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Glutamate and GABA modulate dopamine in the pedunculopontine tegmental nucleus.

The pedunculopontine tegmental nucleus (PPTg) has an important anatomical position connecting basal ganglia and limbic systems with motor execution structures in the pons and spinal cord. It receives glutamatergic and GABAergic input and has additional reciprocal connections with mesencephalic dopaminergic neurons, suggesting that the PPTg plays a key role in frontostriatal information processing. In vivo microdialysis in freely moving rats, in combination with behavioral analysis, was used in this study to investigate whether the dopaminergic input can be modulated at the level of the PPTg via N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) or GABA(B) receptors. Stimulation of the GABA(B) receptor decreased dopamine release in the PPTg while that of the AMPA and NMDA receptors increased it. A time-related comparison of the effects of NMDA (0.75 and 1 mM) and AMPA (50 and 25 microM) revealed a more long-lasting effect after AMPA stimulation than after NMDA. However, only the infusion of the GABA(B) receptor agonist baclofen (100 and 200 microM) stimulated stereotyped behavior (e.g. sniffing, digging or head movements) and contralateral circling. This study clearly demonstrates that GABAergic as well as glutamatergic terminals in the PPTg are critically involved in the modulation of the dopamine system. Moreover, a decrease in PPTg dopamine via GABA(B) receptor stimulation seems to be behaviorally relevant.

Amphetamine↗

Phencyclidine (PCP) acts at sigma sites to induce c-fos gene expression.

Phencyclidine (PCP) is a compound that results in abnormal human behavior and has been proposed as a chemical model for schizophrenia. It was hypothesized that PCP induction of the immediate-early gene, c-fos, should be seen in areas associated with emotional behavior, such as the cortex and limbic system. It was also proposed that PCP may induce c-fos via the sigma receptor. PCP and two sigma ligands, 1,3-di(2-tolyl)guanidine (DTG) and pentazocine, were shown to induce c-fos in similar patterns. The three compounds abundantly induced c-fos in the cingulate, parietal, and piriform cortices and the midline structures of the thalamus and hypothalamus. Neither PCP nor the sigma ligands induced c-fos in the hippocampus. This suggests that PCP binding at NMDA receptors does not result in significant c-fos induction. Rimcazole, a putative sigma2 receptor antagonist, and other sigma ligands have been shown to ameliorate PCP stereotypic behavior. Rimcazole inhibited PCP c-fos induction in the cingulate and parietal cortices and DTG c-fos induction in the cingulate cortex. DTG shows both sigma1 and sigma2 binding affinity. Rimcazole failed to inhibit pentazocine c-fos induction. Pentazocine binds only to sigma1 receptors. This suggests that PCP may produce a significant fraction of its c-fos induction via sigma2 receptors.

Animals↗

Estrogen-induced suppression of intake is not mediated by taste aversion in female rats.

Estrogen treatment can suppress the intake of a previously presented gustatory conditioned stimulus (CS). This finding has been interpreted as an estrogen-induced conditioned taste aversion. However, a distinction must be made between taste aversion and taste avoidance. In particular, tastes are only considered aversive if they elicit a stereotypic behavioral response, otherwise the reduction in intake is classified as an avoidance. Although aversive orofacial responses have been reported in male rats after taste-estrogen pairings, they have not been examined in ovariectomized female rats. The goal of the present investigation, then, was to use similar procedures to determine whether conditioned aversion also mediates the estrogen-induced reduction of intake in female rats. Animals were introduced to a novel 0.1% saccharin solution and immediately thereafter were given a subcutaneous injection of vehicle or estradiol benzoate (10 microg). Responses were assessed using a two-bottle preference test, a one-bottle acceptance test, and a taste reactivity (TR) test. The results confirmed previous reports of a reduced preference for saccharin after saccharin-estradiol pairing using the two-bottle test. The reduction in intake during the one-bottle test, however, was not accompanied by stereotypic aversive responses, such as gaping. Surprisingly, a similar reduction in intake also occurred when using a backward conditioning procedure in which estrogen was injected before, rather than after, CS access. Thus, the present results show that the suppressive effects of estrogen reflect an avoidance, rather than aversion and, moreover, that the reduced intake may be due to an unconditioned, rather than a conditioned, response.

Animals↗

Behavioral alterations induced in rats by a pre- and postnatal exposure to 2,4-dichlorophenoxyacetic acid.

The purpose of this study was to determine whether the behavioral development pattern was altered by a pre- and postnatal exposure to 2,4-Dichlorophenoxyacetic acid (2,4-D). Pregnant rats were daily orally exposed to 70 mg/kg/day of 2,4-D from gestation day (GD) 16 to postnatal day (PND) 23. After weaning, the pups were assigned to one of the two subgroups: T1 (fed with untreated diet until PND 90) and T2 (maintained with 2,4-D diet until PND 90). Effects on offsprings were evaluated with a neurotoxicological test battery. Neuromotor reflexes, spontaneous motor activity, serotonin syndrome, circling, and catalepsy were analyzed during various postnatal ages. 2,4-D neonatal exposure induced delay of the ontogeny of righting reflex and negative geotaxis accompanied by motor abnormalities, stereotypic behaviors (excessive grooming and vertical head movements), and hyperactivity in the open field. Adult rats of both sexes (T2 group) showed a diminution of ambulation and rearing, while excessive grooming responses were only observed in T2 males. Besides, these animals manifested serotonin syndrome behaviors, catalepsy, and right-turning preference. Some behaviors were reversible, but others were permanent, and some were only expressed after pharmacological challenges.

2,4-Dichlorophenoxyacetic Acid↗

Effect of methamphetamine and dopamine receptor antagonists on cholecystokininlike immunoreactivity in the rat medial prefrontal cortex.

A single intraperitoneal administration of methamphetamine (MAP) reduces cholecystokininlike immunoreactivity (CCK-LI) in medial prefrontal cortex (mPFC) of the rat brain. This report examines the effects of various dopamine (DA) receptor antagonists [haloperidol (HAL), sulpiride (SUL), YM09151-2 (YM), and SCH23390 (SCH)] on MAP-induced abnormal behaviors and the changes of CCK-LI in the rat mPFC. A single subcutaneous administration of HAL (0.25 mg/kg), YM (0.1 mg/kg), or SUL (250 mg/kg) significantly reduced the basal CCK-LI in mPFC by 20-40%; a selective D1 antagonist, SCH (up to 1.0 mg/kg), had no effect on basal CCK-LI. However, the reduction of CCK-LI induced by MAP (20-40%) was abolished by the pretreatment with HAL (0.025 and 0.25 mg/kg), YM (0.01 and 0.1 mg/kg), or SCH (1.0 mg/kg), without being affected by SUL (up to 250 mg/kg). This effect of DA antagonists on MAP-induced change in CCK-LI was associated with an inhibition of MAP-induced stereotyped behaviors. These data suggest that the CCK-containing neurons in rat mPFC are functionally related to the mesocortical DA system and may participate in a development of abnormal behaviors induced by MAP.

Animals↗

Factor analysis and norms for parent ratings on the Aberrant Behavior Checklist-Community for young people in special education.

The parents of 601 children and adolescents, responding to a mail survey, rated their children on the Aberrant Behavior Checklist-Community (ABC-C). Factor analysis of ABC-C ratings revealed a factor structure that was similar to the original ABC but without the fifth factor (Inappropriate Speech). Coefficients of congruence were moderate to large for the four-factor model, and alpha coefficients were moderate to high when the original item assignment was imposed. Confirmatory factor analysis indicated a modest level of fit with the traditional method of scoring the ABC and acceptable fit when the items were coded for occurrence (0 or 1). Analysis of subject variables revealed main effects for gender on one subscale (Hyperactivity), main effects for age on two subscales (Irritability; Hyperactivity), and one main effect for classroom assignment on the Stereotypic Behavior subscale. Normative data for parent ratings were presented by age and gender combined, gender alone, and age alone. With some qualifications, the ABC-C appears to be valid for assessing children in special educational settings, although further research is needed on the ABC's factor structure in this population.

Adolescent↗

Variations in dietary iron alter behavior in developing rats.

Iron deficiency in children is associated with retardation in growth and cognitive development, and the effects on cognition may be irreversible, even with treatment. Excessive iron has also been associated with neurological disease, especially in reference to the increased iron content in the brains of Alzheimer's disease and Parkinson's disease patients. This study evaluated the effects of dietary iron deficiency and excess iron on physical activity in rats. The animal model used is developmentally sensitive and permits control of the timing as well as the duration of the nutritional insult. Hence, to study the effects of early, late and long-term iron deficiency or excess iron (supplementation), rats were either made iron deficient or supplemented on postnatal day (PND) 10-21, PND 21-35 and PND 10-35. Some iron-deficient rats were iron repleted between PND 21-35. Different measures of motor activity were taken at PND 14, 17, 20, 27 and 34. Iron-deficient and iron-supplemented rats showed decreased activity and stereotypic behavior; this was apparent for any onset and duration of the nutritional insult. Recovery from iron deficiency did not normalize these functional variables, showing that the deleterious effects of early iron deficiency persist despite subsequent adequate treatment. This study demonstrates that iron deficiency in early life leads to irreversible behavioral changes. The biological bases for these behavioral alterations are not readily apparent, because iron therapy rapidly reverses the iron losses in all brain regions.

Age Factors↗

Neurotensin gene expression and behavioral responses following administration of psychostimulants and antipsychotic drugs in dopamine D(3) receptor deficient mice.

Exposure to psychostimulants and antipsychotics increases neurotensin (NT) gene expression in the striatum and nucleus accumbens. To investigate the contribution of D(3) receptors to these effects we used mice with targeted disruption of the D(3) receptor gene. Basal NT mRNA expression was similar in D(3) receptor mutant mice and wild-type animals. Acute administration of haloperidol increased NT gene expression in the striatum in D(3)+/+, D(3)+/- and D(3)-/- mice. Similarly, acute cocaine and amphetamine induced NT mRNA expression in the nucleus accumbens shell and olfactory tubercle to a comparable extent in D(3) mutants and wild-type mice. Daily injection of cocaine for seven days increased NT mRNA in a restricted population of neurons in the dorsomedial caudal striatum of D(3)+/+ mice, but not in D(3)-/- and D(3)+/- animals. No differences were observed between D(3) receptor mutant mice and wild-type littermates in the locomotor activity and stereotyped behaviors induced by repeated cocaine administration. These findings demonstrate that dopamine D(3) receptors are not necessary for the acute NT mRNA response to drugs of abuse and antipsychotics but appear to play a role in the regulation of NT gene induction in striatal neurons after repeated cocaine. In addition, our results indicate that the acute locomotor response to cocaine and development of psychostimulant-induced behavioral sensitization do not require functional D(3) receptors.

Amphetamine↗

Cardiovascular effects of the N-methyl-D-aspartate receptor antagonist MK-801 in conscious rats.

Evidence from microinjection studies in anesthetized rats suggests that central excitatory amino acid pathways using N-methyl-D-aspartate receptors are involved in the regulation of the cardiovascular system. To test the hypothesis that these pathways are tonically involved in the maintenance of or the baroreceptor reflex regulation of cardiovascular function, we have examined the effects of intravenous injection of the centrally acting, noncompetitive N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), on the mean arterial pressure, heart rate, renal sympathetic nerve activity, and behavior of conscious, freely moving sham-operated and sinoaortic baroreceptor-denervated rats. Administration of MK-801 produced, within 5 minutes, dose-dependent elevations in mean arterial pressure, heart rate, and renal sympathetic nerve activity that were sustained for 0.5 to 2.5 hours. For an equivalent dose, MK-801 produced approximately twice the peak changes in mean arterial pressure and heart rate in the sinoaortic baroreceptor-denervated rats than in the sham-operated rats. Pretreatment results were as follows: 1) The ganglion blocker chlorisondamine markedly attenuated the hypertension and tachycardia in the sham-operated and sinoaortic baroreceptor-denervated rats, 2) pretreatment with the alpha 1-adrenergic receptor antagonist prazosin virtually abolished the hypertension, and 3) the beta 1-adrenergic receptor antagonist atenolol markedly reduced the tachycardia. MK-801 also produced stereotypic behaviors and ataxia in the sham-operated and sinoaortic baroreceptor-denervated rats; however, qualitatively and quantitatively similar changes in behavior were induced in the latter by doses approximately five time lower than required in sham operated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

[A simply designed apparatus and its use for measuring vertical and horizontal motor activities in methamphetamine-treated mice].

A simple apparatus using the infrared ray, which can divide spontaneous motor activity (SMA) of mice into two behavioral components, a vertical movement (VM) and a horizontal movement (HM) was designed. VM and HM were evaluated by counting the number of times that infrared rays were blocked by the mouse in the activity cage [300(H) X 260(D) X 130(W) mm] with 9 infrared photo-couplers for measuring VM and one infrared photo-coupler for measuring HM. When methamphetamine (MAM) was subcutaneously administered to mice pretreated with saline (0.1 ml/10 g, sc) for 3 days, VM and HM were as follows: 1) At 0.1 mg/kg of MAM, the same level of activity was observed as with saline. 2) At 1.0 mg/kg of MAM, increased activity was noted. 3) At 10 mg/kg of MAM, a marked increase was noted, showing more enhancement of HM than VM, which had developed into a stereotyped behavior. In summary, this new apparatus was found capable of dividing the SMA of mice into the two behavioral patterns of VM and HM, and providing their measurements.

Animals↗

Effects of gestational exposure to monoamine oxidase inhibitors in rats: preliminary behavioral and neurochemical studies.

Monoamine neurotransmitters are important in the development of the immature mammalian brain, prior to assuming their role as neurotransmitters. The endogenous levels of these transmitters are highly regulated by the enzyme monoamine oxidase (MAO). Thus, any change in this enzyme should have a profound effect on brain development. In order to test this hypothesis, we treated developing rat pups with the monoamine oxidase inhibitors (MAO-Is), clorgyline (MAO-A, 3 mg/kg), and deprenyl (MAO-B, 3 mg/kg) throughout gestation (MAO-I-birth), or throughout gestation and to sacrifice (MAO-I-sac). The animals were analyzed for serotonin and dopamine terminal density, using 3H-paroxetine and 3H-GBR 12935, respectively. Whereas there were no changes in the development of the dopamine system, the serotonin system was severely affected, particularly in the cortex that showed a significant reduction of innervation at 30 days postnatal. The animals reached all normal development milestones on schedule, and had no changes in measures of anxiety (% light/dark); however, the animals showed increased open field activity and deficits in a passive avoidance paradigm, which may be a measure of impulsivity. The MAO-I-sac animals were severely impaired, showing stereotypic behavior, seizures, and eventually visual impairments. Our results are discussed in terms of relevance to human disease states, such as atypical Norrie's disease, impulsivity, and hyperactivity. As well, our results should be used to caution against the use of MAO-Is in women of child-bearing age.

Animals↗

Topographical variations in behavior during autoshaping, automaintenance, and omission training.

Three pigeons were exposed to an autoshaping and automaintenance procedure while a computer-controlled tracking system continuously recorded the position of the bird's head as it moved freely in the experimental chamber. Although only 2 birds pecked the key during the conditional stimulus (red keylight), all 3 birds exhibited stable patterns of approaching the conditional stimulus and withdrawing from the intertrial stimulus (white keylight). Subsequent exposure to an omission procedure, in which pecks on the red key cancelled the presentation of food upon the termination of the red keylight, greatly reduced key pecking, but approaching and pecking in the vicinity of the conditional stimulus were maintained at high levels. When the omission contingency was removed key pecking increased. During all phases the birds withdrew from the area of the white key and engaged in repetitive back-and-forth or circuiting movements during this intertrial stimulus. The data document (a) the strong control the conditional stimulus in autoshaping and automaintenance exerts over approach to the key and pecking motions whether or not the conditional stimulus elicits key pecking at a high level; and (b) withdrawal from the vicinity of the key and the occurrence of stereotypic behavior during the intertrial interval.

Journal Article↗

Enhanced morphine- and cocaine-induced behavioral sensitization in alcohol-preferring AA rats.

Locomotor stimulation and behavioral sensitization induced by acute and repeated treatment with alcohol, cocaine or morphine were studied in the alcohol-preferring AA (Alko, Alcohol), alcohol-avoiding ANA (Alko, Non-Alcohol) rats and non-selected Wistar rats. Daily treatment with alcohol (ethanol, 0.4 or 1.0 g/kg, IP) for 6 days had no effect on locomotor activity either in the AA or ANA rats. Acute cocaine (5, 10 or 20 mg/kg, IP) produced a locomotor stimulation in the animals of all lines studied, and there was no difference in this effect between the AA and ANA rats. During a 4-day repeated cocaine treatment, the AA rats became sensitized with the 10 mg/kg dose, while the ANA rats did not show any sensitization with this dose. With the 20 mg/kg cocaine dose, in addition to locomotor stimulation, the rats of all lines studied showed stereotyped behavior, which response was enhanced during repeated treatment. Morphine-induced locomotor stimulation was larger in the AA rats than in the ANA or Wistar rats both with 1.0 and 3.0 mg/kg doses and only the AA rats were sensitized during 4-day treatment with the 1 mg/kg dose. With the 3.0 mg/kg morphine dose, only the AA rats showed a weak sensitization evident only during the initial 30 min after morphine injection. As the drug-induced behavioral sensitization is an important factor in the development of drug addiction, it is possible that mechanisms underlying the enhanced susceptibility of the AA rats to morphine- and cocaine-induced sensitization contribute to the high intake of alcohol and other abused drugs by these animals.

Alcohol Drinking↗

Effects on stereotypy and other challenging behavior of matching rates of instruction to free-operant rates of responding.

Research has shown that when individuals are in situations that do not occasion one form of motoric responding, they will engage in another so that the overall level of motoric responding is homeostatic. The purpose of this study was to test whether students would substitute task-related behaviors for stereotypic or other challenging behaviors when the opportunity for active responding did or did not match the level of motoric responding in a free-operant baseline. Four students with mental retardation participated. Results showed that they did substitute behaviors, with stereotypic and other challenging behaviors occurring 1.5-14 times as much in the Non-matched condition for the four students. Further analysis showed considerably more of these behaviors in passive than in active tasks (by a factor up to 21 times as much). Results were discussed in terms of homeostasis, functional assessment, and opportunities to improve educational behaviors.

Attention↗

Environment modifies the expression of behavioral sensitization produced by methamphetamine: behavioral and neurochemical studies.

Effects of environmental modulation of methamphetamine (MA)-induced behavior on the establishment and mode of expression of behavioral sensitization were examined. Rats received daily injection of MA for 10 days (1mg/kg, s.c.). Half of them were immediately returned to the home cage (home cage group) and the other half were individually confined in a cylinder with a diameter of 13cm placed inside the home cage for 3h after each injection (small cage group). Gross observations revealed that rats which received MA in the small cage did not locomote but showed sniffing and rearing. The third group received saline in the home cage (saline control group). After a 7-8 day or 17-18 day withdrawal period, all groups were injected with MA (1mg/kg or 0.5mg/kg) in their home cages. The home cage group showed significant enhancement in horizontal motor activity compared to the saline control group, indicating the establishment of locomotor sensitization. In contrast, the small cage group showed no or slight enhancement in the motor activity. However, they showed significantly more stereotyped behavior compared to both the saline control and the home cage groups. Microdialysis studies revealed no enhancement in the ability of MA to increase dopamine release from the nucleus accumbens in either the home or the small cage group compared to the saline control group, when examined after either a 7-8 day or a 17-18 day withdrawal period. These results suggest that environmental modulation of actual movement under the stimulant effect modifies the pattern and character of the stimulant-induced behavior in sensitized animals. The neurochemical basis of the establishment of behavioral sensitization and the environmental modification of its expression remain unknown.

Journal Article↗

The role of the floor plate in axon guidance.

The data reviewed above have implicated the floor plate in directing axonal growth towards the midline, in directing the behavior of axons at the midline, and finally, in directing the longitudinal growth of axons alongside the midline. In the case of growth to the midline, there is clear evidence for the existence of two types of cues that collaborate to direct growth--short-range cues that can direct axons along the edge of the spinal cord and a long-range chemoattractant secreted by the floor plate cells whose main function may be to direct later-extending commissural axons that must migrate through the complex environment of the developing motor column. Determining the precise contribution of these cues will require identifying them and perturbing them in vivo. The cues that direct growth along the edge are unknown; their identification in the spinal cord would be of quite general significance, since the growth of axons parallel to (but not in contact with) the pial surface is a widespread feature of early axon growth at all axial levels of the neural tube. A strong candidate for the long-range chemoattractant is netrin-1, a homologue of the UNC-6 protein of C. elegans and a distant relative of laminin, which is expressed by floor plate cells and which can both promote and orient commissural axon outgrowth. Netrin-1 may also influence growth of other populations of neurons that exhibit stereotyped behaviors near the ventral midline. Much less is known about the exact role of the floor plate in directing axon growth at the midline, though it is clearly required for accurate guidance. In the absence of the floor plate, a range of errors has been found, the most prominent of which are aberrant midline crossings and errors in longitudinal growth near the ventral midline. The severity of these errors varies with species, which could result from either the variable importance of the floor plate in the different species or the fact that, so far, quite different manipulations of the ventral midline region have been performed in different species. The most specific perturbation of the ventral midline occurs in the zebrafish cyc-1 mutant, where the selective loss of the floor plate leads to stereotyped misrouting events. Perhaps surprisingly, virtually all axons that grow to the midline turn longitudinally (although sometimes in the wrong direction).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Ontogenesis of behavioral sensitization and conditioned place preference induced by psychostimulants in laboratory rodents.

The present review deals mainly with the ontogenesis of two important phenomena involved in vulnerability to several neuropsychiatric disorders, namely with drug-induced sensitization (both contextual and non-contextual) and with conditioned place preference. The term 'infancy' covers the first three postnatal weeks during development in rats and mice. Conversely, the term 'adolescence' may cover the whole postnatal period ranging from weaning (PND 21) to adulthood (at least PND 60) or specifically the period around the onset of puberty (animals aged 33-44 days). Recent studies in rats demonstrated that the establishment of a context-dependent sensitization appears during the first (for repeated drug administration) or during the second (for a single drug administration) postnatal week. However, the memory of drug-context association is transient in developing pups (lasting one or two days following the drug pretreatment). The long-term retention of drug-context associations matures progressively, and is complete by the third week of postnatal life. Finally, those mechanisms responsible for an adult-like profile of context-independent pharmacological sensitization appear later during ontogenesis, being mature by the fourth week of postnatal life. Another set of experiments extended this ontogenetic characterization by comparing adolescent and adult mice. When compared to the latter, the former subjects exhibit a greater amphetamine-induced locomotor sensitization, almost no sensitization of aversive stereotyped behaviors, and a less marked place conditioning. The strength of the drug-induced place conditioning was also directly compared with the unconditioned novelty-seeking drive. In conclusion, neonatal rats are able to show a relatively short-lasting retention of sensitized drug effects (short-term sensitization), whereas the ability to exhibit relatively long-lasting sensitized effects matures progressively during infancy (long-term sensitization). On the other hand, adolescent mice show a reduced sensitization of drug-induced psychotic symptoms, together with a more marked sensitization of arousing and euphorigenic properties of the drug and a reduced incentive memory of its hedonic effects. These age-related changes do imply very different degrees of vulnerability to drug addiction and several other neuropsychiatric disorders.

Age Factors↗