Behavioral and neurochemical modifications caused by chronic alpha-methylparatyrosine administration.

The chronic administration of alpha-methylparatyrosine (AMT) caused a reduction of the noradrenaline levels in the hippocampus (at 150 and 300 mg/kg/day) and in the subcortex (at 30, 150 and 300 mg/kg/day). The acetylcholine levels were reduced in the hippocampus and in the olfactory brain at all the tested doses of AMT. An increase of the Bmax of muscarinic and alpha 1-adrenoceptors was observed at 30 mg/kg/day of AMT; only in the subcortex AMT caused no modification of the density of muscarinic receptors. The degree of increase of the receptors density at 30 mg/kg/day was reduced at the higher doses of AMT. AMT 30 mg/kg/day caused a reduction of the errors in the staircase maze after 20 days of interruption of the daily training. These results might suggest a correlation between the behavioral effect and the increase of density, not only of the adrenoceptors, but also of the muscarinic receptors. It is proposed that the behavioral effects caused by chronic AMT are the consequence of complex neurochemical interactions.     

Behavioral and neurochemical effects of intraventricular AF64A administration in rats

Ethylcholine aziridinium ion solution (AF64A), a putative specific cholinergic neurotoxin, was injected bilaterally into the lateral ventricles of rats. Following administration of 3 or 6 nmoles of AF64A, drinking and eating were depressed but returned to normal levels after several days; increased activity in the 6 nmole group persisted throughout the 21 days of observations. Performance on complex place and cue tasks indicated that injected animals were impaired in reference memory only on the place task, but working memory was impaired on both tasks. Neurochemical measurements in a separate group of animals one week after AF64A injections found large depletions of acetylcholine in hippocampus and corpus striatum, but not depletions of norepinephrine (hippocampus) or dopamine (striatum). Histological examination of the injection site revealed extensive damage to the fimbria-fornix similar to that seen after electrolytic lesions. Since the behavorial and neurochemical changes are similar to those previously found following fimbria-fornix lesions, it is concluded that the present results are possibly due to non-specific lesion effects of the neurotoxin rather than a specific effect on cholinergic systems.     

Behavioral and neurochemical effects induced by subchronic exposure to 40 ppm toluene in rats

Chronic toluene inhalation at concentrations above occupational exposure limits (e.g., 100 ppm; NIOSH) has been repeatedly shown to induce neurotoxic effects. In contrast, although few clinical and experimental data are available on the effects of toluene exposure at concentrations below occupational exposure standards, some of these data may support adverse effects of long-term exposure to low toluene concentrations. To test this hypothesis, we investigated the neurobehavioral and neurochemical effects of 40 ppm inhaled toluene in a rat model of 16-week subchronic exposure, examining locomotor and rearing activities; adaptation/sensitization to narcosis produced by acute exposure to toluene at high concentration; and tyrosine hydroxylase and tryptophan hydroxylase activities, and dopamine (DA) and serotonin (5-HT) turnovers in the caudate-putamen, nucleus accumbens, hippocampus, prefrontal cortex, and cerebellum. Our results mainly show that subchronic exposure to 40 ppm toluene significantly resulted in a sensitization to toluene-induced narcosis, a decrease in rearing activity, and alterations in DA and 5-HT transmissions. This demonstrates that subchronic toluene exposure at a low concentration may lead to adverse changes in neurobehavioral and neurochemical functioning, and further questions in a public health perspective the actual neurotoxic potential of toluene and other organic compounds, because deficits in functioning are generally viewed as precursors of more serious adverse effects.     

Behavioral and neurochemical changes caused by repeated ethanol and cocaine administration

Combined cocaine and ethanol abuse has become increasingly popular, yet research on the behavioral and neurochemical interactions of these two substances is limited. Four groups of male rats received either daily cocaine (10 mg/kg, IP) or saline injections with either water (groups C and S) or only 15% ethanol to drink (groups CE and E). Initially, locomotor activity was increased equally by ethanol or cocaine and to the greatest extent by both. After 2 weeks of drug treatment, group C exhibited behavioral sensitization to cocaine, group E exhibited ethanol tolerance and group CE exhibited greater cocaine sensitization with no indication of ethanol tolerance. In support of enhanced sensitization to cocaine, amphetamine-stimulated³H-dopamine (DA) release in striatum and D₂ DA receptor binding in the nucleus accumbens (NAC) were increased in group CE compared to group C. In support of a loss of ethanol tolerance, increases in striatal D₂ DA and³⁵S-TBPS binding seen in group E (which exhibited ethanol tolerance) were absent in group CE (which did not exhibit tolerance). Thus, the synergistic effect of ethanol and cocaine on behavior may be due to complex interactions of these two drugs both on DA and GABA transmission in mesolimbic and nigrostriatal areas.     

Behavioral and neurochemical effects of repeated administration of delta 9-tetrahydrocannabinol in rats

The effects of repeated administrations of Δ⁹-tetrahydrocannabinol (THC, 10 mg/kg i.p. twice daily at 8-hr interval) were investigated on spontaneous motor activity (SMA) in 2.5 hr daily sessions and on the levels of various neurotransmitters (e.g. norepinephrine, NE; dopamine, DA; serotonin, 5-HT) in different brain areas such as caudate nucleus (CN), pons-medulla (PM) and diencephalon-midbrain (DM) in rats. After a single dose of the drug, the SMA of rats decreased during the first hour postdrug along with a decrease of DA levels in the CN and DM and NE levels in the DM and PM, and increase of 5-HT levels in the DM and PM. Following repeated daily administration, the SMA gradually decreased during the first hour postdrug to a minimum on day 5, and then increased beyond the normal level on day 8 reaching its peak on day 10. The SMA then decreased again and remained close to the normal level on day 15 onwards. Concomitantly, DA and NE levels decreased to their minimum, and 5-HT levels increased to their maximum in the respective brain areas on day 5; the levels of neurotransmitters then gradually approached their normal up to day 15. Thus, during the first hour after repeated administration of THC, the changes in behavioral depression can be correlated to the changes in the brain neurotransmitter levels. During the second hour of THC action, SMA was enhanced. On its repeated administration, this increase was gradually reduced up to day 6 after which SMA was again increased to its peak between day 8 and day 10 and then decreased. These behavioral changes could also be correlated with the changes in DA and 5-HT levels in the brain areas during the second hour postdrug after repeated administration.     

Behavioral effects of chronic phencyclidine administration in rats

The development of tolerance to phencyclidine (PCP) was examined in rats using behavioral rating scales with simultaneous measurements of locomotor activity, stereotyped behaviors, and ataxia. Significant tolerance to the stereotyped behaviors and ataxia induced by 5 or 10 mg/kg PCP was found on day 5 of chronic drug treatment. Because ataxia interferes with PCP-induced locomotor activity (Sturgeon et al. 1979), tolerance to PCP-induced ataxia produced an increase in locomotor activity on day 5. Tolerance to the ataxia, but not to the stereotyped behaviors induced by PCP, was more prominent after day 15 of PCP administration than after day 5. Administration of PCP for 15 days resulted in a significant decrease in locomotor activity for the 5 mg/kg group but not for the 10 mg/kg group. These results suggest that behavioral tolerance, rather than supersensitivity, develops after chronic PCP administration. The effects of PCP returned to baseline over a 14-day withdrawal period for rats treated with 5 mg/kg PCP for 15 days. Rats treated with 10 mg/kg PCP for 15 days still had not returned to baseline when tested 28 days after cessation of PCP treatment.     

Gangliosides enhance behavioral and neurochemical effects induced by chronic desipramine (DMI) treatment

Rats pretreated with gangliosides showed a significant enhancement of the anti-immobility effect of desipramine (DMI) in the forced swimming test. Accordingly, an associated treatment of gangliosides and DMI for 7 days significantly enhanced beta-adrenergic down-regulation in the frontal cortex as compared with the effect of DMI alone. Gangliosides exerted an accelerating effect on the decrease of beta-adrenoceptor density induced by DMI, since the down-regulation phenomenon appeared after 3 days of treatment. Gangliosides did not affect the pharmacokinetics of DMI, since associated acute or prolonged treatments did not modify the brain levels of DMI as compared to the levels of animals that had received DMI alone. These results evidence a stimulating effect of gangliosides on the development of adaptative receptor changes induced by chronic DMI treatment.     

Behavioral and neurochemical effects of intraperitoneally injected dendrotoxin

Intraperitoneal administration of dendrotoxin, a polypeptide isolated from Dendroaspis angusticeps venom, provoked in mice the appearance of a complex stereotyped behavior including biting, head nodding, 'wet-dog' shakes and rearing. Signs of autonomic hyperactivity as well as hyperreactivity to sound and touch were prominent. Neurochemical analyses of monoamines and monoamine metabolites showed no change 90 min after dendrotoxin, with a decrease in dopamine concentrations and an increase in their metabolites in the striatum starting 3 hr later. Moreover, at this time, dendrotoxin also produced a significant increase of 5-hydroxytryptamine metabolites. These data are interpreted as indicating that dendrotoxin crosses the blood-brain barrier and provokes an increase of the activity at monoaminergic terminals.     

Behavioral effects of morphine and naloxone following chronic morphine administration

The effects of morphine, naloxone, and combinations of these drugs were examined in squirrel monkeys under shock-postponement schedules. In the absence of a lever press, shocks could be presented every 4s, and each response postponed shock for 20s. Acutely, morphine (0.10–3.00 mg/kg) produced not only overall response-rate decreases, but also increases in the number of shocks, whereas naloxone (0.10–30.00 mg/kg) had little effect on responding. When given in combination with morphine, several doses of naloxone antagonized the rate-reducing and shock-increasing effects of morphine. Daily administration of morphine resulted in a substantial decrease in the number of shocks received and a moderate attenuation of the rate-decreasing effects of morphine (tolerance). Lower doses substituted for the fixed daily dose resulted in a smaller effect on behavior than under acute administration. Naloxone given in combination with the daily morphine dose or substituted for the daily administration of morphine, produced effects similar to those seen prior to chronic drugging. Thus, behavioral effects of naloxone were not altered even though tolerance to morphine was observed. Larger doses of naloxone continued to antagonize the effects of morphine for at least 24h. No signs of physical dependence were noted when naloxone was administered or when administration of morphine ended.     

Anxiogenic effects of acute and chronic cocaine administration: neurochemical and behavioral studies.

The effects of cocaine on defensive withdrawal behavior in rats and elevated plus-maze behavior in mice were investigated. Cocaine (20 mg/kg IP) injected daily for 7 or 14 days induced defensive withdrawal; that is, the latency to emerge from a small chamber in an open field and the mean time in the chamber were both significantly increased. Acute cocaine administration also induced defensive withdrawal, and this effect was prevented by prior treatment with chlordiazepoxide (5 mg/kg IP). Both acute and chronic cocaine treatments significantly increased plasma concentrations of corticosterone and reduced the ratios of 3,4-dihydroxyphenylacetic acid to dopamine and 5-hydroxyindoleacetic acid to serotonin in several brain regions. Further evidence for an acute anxiogenic effect of cocaine was obtained from mice studied in the elevated plus-maze. Acute cocaine administration decreased both the number of entries into and the time spent in the open arms of the maze. These results taken together strongly support an anxiogenic action of acute and chronic cocaine administration.     

Behavioral and neurochemical effects of apomorphine in the cat

Administration of apomorphine (2–10 mg/kg i.p.) elicited a number of behaviors, such as limb flicking, abortive grooming, investigatory and hallucinatory-like responses, head and body shakes, and excessive grooming, which we have previously proposed as an animal model for studying the actions of LSD and related hallucinogens. Repeated administration of apomorphine resulted in a significant tolerance, which occurred within 2h of the initial injection, and completely dissipated within 24 h. A pronounced LSD-apomorphine cross tolerance was observed; however there was no significant apomorphine-LSD cross tolerance. Apomorphine-induced behavioral changes were blocked by prior treatment with haloperidol, but were unchanged by pretreatment with L-DOPA. Administration of L-DOPA, in combination with a peripheral decarboxylase inhibitor, did not elicit these characteristic behavioral changes. Increasing synaptic serotonin levels by monoamine oxidase inhibition, precursor administration, or reuptake blockade in general did not alter the behavioral response to apomorphine. Similarly, pretreatment with serotonin receptor blockers produced no large changes in apomorphine-induced behaviors. Prior serotonin depletion with chronic p-chlorophenylalanine administration, however, potentiated certain apomorphine-induced behaviors. Neurochemical studies revealed that apomorphine administration increased striatal dopamine, and decreased dopamine metabolites. Norepinephrine levels were generally decreased throughout the CNS by apomorphine treatment. Administration of apomorphine increased CNS serotonin and 5-hydroxyindoleactic acid levels, while tryptophan levels were unchanged. The biological bases of the limb flick model is discussed in the context of these pharmacological and neurochemical studies.     

Behavioral and neurochemical effects induced by pyrethroid-based mosquito repellent exposure in rat offsprings during prenatal and early postnatal period

Synthetic pyrethroids, besides their use in agriculture, are prevalently used in our houses as mosquito repellent (MR) in the form of aerosol, mats, coils and liquid vaporizers. Inhalation of fumes of the MR/liquid vaporizers may get entry into the brain by breaching the developing blood-brain barrier, hence deleterious to developing nervous system and can lead to long-term functional deficits. In the present study the consequence of MR exposure has further been investigated at various stages of development, evaluating free radical mediated effect pertinent to neurobehavioral and neurochemical functioning. Rat pups were exposed to pyrethroid-based MR (allethrin 3.6% w/v, 8 h/day through inhalation) during prenatal (GD1-20), postnatal (PND1-30) and perinatal (GD1-PND30) period of development and assessments were made on PND31. We observed significant oxidative stress, where an increase in lipid peroxidation and a decrease in antioxidants, glutathione, superoxide dismutase and catalase in various brain areas (cerebellum, corpus striatum, frontal cortex and hippocampus) were evident at all the exposure schedules. The hippocampus was the most affected region and further exhibited altered cholinergic functioning in the form of significant decrease in cholinergic (muscarinic) receptor binding (prenatal 32%, postnatal 35%, perinatal 38%) and inhibition in acetylcholinesterase activity (prenatal 20%, postnatal 31% and perinatal 33%). The neurochemical changes were found to accompany decrease in learning and memory performance in exposed rats, the function governed by hippocampus. The result suggests that pyrethroid-based MR inhalation during early developmental period may have adverse effect on developing nervous system causing cholinergic dysfunction leading to learning and memory deficit.     

Behavioral effects of chronic narcotic antagonist administration of infant rats

Rat pups were given daily subcutaneous injections of Naltrexone, an opiate antagonist, throughout infancy. Compared to saline-treated controls, the ontogeny of reflex behavior and body growth was not altered by the chronic drug treatment. However, the latency to morphine-induced analgesia was shorter in Naltrexone-treated pups 9 days following their last injections of Naltrexone.     

Behavioral effects of acute and chronic administration of caffeine in the rat

This study investigated the effects of acute and chronic caffeine treatment on behavior in the social interaction, holeboard and home-cage aggression tests and on proconvulsant actions with pentylenetetrazol. Acutely-treated rats received an IP injection of caffeine (20 or 40 mg/kg). Chronically-treated rats received caffeine in their drinking water for 21 days (50 or 100 mg/kg/day) followed by an injection of caffeine on the test day (20 or 40 mg/kg respectively). Acutely, the higher dose of caffeine (40 mg/kg) decreased levels of social interaction. In the holeboard test, 20 mg/kg of acute caffeine increased motor activity whilst 40 mg/kg reduced head-dipping behavior. In the home-cage aggression test, acute caffeine (40 mg/kg) reduced offensive aggressive behaviors. After chronic treatment with caffeine none of these behaviors differed significantly from controls. After both acute and chronic treatment, caffeine (20 and 40 mg/kg) was proconvulsant with pentylenetetrazol.     

Behavioral and biochemical effects of chronic administration of bromide in the rat

Oglesby, Rosenberg, Winter: Behavioral and biochemical effects of chronic administration of bromide in the rat. Bromide, a sedative in low doses and a psychotogen in high doses in man, was tested for behavioral and biochemical effects in the rat. The kinetics of bromide excretion following chronic administration were studied in the rat to determine drug regimens necessary to achieve stable, non-lethal levels of blood bromide. When administered daily to animals performing on a variable-interval schedule of positive reinforcement (VI 44), a low dose of bromide increased rates of responding while a high dose depressed response rates. Following withdrawal of the drug after six weeks of administration, response rates returned to previously determined control levels. Chlorpromazine failed to antagonize bromide-induced rate depression. No change in the concentration of norepinephrine or 5-hydroxytryptamine was seen with any dose of bromide studied.     

Behavioral effects of chronic administration of psychoactive drugs to anxious patients

Summary The effects of chronic administration of (a) 1600 mg. meprobamate, (b) five Tranquil tablets (the maximum recommended daily dose), and (c) placebos were examined, in a counterbalanced partially blinded design. Thirty-two subjects, including 23 anxious patients, employed as their own controls, were given behavioral tests, psychiatric interviews, and ratings at the end of each 21 day treatment period.On the behavioral tests, meprobamate led to a slowing of reaction time in simulated driving at high speed, accompanied by a slight lowering of accuracy, and an improvement in accuracy of time estimations under a distracting influence. Tranquil led to a similar slowing of reaction time at high speed, along with a nonsignificant tendency toward decreased accuracy, and significantly poorer visual acuity and hyperventilation scores.On psychiatric evaluations, meprobamate led to marked psychological reactions, daytime sleepiness, longer nighttime sleep, greater restfulness, better retention, need for more physical effort, less tension, decreased appetite, and a feeling that the drug was active. Tranquil led to similar effects as to psychological reactions, daytime sleepiness, nighttime sleep, need for more physical effort, decreased appetite, and judgment of drug activity but no increase in restfulness, improved retention, or lessened tension.Self-ratings did not differentiate between the three treatments. Ratings by observers indicated decreased anxiety under meprobamate and decreased symptoms under both treatments.The authors wish to thank Mr. Gershom Morningstar for conducting the behavioral tests, Drs. Ralph W. Gerard and E. Lowell Kelly for consultation in planning and designing the experiment, Mrs. Mona Morningstar and Messrs. Cameron Yerian and Arthur Platz for help in coding, and Dr. George Fink and The University of Michigan Health Service for referring patients. Partial support and drugs for this study were supplied by the United States Food and Drug Administration, and part from USPHS Grant No. M-1871, Dr. James G. Miller, Principal Investigator.     

Behavioral and neurochemical effects of caffeine in normal and aggressive mice

Caffeine is known to exert psychostimulant effects both in man and in animals and it has been shown to modify the levels of brain neurotransmitters. In normal and isolated-aggressive mice, caffeine induces modifications of both the level and the turnover of brain serotonin. Such modifications are however more evident in normal than in aggressive mice. Moreover, caffeine shows an antiaggressive effect and increases the exploratory activity of aggressive mice, without altering the performance of normal animals. It seems possible to conclude that the biochemical and behavioral effects of this drug differ in extent and intensity depending upon the emotional baseline on which it acts.