole, these data support the hypothesis that memory is involved in the lack of an anxiolytic effect in the elevated plus-maze trial 2.     

Long-term increase in GAD67 mRNA expression in the central amygdala of rats sensitized by drugs and stress

Repeated administration of addictive drugs and prolonged exposure to stressful stimuli induce sensitization to their behavioural stimulant properties. In this study, male Sprague–Dawley rats were repeatedly exposed to morphine [twice a day for 3 days at increasing doses, 10, 20, 40 mg/kg subcutaneously (s.c)], amphetamine (1 mg/kg s.c., once a day for 10 days), nicotine (0.4 mg/kg s.c., once a day for 5 days) and stress (food restriction for 7 days). After an interval of 3–30 days, depending on the pretreatment, rats were challenged with vehicle, with the same drug received as pretreatment (5 mg/kg of morphine, 0.5 mg/kg of amphetamine or 0.4 mg/kg of nicotine, respectively) or, in the case of food-restricted rats, with 0.5 mg/kg of amphetamine. Thereafter, changes in the expression of glutamic acid decarboxylase (GAD)67 mRNA were estimated by in situ hybridization in the central nucleus of the amygdala (CeA), basolateral amygdala (BLA), dorsolateral striatum (dLStr), nucleus accumbens shell (AcS) and core (AcC). All sensitizing pretreatments increased GAD67 mRNA in the CeA. Drug challenge did not further affect GAD67 mRNA in the CeA of saline, drug and stress pre-exposed rats. As to the other areas, no differences were observed in drug pre-exposed compared with saline pre-exposed and fed ad libitum rats, except for amphetamine. Amphetamine pre-exposure decreased GAD67 mRNA levels in the dLStr and the AcC and AcS, and this effect was reversed by amphetamine challenge. The results show that different drugs and stress models of behavioural sensitization have in common an increase of GA67 in the CeA but not in the BLA, and suggest the changes of GAD67 in the CeA are a substrate of the sensitized response to drug challenge.     

Partial reversal of stress-induced behavioral sensitization to amphetamine following metyrapone treatment

Several studies indicate that blockade of stress-induced corticosterone secretion prevents the development of stress-induced sensitization to the behavioral effects of stimulants. The present study examined whether chronic blockade of corticosterone synthesis with metyrapone could reverse stress-induced amphetamine sensitization in rats. Restraint stress in cylindrical chambers, 2 times 30 min/day for 5 days over an 8-day schedule, was used as the stressor. Following completion of the stress protocol, animals were cannulated with microdialysis guide cannulae over the nucleus accumbens, and then treated with either metyrapone (50 mg/kg, i.p.) or vehicle (1 ml/kg) for 7 days. On the seventh day, animals were implanted with microdialysis probes in the nucleus accumbens, and on the following day, all animals were tested for their locomotor, stereotypy, and nucleus accumbens dopamine and DOPAC release responses to an injection of saline followed 60 min later by d-amphetamine (1.5 mg/kg, i.p.). Neither stress or metyrapone treatment had an effect on the behavioral or dopamine release response to saline. However, amphetamine-stimulated locomotion and stereotypy were strongly enhanced, while amphetamine-stimulated dopamine release response was slightly enhanced (significant only by drug×time interaction), in stressed animals. Metyrapone treatment reduced the stress-induced increase in the locomotor, but not stereotypy, response to amphetamine. In contrast, the dopamine release response to amphetamine was enhanced in metyrapone-treated animals, in both stressed and non-stressed groups, while DOPAC levels were unaffected by treatment group. This augmentation was particularly evident in the stressed-metyrapone-treated animals. Furthermore, non-stressed animals showed an increased locomotor and stereotypy response to amphetamine after treatment with metyrapone. These findings indicate that metyrapone treatment can reverse, or inhibit the expression of, stress-induced sensitization to the behavioral effects of amphetamine. However, the ability of metyrapone treatment to enhance the behavioral (in non-stressed animals) and dopamine release (in non-stressed and stressed animals) responses to amphetamine indicate that chronic metyrapone treatment will produce stimulant sensitization when given alone.     

Influence of acute and sub-chronic nicotine pretreatment on morphine state-dependent learning

In the present study, the effects of acute and sub-chronic pretreatment of nicotine on impairment of memory formation and the state-dependent learning by morphine have been investigated in mice. Pre-training administration of morphine (5mg/kg) decreased the learning of a one-trial passive avoidance task, which was reversed by pre-test administration of the same dose of morphine. Amnesia induced by pre-training morphine was also significantly reversed in nicotine (0.001, 0.01 and 0.1 mg/kg)-treated animals on the test day. Morphine induced amnesia was also reversed in animals which had previously received sub-chronic injections of nicotine, once daily for 3 days followed by 14 days of no drug treatment. The restoration of memory by pre-test morphine was also reduced in animals which had previously received once daily injections of atropine (0.25, 0.5 and 1 mg/kg, i.p.) for 3 days after 14 of being days drug free. In the animals, restoration of memory by sub-chronic nicotine administration, was also decreased by once daily administration of atropine (0.25, 0.5 and 1 mg/kg) 10 min prior to injection of nicotine (0.1 microg/kg/day, for 3 days) but not with SCH 23390; R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (0.01, 0.05 and 0.1 mg/kg) or sulpiride (25, 50 and 100 mg/kg) during 3-days of treatment with nicotine. The results suggest that nicotine may induce sensitization which affects the impairment of memory formation via cholinergic but not dopaminergic systems.     

MPTP-induced deficits in motor activity: Neuroprotective effects of the spintrapping agent, α-phenyl-tert-butyl-nitrone (PBN)

Summary In Experiment 1, groups of mice were administered either saline or MPTP (2 × 30mg/kg, s.c., separated by a 24-hr interval) 30min after being injected either PBN (15, 50 or 150mg/kg, s.c., low, medium and high doses, respectively) or L-Deprenyl (0.25 or 10.0mg/kg, s.c., low and high doses, respectively), the reference compound used, or saline. Tests of spontaneous motor activity 14 days later indicated that the MPTP-induced hypokinesia for locomotion and rearing was alleviated by prior administration with PBN (50 or 150mg/kg) or L-Deprenyl (10.0mg/kg); lower doses of PBN (15mg/kg) and L-Deprenyl (0.25mg/kg) did not affect the MPTP-induced deficits. Dopamine (DA) concentrations in the striatum confirmed a more severe loss of DA in the MPTP, PBN(15) + MPTP and Deprenyl(0.25) + MPTP groups than in the control group. Significant protection of DA was observed in the PBN(50) + MPTP, PBN(150) + MPTP and Deprenyl(10) + MPTP groups that did not exhibit an hypokinetic behaviour. In Experiment 2, the effects of repeated treatment with PBN (50mg/kg, s.c. over 12 days), post-MPTP, were studied in aged (15-month-old) and young (3-month-old) mice. Subchronic administration of PBN increased substantially the motor activity of old and young mice that had received MPTP. Aged control (saline) mice showed an activity deficit compared to young control mice; this deficit was abolished by repeated PBN treatment. The results suggest that moderate-to-high doses of PBN whether injected in a single dose prior to MPTP or subchronically following MPTP injections may afford protective effects against both the functional changes and DA-loss caused by MPTP treatment, possibly through an antioxidant mechanism.     

NMDA glutamate receptor role in the development of context-dependent and independent sensitization of the induction of stereotypy by amphetamine or apomorphine

We have been studying sensitization of psychostimulant-induced stereotyped behavior in mice using both a context-dependent and a context-independent paradigm. In the present study, we tested whether N-methyl-D-aspartate (NMDA) receptor antagonists prevent development of sensitization in either of these models. Male CF-1 mice were pretreated with 20 mg/kg (+)3-(2-carboxypiperazine-4yl)-propyl-1-phosphonic acid (CPP), 0.1 mg/kg (+)5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohopten-5, 10-imine maleate (MK-801, dizocilpine maleate), or 25 mg/kg 7-nitroindazole 30 min before a single dose (context-dependent paradigm) or each of three daily doses (context-independent paradigm) of 14 mg/kg amphetamine or 40 mg/kg apomorphine. Two days following this pretreatment, mice were injected with 7 mg/kg amphetamine or 3 mg/kg apomorphine. The stereotyped behavioral response was enhanced in mice pretreated with amphetamine or apomorphine alone, indicating that sensitization had developed. Both CPP and MK-801 prevented the development of sensitization in the context-dependent model but not in the context-independent paradigm. 7-Nitroindazole did not attenuate development of sensitization in either model. The results suggest that activation of glutamatergic receptors is important in some sensitization paradigms but not others, indicating that glutamate can be important but is not always required for the development of sensitization.     

Exploration of a hole-board matrix in nervous mutant mice

Male Sprague-Dawley rats were injected with phenytoin (PHT) once a day for 20 consecutive days and then tested as to their response to 5-methoxy-N,N-dimethyltryptamine (5-MDMT), a 5-hydroxytryptamine (5-HT) agonist, at 1 and 3 mg/kg on days 21 and 28. It was found that long-term PHT administration decreased the intensity of a stereotyped motor response induced by 5-MDMT (3 mg/kg) on day 21 but not on day 28. A single injection of PHT (25 mg/kg) did not modify the motor response induced by 5-MDMT (3 mg/kg) on day 21 but not on day 28. A single injection of PHT (25 mg/kg) did not modify the motor response induced by 5-MDMT (1.7, 3.2 mg/kg). It is suggested that PHT increases the functional availability of 5-HT before its receptors, and thereby causes 5-HT receptor subsensitivity.     

Chronic corticosterone administration enhances behavioral sensitization to amphetamine in mice

The role of corticosterone (CCS) in regulating sensitization to ampetamine's locomotor activating effects was measured in female DBA/2 mice that had been sham-operated or adrenalectomized and implanted with CCS-containing or cholesterol pellets. Three days following surgery, the mice were injected with saline and circular open field locomotor activity was measured for a 5-min time period starting 15 min after injection. Over the next 4 days, amphetamine (1.0–10.0 mg/kg) was injected and locomotor response measured. Control animals (sham-operated, cholesterol pellet) showed increased locomotor activity following their first injection of 5.0 mg/kg and 10.0 mg/kg amphetamine, while ADX animals showed increased activity only after treatment with the 10 mg/kg dose. Chronic CCS treatment did not significantly alter initial responsiveness to amphetamine in either sham-operated or ADX animals, but it did alter the dose-dependent sensitization to amphetamine. Both sham-operated and ADX animals implanted with cholesterol pellets showed increased locomotor respponse to amphetamine (sensitation) following injection with 2.5, 5.0 and 10.0 mg/kg doses of amphetamine. However, the enhancement of locomotor activity was greater in the sham-operated control animals. CCS-treated sham-operated animals exhibited sensitization to the locomotor-activating effects of amphetamine at the lowest dose used (1.0 mg/kg) and increased stereotypy following treatment with the higher doses. ADX/CCS animals developed sensitization to the locomotor-activating effects of amphetamine following chronic injection with the 2.5 mg/kg dose, and showed sensitization to amphetamine-induced stereotypy at higher doses. These data demonstrate that adrenocortical status modulates the effects of chronic and acute amphetamine administration and suggest that CCS may be an important component of stress-induced alterations in amphetamine sensitivity.     

Paradoxical sleep deprivation potentiates amphetamine-induced behavioural sensitization by increasing its conditioned component

The effects of paradoxical sleep deprivation (PSD-48 h) on the conditioned and unconditioned components of behavioural sensitization to amphetamine (two injections of 2.0 mg/kg, separated by 7 days) were studied using locomotion frequency of mice observed in an open-field as experimental parameter. Behavioural sensitization only occurred in PS deprived mice that were exposed to the open-field after the first amphetamine injection. The possible involvement of PSD in the development of a Pavlovian association between the stimulant effect of amphetamine and environmental as well as interoceptive drug cues is discussed.     

Conditioning, habituation and behavioral reorganization factors in chronic cocaine effects.

Rats were administered cocaine (50.0 mg/kg i.p.) daily for 7 days in a Pavlovian paradigm either immediately prior (paired group) or 30 min following (unpaired group) a 20-min placement in an open field test environment. After 7 days of drug withdrawal, the animals were retested 3 days apart, once with saline and once with cocaine (50 mg/kg). Measurement of locomotion as distance traversed (m) revealed a higher level of locomotion in the paired group on all test trials. Analysis of the paired vs. unpaired differences indicated an antihabituation effect of cocaine rather than a hyperlocomotion or a conditioned locomotor effect. Rotation pattern analysis for each animal showed a new frequency distribution of rotations across four categories of diameter size in the paired but not in the unpaired group by Day 5. This new pattern was characterized by a shift in skewness toward large greater than or equal to 55 cm diameter rotations. These qualitative changes in rotation pattern point to a context specific behavioral reorganization process in response to repeated cocaine drug treatment.     

Calcium channel antagonists suppress cross-tolerance to the anxiogenic effects of D-amphetamine and nicotine in the mouse elevated plus maze test

The purpose of the current experiments was to examine the anxiety-related effects of repeated amphetamine and nicotine administration using the mouse elevated plus maze (EPM). d-amphetamine was administered daily for 8 days (2 mg/kg, i.p.). On the 9th day, mice were challenged with amphetamine (2 mg/kg, i.p.) or nicotine (0.1 mg/kg, s.c.), and were tested 30 min after this last injection. Additionally, a distinct group of mice was pretreated with nicotine (0.1 mg/kg, s.c., 6 days). These mice were subjected to nicotine (0.1 mg/kg, s.c.) or amphetamine (2 mg/kg, i.p.) challenge on the seventh day to see if full crossover effects developed after the pretreatment of both psychostimulant drugs. Moreover, the L-type voltage-dependent calcium channel antagonists nimodipine (5 and 10 mg/kg, i.p.), flunarizine (5 and 10 mg/kg, i.p.), verapamil (5 and 10 mg/kg, i.p.) and diltiazem (5 and 10 mg/kg, i.p.) were injected prior to each injection of chronic d-amphetamine or nicotine. We observed cross-tolerance to the anxiogenic effects of d-amphetamine and nicotine that was blunted by a pretreatment with calcium channel blockers. Overall our findings imply that similar neural calcium-dependent mechanisms are involved in the anxiety-related responses to chronic amphetamine and nicotine injections. As anxiety seems to be an important factor for the development of psychostimulant dependence, the L-type VDCC antagonists can offer an interesting approach for the pharmacotherapy of addiction, including amphetamine and/or nicotine dependence.     

Behavioral and antiepileptic effect of acute administration of the extract of the aquatic plant Echinodorus berteroi (Sprengel) Fassett (upright burhead)

Echinodorus berteroi is an aquatic plant found in Central America and the Caribbean to which antiepileptic action has been attributed by folk medicine. The aim of the present study was to investigate the potential behavioral and antiepileptic effect of decoctions (1, 5, and 30%, intraperitoneally) of the dried roots. One and five percent decoctions produced hypoactivity in mice. Hyperactivity induced by amphetamine (3mg/kg, subcutaneously) was significantly reduced by the 30% decoction, in rats. The extracts did not modify the latency to the first clonic convulsion or the survival time of isoniazid (210 mg/kg, ip)-treated mice. The 30% decoction significantly increased the latency to the first picrotoxin-induced clonic convulsion (7 mg/kg, intraperitoneally), as well as survival time. Repeated administration of the 5% decoction (30-minute intervals) significantly reduced the amplitude (muV) of the epileptic spikes induced by topical application of penicillin to sensorimotor cortex, in curare-treated rats. In summary, the root decoctions of E. berteroi paradoxically exhibited neuroleptic and antiepileptic actions. Nevertheless, these results partly justify the use of the plant for the treatment of epilepsy by practitioners of folk medicine.     

Blockade of neurotensin receptors during amphetamine discontinuation indicates individual variability

Psychostimulant-induced locomotor sensitization has been related to changes within the mesolimbic dopamine system and has been suggested to be useful to study mechanisms underlying drug craving. Neurotensin is a neuropeptide co-localized with dopamine in the mesolimbic system. The response to novelty has been suggested to be a predictor of enhanced vulnerability to behavioral sensitization. The effects of repeated treatment with the neurotensin antagonist SR48692 after amphetamine discontinuation were investigated in mice previously classified as high responders (HRs) or low responders (LRs) to novelty. Mice were repeatedly treated with 2.0mg/kg amphetamine, every other day for 11 days. During the first 7 days after amphetamine discontinuation, the animals received a daily injection of saline or 0.3mg/kg SR48692. On the eighth day after amphetamine discontinuation all subjects received a 2.0mg/kg amphetamine challenge injection. Then, mice were tested for an open field behavior and after 90min, were sacrificed for Fos expression quantification in the nucleus accumbens. Both HRs and LRs expressed amphetamine-induced sensitized locomotor activation and increased expression of Fos protein. Treatment with SR48692 prevented behavioral sensitization and Fos protein expression enhancement in LRs but not in HRs mice. These data suggest that neurotensin plays a role in individual variability to amphetamine-induced sensitization.     

Influence of morphine- or apomorphine-induced sensitization on histamine state-dependent learning in the step-down passive avoidance test

Effects of morphine- or apomorphine-induced sensitization on histamine state-dependent memory of passive avoidance task were examined in mice. Pre-training intracerebroventricular (i.c.v.) administration of histamine (20 microg/mouse) decreased the learning of a one-trial passive avoidance task. Pre-test administration of histamine (10 and 20 microg/mouse) reversed amnesia induced by pre-training of histamine, with maximum response at 20 microg/mouse. Pre-training histamine-induced amnesia was also reversed in morphine- or apomorphine-sensitized mice that had previously received once daily injections of morphine (20 and 30 mg/kg) or apomorphine (0.5 and 1 mg/kg) for 3 days. The reversion of histamine-induced amnesia in morphine-sensitized mice was decreased by once daily administration of naloxone (0.5 and 1 mg/kg), SCH 23390 (0.05 and 0.1 mg/kg) or sulpiride (25, 50 and 100 mg/kg) prior to injection of morphine (30 mg/kg/day, 3 days). Furthermore, once daily administration of sulpiride (50 and 100 mg/kg) but not SCH 23390 (0.01, 0.05 and 0.1 mg/kg) prior to apomorphine (1 mg/kg, for 3 days) decreased the reversion of pre-training histamine-induced amnesia by apomorphine. The results suggest that apomorphine or morphine sensitization affects the impairment of memory induced by histamine and thus it is postulated that opioid and dopamine receptors may play an important role in this effect.     

Striatal c-fos levels do not correlate with haloperidol-induced behavioral supersensitivity

Striatal c-fos levels and stereotyped behavior have been evaluated in chronically haloperidol-treated rats which received subsequent subacute dopamine (DA) agonist treatment to investigate the possible relationship between striatal c-fos and behavioral supersensitivity. Haloperidol treatment (1 mg/kg/day for 21 days) increased apomorphine-induced stereotypies but did not modify striatal c-fos levels. The subacute administration of the DA D-1 agonist SKF38393 (10 mg/kg/day for 5 days) and the combination of the D-1 agonist with the D-2 agonist quinpirole (1 mg/kg/day for 5 days) attenuated apomorphine-induced stereotypies after haloperidol pretreatment. The administration of quinpirole alone, however, did not modify the response to haloperidol. All DA agonists significantly increased c-fos levels after apomorphine injection. The dissociation between haloperidol-induced behavioral supersensitivity and striatal c-fos levels observed in this study suggests that mechanisms different from striatal c-fos induction might be involved, and that striatal c-fos levels are not a good marker of behavioral supersensitivity expression. © 1996 Wiley-Liss, Inc.     

Co-administration of memantine and amantadine with sub/suprathreshold doses of L-Dopa restores motor behaviour of MPTP-treated mice

Summary. The antiparkinsonian effects of the uncompetitive NMDA antagonists, memantine, amantadine and MK-801, in combination with an acute subthreshold dose of L-Dopa (5 mg/kg) in drug-naive MPTP-treated mice or a suprathreshold dose (20 mg/kg) in L-Dopa tolerant MPTP-treated mice were investigated. In the former case, memantine (locomotion: 3 mg/kg; rearing: 1 mg/kg) and amantadine (locomotion and rearing: 10 mg/kg) injected 60 min before the subthreshold dose of L-Dopa (5 mg/kg), each induced an antiparkinsonian action in hypokinesic MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. At the same time, higher doses of memantine reduced further the rearing (10 and 30 mg/kg) and locomotor (30 mg/kg) behaviour of the MPTP-treated mice. MK-801 plus L-Dopa elevated locomotion (0.1 mg/kg) but reduced rearing at the 0.3 mg/kg dose. In control, saline-treated mice, memantine (3, 10 and 30 mg/kg) and MK-801 (0.1 and 0.3 mg/kg) increased locomotor behaviour but decreased rearing behaviour, while amantadine produced no effects. Memantine increased locomotor (1 and 3 mg/kg, s.c.; 1 mg/kg dose restored activity) and rearing (0.3 and 3 mg/kg) activity in the L-Dopa tolerant MPTP-treated mice, whereas amantadine (3 and 10 mg/kg) restored both locomotor (30 mg/kg significantly increased locomotion but did not restore the activity level) and rearing (3 mg/kg only) activity. MK-801 (0.1 and 0.3 mg/kg, s.c.) also increased significantly locomotor activity of L-Dopa-tolerant MPTP mice although the antikinetic action was not reversed, thereby precluding a restorative effect of the compound. These results, demonstrating both a synergistic and a restorative effect of the NMDA antagonists in co-administration with L-Dopa, demonstrate a putative antiparkinson action by these compounds in a functional animal model that incorporates the "wearing-off" complications of L-Dopa administration in the disorder. Received May 29, 2000; accepted September 13, 2000