Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease.

In addition to classic motor symptoms, Parkinson's disease (PD) is characterized by cognitive and emotional deficits, which have been demonstrated to precede motor impairments. The present study addresses the question of whether a partial degeneration of dopaminergic neurons using 6-hydroxydopamine (6-OHDA) in rats is able to induce premotor behavioral signs. The time-course of nigrostriatal damage was evaluated by tyrosine hydroxylase immunohistochemistry and the levels of dopamine, noradrenaline, and 5-HT in various brain regions were analyzed by high performance liquid chromatography (HPLC). Behavioral tests that assessed a variety of psychological functions, including locomotor activity, emotional reactivity and depression, anxiety and memory were conducted on 6-OHDA lesioned rats. Bilateral infusion of 6-OHDA in the striatum of rats caused early (1 week) damage of dopaminergic terminals in striatum and in cell bodies in substantia nigra pars compacta. The nigrostriatal lesion was accompanied by early loss of dopamine in the striatum, which remained stable through a 3-week period of observation. In addition, a late (3 weeks) loss of dopamine in the prefrontal cortex, but not in the hippocampus, was seen. Additional noradrenergic and serotonergic alterations were observed after 6-OHDA administration. The results indicated that 6-OHDA lesioned rats show decreased sucrose consumption and an increased immobility time in the forced swimming test, an anhedonic-depressive-like effect. In addition, an anxiogenic-like activity in the elevated plus maze test and cognitive impairments were observed on the cued version of the Morris water maze and social recognition tests. These findings suggest that partial striatal dopaminergic degeneration and parallel dopaminergic, noradrenergic and serotonergic alterations in striatum and prefrontal cortex may have caused the emotional and cognitive deficits observed in this rat model of early phase PD.

Genetic deletion or antagonism of kinin B(1) and B(2) receptors improves cognitive deficits in a mouse model of Alzheimer's disease.

Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signs of Alzheimer's disease (AD) that have been widely associated to inflammatory response. We have recently shown that a single i.c.v. injection of aggregated beta-amyloid peptide-(1-40) (Abeta(1-40)) (400 pmol/mouse) results in marked deficits of learning and memory in mice which are related to oxidative stress and synaptic dysfunction. In the present study, we investigated by means of genetic or pharmacological approaches the role of kinin system in the Abeta(1-40) cognitive effects on the water maze paradigm. Spatial learning and memory deficits observed at 7 days following Abeta(1-40) treatment were significantly reduced by the i.c.v. administration of the selective kinin B(2) receptor antagonist d-Arg-[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-BK (Hoe 140). A similar effect was found in mice lacking kinin B(2) receptor. On the other hand, genetic deletion of the inducible kinin B(1) receptor or its blockage by i.c.v. injection of des-Arg(9)-[Leu(8)]-BK antagonist attenuated only the long-term (30 days after treatment) cognitive deficits induced by Abeta(1-40). Moreover, treatment with Abeta(1-40) resulted in a sustained increase in the expression of the kinin B(1) receptor in the hippocampus and prefrontal cortex of mice, while it did not alter the expression of the kinin B(2) receptor in these brain areas. These findings provide convincing evidence that kinins acting via activation of B(1) and B(2) receptors in the CNS exert a critical role in the spatial learning and memory deficits induced by Abeta peptide in mice. Therefore, selective kinin receptor antagonists, especially the new orally active non-peptide antagonists, might represent drugs of potential interest for the treatment of AD.

Study pharmacologic of the GABAergic and glutamatergic drugs on seizures and status epilepticus induced by pilocarpine in adult Wistar rats.

This work was designed to study the influence of drugs during seizures and status epilepticus (SE) induced by pilocarpine and mortality in adult rats. Glutamate (10 and 20 mg/kg), N-methyl-d-aspartate (NMDA, 5 and 10 mg/kg), ketamine (1.5 and 2.0 mg/kg), gabapentin (200 and 250 mg/kg), phenobarbital (50 and 100 mg/kg) and vigabatrin (250 and 500 mg/kg) were administered intraperitoneally, 30 min prior to pilocarpine (400 mg/kg, i.p.). The animals were observed (24 h) to determine: number of peripheral cholinergic signs, tremors, stereotyped movements, seizures, SE, latency to first seizure and number of deaths after pilocarpine treatment. NMDA and glutamate had pro-convulsive effects in both doses tested. Smaller and higher doses of these drugs no protected and increased pilocarpine-induced seizures and/or mortality. Gabapentin, vigabatrin, phenobarbital and ketamine protected against seizures and increased the latency to first seizure. Thus, these results suggest that caution should be taken in the selection of pharmacotherapy and dosages for patients with seizures and SE because of the possibility of facility the convulsive process toxicity, SE and the mortality of adult animals in this seizures model that is similar temporal lobo epilepsy in humans.

Effects of the vitamin E in catalase activities in hippocampus after status epilepticus induced by pilocarpine in Wistar rats.

Experimental manipulations suggest that in vivo administration of exogenous antioxidants agents decreases the concentration of free radical in the brain. Neurochemical studies have proposed a role for catalase in brain mechanisms responsible by development to status epilepticus (SE) induced by pilocarpine. The present study was aimed at was investigating the changes in catalase activities after pilocarpine-induced SE. Animals were treated with vitamin E (VIT E) 200 mg/kg (intraperitoneally (i.p.)) and, 30 min later, they received pilocarpine hydrochloride, 400 mg/kg, subcutaneous (s.c.) (P400). Other three groups received VIT E (200 mg/kg, i.p.), pilocarpine (400 mg/kg, s.c.) or 0.9% NaCl (control) alone. Animals were closely observed for behavioral changes, tremors, stereotyped movements, seizures, SE and death, for 24 h following the pilocarpine injection. The brains were dissected after decapitation. The results have shown that pilocarpine administration and resulting SE produced a significant increase in hippocampal catalase activity of (88%). In the group pre-treated which VIT E in hippocampal catalase activity was increase of 67% and 214% when compared with P400 and control group, respectively. Our results demonstrated a direct evidence of an increase in the activity of the hippocampal catalase of rat adults during seizure activity and after the pre-treated which VIT E that could be responsible by regulation of free radical levels during the establishment of SE.

Evidence for a female-specific effect of a chromosome 4 locus on anxiety-related behaviors and ethanol drinking in rats.

Previous studies using the inbred rat strains Lewis (LEW) and spontaneously hypertensive rats (SHR) led to the mapping of two quantitative trait loci, named Ofil1 (on chromosome 4 of the rat) and Ofil2 (on chromosome 7), for open-field inner locomotion, a behavioral index of anxiety. Studies using other strains showed that the region next to Ofil1 influences measures of not only anxiety but also ethanol consumption. In view of the high prevalence of psychiatric disorders such as anxiety and alcoholism, as well as the comorbidity between them, the present study was designed to better characterize the contribution of these two loci to complex emotional and consummatory responses. Rats deriving from an F2 intercross between the LEW and the SHR strains were selected according to their genotype at markers flanking the loci Ofil1 and Ofil2 and bred to obtain lines of rats homozygous LEW/LEW or SHR/SHR for each of the two loci, thus generating four genotypic combinations. These selected animals as well as purebred LEW and SHR rats of both sexes were submitted to a battery of tests including measures of locomotor activity, anxiety, sweet and bitter taste reinforcement and ethanol intake. Lewis rats displayed more anxiety-like behavior and less ethanol intake than SHR rats. Ofil1 (on chromosome 4) affected both the activity in the center of the open field and ethanol drinking in females only. These results suggest that Ofil1 contains either linked genes with independent influences on anxiety-related responses and ethanol drinking or a pleiotropic gene with simultaneous effects on both traits.

Stimulant activities of dimethocaine in mice: reinforcing and anxiogenic effects.

The present study evaluated the effects of dimethocaine and procaine, esteratic local anesthetics, on locomotor activity, conditioned place preference and on the elevated plus-maze test of anxiety in mice, behavioral tests believed to be sensitive to cocaine action. Acute administration of dimethocaine (10-40 mg/kg, IP) significantly increased locomotor activity and time spent on the drug-paired side and reduced the relative number of entries and time spent on the open arms of the plus-maze in mice. Procaine (20-50 mg/kg, IP) failed to affect these responses. These data demonstrate the locomotor stimulant, reinforcing and anxiogenic actions of dimethocaine similar to those reported for cocaine in animals. In addition, these findings support a role for dopaminergic activity, rather than local anesthetic action, in the behavioral effects caused by dimethocaine.

Memory disruption in rats with nigral lesions induced by MPTP: a model for early Parkinson's disease amnesia.

Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) caused a lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. The animals were then tested in the two-way active avoidance task. MPTP-treated animals presented lower learning scores in the training and test sessions, an effect that was not caused by motor impairment or by a decreased sensitivity to footshock since their reaction time to the footshock (unconditioned stimulus - UCS) was not reduced. These lower scores were also not attributable to lower acoustic sensitivity or to a slowing in the association of the sound cue (conditioned stimulus - CS) with the UCS since the reaction time to the CS in the active avoidance response did not differ between MPTP-treated and control groups. Therefore, these results are more properly attributable to an impairment of the memory acquisition and retention processes. In addition, this study is presented as a model of early Parkinson's Disease amnesia and is discussed in terms of the importance of the nigrostriatal pathway to memory acquisition and storage processes.

Mazindol and lidocaine are antinociceptives in the mouse formalin model: involvement of dopamine receptor.

The antinociceptive potential of mazindol, an anorectic drug, and lidocaine, an amide-type local anesthetic, were investigated in the mouse formalin test with concurrent motor function assessment. In addition, the role of dopamine and opioid receptors in mediation of the antinociceptive action of these drugs was examined. The i.p. injection of mazindol (1.25-10 mg/kg) and lidocaine (10-30 mg/kg) induced significant antinociceptive responses in both phases of the test. Cocaine (20 mg/kg, i.p.), used as positive control, also inhibited the pain responses caused by formalin. Haloperidol (0.2 mg/kg, i.p.), and sulpiride (5 mg/kg, i.p.), a dopamine D2 receptor antagonist, reduced the antinociceptive actions of mazindol and cocaine, while SCH 23390, R(+)-7-chloro 8-hydroxy-3methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine (0.03 mg/kg, i.p.), a dopamine D1 receptor antagonist, did not affect these responses. Only the antinociception associated with mazindol was reversed by naloxone (2 mg/kg, i.p.). The same pretreatments failed to modify lidocaine-induced antinociception. The drug conditions used in this study did not reveal any motor impairment in the rotarod test. These observations suggest an involvement of dopaminergic mechanisms, mainly via dopamine D2 receptors, in the antinociceptive action of mazindol in the formalin test, but the nature of mechanisms involved in the lidocaine responses remains unsolved.

Rapid tolerance to Delta(9)-tetrahydrocannabinol and cross-tolerance between ethanol and Delta(9)-tetrahydrocannabinol in mice.

Motor incoordination in the rota-rod test was used to assess the development of rapid tolerance to Delta(9)-tetrahydrocannabinol and rapid cross-tolerance between ethanol and Delta(9)-tetrahydrocannabinol in mice. Further, the influence of the cannabinoid receptor antagonist SR 141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide) on the motor impairment induced by both drugs was examined. Mice were injected on day 1 with equipotent doses of Delta(9)-tetrahydrocannabinol (28 mg/kg, i.p.) and ethanol (2.25 g/kg, i.p.) and tested at 30, 60 and 90 min after the injections. On day 2, control groups received ethanol or Delta(9)-tetrahydrocannabinol, some groups received the same treatment as the day before, while the remaining groups switched the treatment. All groups were tested to evaluate tolerance. The development of rapid tolerance to Delta(9)-tetrahydrocannabinol was observed and pretreatment with ethanol resulted in rapid cross-tolerance to Delta(9)-tetrahydrocannabinol. SR 141716A (2 mg/kg, i.p.) failed to block the development of rapid tolerance to both drugs, ethanol and Delta(9)-tetrahydrocannabinol. These results suggest that Delta(9)-tetrahydrocannabinol, similarly to ethanol, can induce rapid tolerance to motor incoordination in mice. They also support the use of the 2-day protocol as an effective procedure to reduce the length of drug exposure necessary to induce tolerance.

Sex difference in sensitization to the locomotor effects of mazindol in rats.

Male and female rats were treated daily for 7 days with mazindol (5, 10, and 20 mg/kg), an anorectic drug, and tested in the open field. Mazindol developed sensitization to its locomotor stimulatory effect in both sexes on day 7 with a nondose-dependent pattern of response. However, the locomotor activity appeared to be sex dependent, female rats being more sensitive. Following a challenge dose of mazindol (10 and 20 mg/kg) on day 10, a marked enhancement of locomotion was seen in female rats. These findings indicate that repeated administration of mazindol produces sex-dependent sensitization to its effect on locomotor behavior.

Caffeine reverses the memory disruption induced by intra-nigral MPTP-injection in rats.

The present study was carried out to test the possible effects of caffeine in improving the memory deficits observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP)-lesioned rats, an animal model of early stage Parkinson's disease. Caffeine at the doses of 0.1-0.3 mg/kg (intraperitoneal) reversed the impairing effect of the administration of MPTP (1 micromol/side) into the substantia nigra, compact part, of rats on the avoidance scores in the training and test sessions of a two-way active avoidance task. This effect was not due to a motor or sensory alteration because the caffeine-induced learning and memory improvement was independent of the locomotor stimulant effect of the drug and there were no differences in the reaction time of the animals to a footshock (unconditioned stimulus) or a sound cue (conditioned stimulus) after caffeine treatment. These results suggest that the reported dopamine/adenosine-receptor interaction can be used to restore defective learning and memory processes in Parkinson's disease and indicate that caffeine and other adenosine receptor antagonists are drugs with the potential for treatment of the cognitive disabilities of Parkinson's disease.

Anxiogenic properties of cocaine in the rat evaluated with the elevated plus-maze.

In previous work, we reported that cocaine (5, 10, and 20 mg/kg) failed to induce significant responses in naive rats in the elevated plus-maze test of anxiety. This study investigates the putative anxiogenic properties of cocaine in rats selected as "anxious" or "nonanxious" on the basis of their behavior in the plus-maze prior to drug treatment. In nonanxious rats, cocaine (10 mg/kg) increased the latency to the first entry into the open arms and reduced the number of entries into and time spent on the open arms. All these measures are indicative of an anxiogenic action of cocaine. In contrast, cocaine failed to modify the behavior of anxious rats. These findings demonstrate that rats with high exploratory activity in the plus-maze and regarded as nonanxious are more sensitive to cocaine's anxiogenic effects. Further, the present manipulation provides a useful procedure for investigating the anxiogenic effects of cocaine in rats.

Self-administration of delta 9-tetrahydrocannabinol by rats.

The present study examines the dose-response pattern of delta 9-tetrahydrocannabinol self-injection in naive rats at 80% reduced body weight and 100% body weight, both conditions with a fixed-time 1 min (FT-1) food delivery schedule. The results indicated that food deprived animals tested on a FT-1 min schedule self-injected low doses of delta 9-THC at a higher rate than those animals at 100% body weight and on a FT-1 min schedule. Animals at 80% reduced body weight without a schedule did not differ from rats self-injecting delta 9-THC at free feeding situation. These findings suggest that rats without previous history of drug dependence self-administer low doses of delta 9-THC and that the interaction between the food deprivation state and the environmental contingencies introduced by a FT-1 min schedule is a critical variable in the acquisition period.

Effects of body weight levels on cannabis self-injection.

Previous findings have shown that naive rats self-inject IV delta 9-THC 12.5 microgram/kg/infusion in the presence of a FT-1 non contingent food delivery schedule. In the present study the effects of three different body weight levels, 80%, 90% and 100%, with and without a FT-1 food delivery schedule, were examined on the THC self-injection behavior. Results confirmed that 80% body weight plus the FT-1 schedule condition leads to the highest intake of THC. In a further experiment, naive rats acquired THC self-injection at 80% body weight with a FT-1 schedule. Rats were then allowed to regain body weight to their free feeding level and were tested again in the same basic paradigm. Animals recovering body weight did not maintain the self-injection rates. The data indicate that the environmental conditions necessary in the acquisition phase are also required to maintain intake of THC 12.5 microgram/kg/infusion.

Involvement of dopamine receptors on locomotor stimulation and sensitization elicited by the interaction of ethanol and mazindol in mice.

We have previously observed that the combination of ethanol (EtOH) and the anorectic drug mazindol (MZ) produces more marked effects on behavior than either substance alone. In the present study we examined whether the repeated administration of the drug combination could induce sensitization to its motor activating effects in mice and, if so, whether this response could be affected by dopamine (DA) receptors antagonists. Male Swiss albino mice were treated daily for 7 days with combined EtOH+MZ (1.2 g/kg, 5.0 mg/kg IP), EtOH (1.2 g/kg IP), MZ (5.0 mg/kg IP), or control solution coadministered with the D1 dopamine antagonist SCH-23390 (0.025 or 0.05 mg/kg IP), the mixed dopamine antagonist haloperidol (0.05 or 0.075 mg/kg IP), or vehicle. After the injections on days 1, 7, and 10, mice were assessed in activity cages at different time intervals. Repeated administration of MZ resulted in an enhancement of its locomotor activating effects, behavioral sensitization. Further, the combined EtOH+MZ treatment also resulted in sensitization to its locomotor effects. Moreover, the development of MZ and EtOH+MZ sensitization was attenuated by both SCH-23390 and haloperidol. These data demonstrate that following repeated MZ or EtOH+MZ exposure mice show locomotor sensitization through DA receptor stimulation. Also, these findings suggest that a major determinant of combined anorectic-alcohol misuse may be the increased stimulating effects produced by such combination.

Dexamethasone reverses the ethanol-induced anxiolytic effect in rats.

The effects of intraperitoneal and intrahippocampal administration of the glucocorticoid dexamethasone were assessed regarding ethanol-induced anxiolysis in the elevated plus-maze in rats. Animals pretreated with systemic injections of dexamethasone (0.5, 1. 0, or 2.0 mg/kg, IP) 15 min before ethanol (1.2 g/kg, 14% w/v, IP) administration showed a significant dose-dependent attenuation of the increased percentage of frequency and time spent on open arms of the maze. However, IP dexamethasone treatment 4 h before the test had no effect. Unilateral intrahippocampal injection of dexamethasone (2 and 20 nmol in 0.5 microl) also significantly attenuated the increased exploration of the open arms induced by ethanol. The results are interpreted in terms of the modulation of the anxiolytic effects of ethanol by glucocorticoids and the possible involvement of hippocampus in this response. The rapid blockade of ethanol induced anxiolysis by dexamethasone strengthens the suggestion that a nongenomic mechanism may underlie this response.

Methylnalorphinium fails to reverse naloxone-sensitive stress-induced analgesia in mice.

Exposure of mice to cold-restraint stress markedly decreased the number of abdominal constrictions induced by IP acetic acid. Naloxone pretreatment significantly attenuated the antinociceptive effect of cold-restraint stress, suggesting a partial mediation by opioid mechanisms. Pretreatment with the quaternary opioid antagonist methylnalorphinium did not reverse analgesia in stressed mice. Also, nociception in both stressed and non-stressed mice was not modified by pretreatment with the selective alpha 2-adrenoceptor blocker yohimbine. The results suggest that cold-restraint stress promotes analgesia in mice which is mediated in part by opioid but not alpha 2-adrenoceptor mechanisms. Furthermore, the results do not substantiate a peripheral analgesic role for circulating opioids in this model of stress.

Acute exposure to maneb alters some behavioral functions in the mouse.

Maneb, an organomanganese fungicide, is largely used in agricultural regions for control of field crop pathologies. Despite its apparent low toxicity, there are reports showing that maneb has harmful effects on peripheral and central nervous systems. In this work the effects of acute administration of maneb were studied on some experimental animal models. Male adult mice were treated with several doses of maneb, IP, and submitted to gross behavioral observation (200-1000 mg/kg) and measurement of locomotor activity, barbiturate-induced sleeping time, isolation-induced aggressiveness, catatonia, climbing behavior and of rota-rod performance (30, 60 and 100 mg/kg). The results showed that maneb has an inhibitory effect on locomotor activity and aggressiveness and increases barbiturate-induced sleeping time and haloperidol-induced catatonia. However, maneb did not affect the apomorphine-induced climbing behavior of animals. These data indicate that maneb has a CNS depressant-like effect, and suggest, at least partially, the involvement of dopaminergic systems in the mediation of this effect.

Effects of age on behavioral and physiological responses to carbaryl in rats.

Motor, sensory and thermoregulatory functions were examined in young (3 months) and mature (12 months) rats following PO administration of single low doses (10 and 50 mg/kg) of carbaryl, a carbamate insecticide, and these effects were related to blood cholinesterase activity. Carbaryl 50 mg/kg decreased the frequency of ambulation in the open-field arena within 30 min while it enhanced the duration of haloperidol-induced catalepsy in both young and mature rats. Administration of carbaryl also resulted in an increased nociceptive threshold to thermic stimuli mainly in mature rats. An age-related reduction in body temperature was observed at 30, 60 and 90 min after injection. Activity of blood cholinesterase was reduced in young and mature rats at 30 and 60 min following carbaryl exposure. These results indicate that carbaryl can induce an age-related impairment on some behavioral and autonomic functions in rats correlated to the inhibition of cholinesterase activity.