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Biomedical subjects

M H Teicher

Publications and source records attributed to M H Teicher.

At least 91 records · Page 5Linked to original sources
PubMed1987

Amphetamine reverses learning deficits in 6-hydroxydopamine-treated rat pups.

At 5 days of age, rat pups were treated with a combination of desmethylimipramine (DMI) and 6-hydroxydopamine (6-OHDA) to selectively deplete brain dopamine (DA) or with vehicle (saline) control solutions. Two days later, all animals received conditioning to a novel odor by pairing the odor with intraoral milk. When the odor was anise, treated pups spent less time near the conditioned stimulus than did controls, but there were no 6-OHDA effects when the stimulus was a lemon odor (Experiment I). The difference in performance between the treated and control animals was not attributable to alterations in activating effects of the reinforcer (Experiment I), changes in olfactory sensitivity or olfactory preference (Experiment II), or sensitization to the stimulus (Experiment III). In Experiment IV, animals received d-amphetamine sulfate (0.5 mg/kg) prior to conditioning, testing, or both conditioning and testing. Amphetamine treatment before conditioning produced an improvement in performance in animals previously treated with 6-OHDA/DMI, but it impaired performance in controls, regardless of the time of injection. The results indicate a role of brain DA in learning in young rats.

Animals↗
PubMed1986

Behavioral effects of apomorphine isomers in the rat: selective locomotor-inhibitory effects of S(+)N-n-propylnorapomorphine.

The optical isomers of apomorphine (APO) and N-n-propylnorapomorphine (NPA) were evaluated behaviorally in the rat. Both R(-) isomers induced motor-excitatory effects and strong stereotyped sniffing, licking, and gnawing, as has been reported previously. The S(+) isomers selectively inhibited locomotor activity and did not induce stereotypy or catalepsy. These actions of the S(+) aporphines were selective against locomotor activity stimulated by low doses of R(-) isomers. (+)NPA (ID50 = 0.2 mg/kg) was 20 times more potent than (+)APO (ID50 = 4 mg/kg) in antagonizing the locomotor arousal-inducing effects of (-)APO (at ED50 = 0.3 mg/kg). (+)NPA also inhibited spontaneous locomotor activity much more potently (ID50 = 3.0 mg/kg) than did (+)APO (ID50 greater than 50 mg/kg). Neither S(+) aporphine had a significant effect against stereotypy induced by the R(-) isomers, even at high doses (up to 30 mg/kg). Inhibition of the effects of (-)APO by (+)NPA appeared not to be due to altered uptake of (-)APO into brain. These results suggest that S(+)NPA or its congeners and analogs may have selective antidopaminergic actions in limbic rather than striatal areas of mammalian brain.

Animals↗
PubMed1986

Altered locomotor activity in neuropsychiatric patients.

Movement was monitored continuously for 24-48 hours in representative neuropsychiatric patients, using a wrist-worn portable piezoelectric activity monitor with solid-state memory. Striking differences were observed in both circadian and more rapid (ultradian) rhythms between these patients and normal controls of a similar age. We found a loss of circadian rhythm following stroke, and a marked 4-hour activity rhythm in patients with dementia and brain tumor. These results may provide insights into the neural substrate of activity rhythms and may lead to better care of neuropsychiatric patients.

Affective Disorders, Psychotic↗
PubMed1986

Selective depletion of cerebral norepinephrine with 6-hydroxydopamine and GBR-12909 in neonatal rat.

Specific and extensive neonatal depletions of norepinephrine were produced in 3-day-old rats by combined administration of GBR-12909 (40 mg/kg, i.p.), a specific inhibitor of dopamine uptake, and the neurotoxin 6-hydroxydopamine (125 micrograms, i.c.). Norepinephrine concentrations in prefrontal cortex and hippocampus were reduced by more than 95%, and hypothalamic concentrations were reduced by 57%. Concentrations of dopamine, serotonin, and their respective metabolites were not affected in these regions or in the striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Prolonged antidopaminergic actions of single doses of butyrophenones in the rat.

Rats were treated once with doses of haloperidol or of droperidol below and above the acute ID50 vs the dopamine agonist apomorphine; they were later challenged with an acute dose of apomorphine (0.3 mg/kg, SC) and rated for stereotyped behavioral responses. The two neuroleptics were similar in acute anti-apomorphine potency (ID50 = 0.12 and 0.18 mg/kg for haloperidol and droperidol, respectively). The antidopaminergic effects of droperidol persisted for nearly 1 week and those of haloperidol lasted for 20-40 days, depending on the dose given. The computed half-time of disappearance of their antidopaminergic effects was 7.6 +/- 1.0 days and 0.59 +/- 0.17 days for haloperidol and droperidol, respectively, following a dose of 0.3 mg/kg, and these indices of duration of action did not vary significantly at doses between 0.1 and 1.0 mg/kg. Haloperidol reduced the acute entry of 3H-apomorphine into brain by 21.5% 1 week later. Treatment with apomorphine alone just prior to haloperidol (both at 0.3 mg/kg) prevented the prolonged antidopaminergic effects of the neuroleptic evaluated 1 week later. These results indicate that some neuroleptics may have very prolonged activity or retention in tissue at sites of action, even after moderate, single doses. Caution is recommended in the interpretation of studies which assume "neuroleptic-free" conditions of subjects previously exposed to a neuroleptic agent.

Animals↗
PubMed1985

S(+)Apomorphines. Selective inhibition of excitatory effects of dopamine injected into the limbic system of the rat.

Dopamine (DA) injected unilaterally into the corpus striatum of the brain of the rat after pretreatment with a monoamine oxidase inhibitor, induced contralateral deviation of the head (ED50 = 23 micrograms). Dopamine, administered similarly into the nucleus accumbens septi, induced strong locomotor arousal effects (ED50 = 32 micrograms), as reported by others. Systemic administration of the S(+) isomers of apomorphine (APO) and its N-n-propyl analog (NPA) had no significant action on the effects on posture of DA given intrastriatally, even in large doses. In striking contrast, both agents selectively inhibited the locomotor-arousal effects of DA injected into the accumbens, but (+)NPA was seven times more potent (ED50 = 0.5 mg/kg vs 16 micrograms of DA) and its effects lasted for about 70 min. The dose-effect curves for (+)NPA against two doses of DA demonstrated parallel, lateral displacement, indicating a competitive interaction. These results support the impression that enantiomers and analogs of apomorphine, and especially S(+)N-propylnorapomorphine, have potent antidopaminergic actions that may be selective for limbic areas of the forebrain.

Animals↗
PubMed1984

Dopaminergic but not noradrenergic mediation of hyperactivity and performance deficits in the developing rat pup.

The relative contribution of dopamine (DA) and norepinephrine (NE) in behavioral arousal was examined in developing rat pups using intracisternal 6-hydroxydopamine (6-OHDA) either alone or following pretreatment with desmethylimipramine (DMI). Such treatments were designed to examine the effects of preferential reduction of DA (DA depletion), NE (NE depletion), or both catecholamines (CA depletion) in the development of motor activity and escape performance. General motor activity increased with age and, over all ages, DA-depleted pups tended to exhibit greater activity. This was most apparent at 15 days of age, where DA-depleted pups were significantly more active than controls, NE-depleted, or CA-depleted pups. DA-depleted pups failed to exhibit the steep decline in activity over time (habituation of activity) demonstrated by the control and NE-depleted pups, while pups depleted of both CA fell into an intermediate position in habituation. Escape latency in a T-maze at 20 days and shuttle box at 26 days of age indicated comparable performance to controls for NE-depleted pups, while those animals in DA-depleted and CA-depleted groups appeared unable to perform the task. Brain CA concentrations (determined by a radioenzymatic assay) indicated preferential reduction of DA in the DA-depleted group to concentrations 25% of controls, reduction of NE to 62% of controls in the NE-depleted group, and reductions of DA to 42% and NE to 60% in the CA-depleted group. These results suggest that preferential reduction of brain DA in the developing rat pup increases motor activity and impairs habituation of activity during the stage of behavioral arousal in week 3 of postnatal life.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1984

Binding of [3H]apomorphine to an aporphine binding site as well as to dopamine sites in tissue from bovine caudate nucleus.

Binding of the tritiated dopamine (DA) agonists, apomorphine (APO) and a dihydroxyaminotetralin (ADTN) to a membrane preparation from the caudate nucleus of calf brain was compared. Binding of [3H]dihydroxyaminotetralin at small (nM) concentrations followed simple, monophasic inhibition (over 80% at less than 500 nM) by concentrations of apomorphine between 50 pM and 1 mM. Inhibition of the binding of [3H]apomorphine by dihydroxyaminotetralin was more complex, and included in component with a low (microM) affinity for dihydroxyaminotetralin accounting for approx. 20% of total binding. The kinetics of binding of the ligands to high-affinity sites were virtually identical (apparent Kd = 0.81 nM; Bmax = 211 fmol/mg protein) and could not be distinguished by curve-fitting techniques adapted to analysis by microcomputer. In contrast, the binding of [3H]apomorphine with a "blank" defined by excess (10 microM) dihydroxyaminotetralin could be resolved into the same high-affinity component and a lower-affinity site (Kd = 124 nM; Bmax = 5740 fmol/mg). The pharmacology of the lower-affinity binding of [3H]apomorphine was evaluated by coincubating with 0.5 microM dihydroxyaminotetralin to "mask" high-affinity sites, and was compared to high-affinity binding of [3H]apomorphine and [3H]dihydroxyaminotetralin. The high-affinity binding was stereoselective for DA receptor agonists and antagonists. The pharmacology of the lower-affinity site resembled no known DA receptor type and showed highest affinities for aporphines but was not stereoselective and reacted weakly and nonspecifically with dihydroxyaminotetralin, DA, other catecholamines and neuroleptics. Thus, [3H]apomorphine, under certain conditions, may detect an aporphine binding site of uncertain pharmacological significance, as well as high-affinity DA agonist (D-3) sites.

Animals↗
PubMed1984

Effect of age on behavioral responses and tissue levels of apomorphine in the rat.

Rats of several ages between 2 and 24 months were tested for stereotyped behavioral responses to R(-)apomorphine-HCl (APO), a potent and selective dopamine agonist. Between 2 and 24 months, the ED50 for apomorphine decreased 2.5-fold (0.14-0.06 mg/kg, i.p.), as assessed by a microcomputer-assisted technique. Not only were older rats more sensitive to apomorphine, but the duration of the behavioral effects increased with age and showed a greater change at doses which were greater than the ED50. When levels of apomorphine in brain were assayed by liquid chromatography and electrochemical detection, there was a progressive increase in peak levels of the agent in the tissue as well as a delay in its elimination from brain, with increasing age. Moreover, there was a highly significant correlation between increased behavioral effect and the level of apomorphine in brain with increasing age (r greater than 0.8). These results indicate that increased levels in brain or decreased elimination of apomorphine may be an important factor contributing to a marked increase in behavioral sensitivity to apomorphine with age in the rat.

Aging↗
PubMed1984

Olfactory and vomeronasal system mediation of maternal recognition in the developing rat.

Olfactory-mediated arousal and maternal recognition were evaluated in neonatal rat pups. Non-nutritionally deprived pups which underwent bilateral olfactory bulbectomies on day 5, failed to distinguish between the ventral and dorsal surfaces of a nursing rat and a heating pad. They showed virtually no arousal response to any of these surfaces. In contrast, pups with unilateral bulbectomies, and sham controls, graded their arousal response, and were maximally aroused by the mother's ventral surface. Following 24 h of maternal deprivation, bilaterally bulbectomized pups displayed a modest arousal response, directed primarily towards the dorsal surface. Pups with complete vomeronasal nerve sections displayed maximal arousal responses toward the dorsal surface. However, they were far more aroused than the bilaterally bulbectomized pups. Rat pups with incomplete vomeronasal lesions graded their response like controls, with maximal responsiveness directed toward the ventral surface. Shaving the dorsal surface markedly diminished the arousal response of bilaterally bulbectomized pups, but had only modest effects on sham and unilaterally bulbectomized controls. Thus, lesions that destroyed both the main and accessory's olfactory bulb systems severely impaired the pups' ability to effectively recognize a lactating female and markedly diminished maternally-induced arousal. Selective damage to the vomeronasal-accessory olfactory system appeared to disrupt discriminative capacity, but had little effect on the magnitude of the arousal response.

Animals↗
PubMed1983

Differential effects of selective dopamine, norepinephrine or catecholamine depletion on activity and learning in the developing rat.

The present experiment investigated the behavioral changes which occurred following neonatal depletion of central catecholamine systems in the rat. The behavioral effects which resulted from selective dopamine (DA) depletion were compared with those resulting from selective norepinephrine (NE) depletion as well as depletion of both catecholamines (CA). Neonatal 6-hydroxydopamine (6-OHDA) was administered intracisternally at 5 days of age following pretreatment with desmethylimipramine in order to selectively deplete DA. NE levels were reduced by intraperitoneal injections of 6-OHDA at 1 and 2 days of age. Depletion of both catecholamines was effected by combining the procedures used for selective depletion of both DA and NE. Activity was time sampled during an hour at 3 preweanling ages. Avoidance and escape learning were measured in a T maze when pups were 20 days of age and in a Shuttlebox apparatus on day 28. Results revealed that DA and CA depleted animals were hyperactive in comparison to controls and displayed severe learning impairments in both T maze and Shuttlebox performance. In contrast, NE depleted animals showed activity levels which were similar to controls but were significantly impaired on both learning paradigms. These results suggest that selective lesions of DA and NE in infancy lead to a constellation of behaviors which are distinctly unique. The implications of these findings is discussed in terms of clinical research into the Attentional Deficit Disorder of childhood.

Animals↗
PubMed1983

The effect of intranasal zinc sulfate treatment on odor-mediated behavior and on odor-induced metabolic activity in the olfactory bulbs of neonatal rats.

This study describes the effect of lesions of the peripheral olfactory receptor sheet on odor-mediated behavior and on odor-induced metabolic activity in the neonatal olfactory bulb. Nine-day-old rats were treated by intranasal irrigation with a solution of 1% ZnSO4 or 5% ZnSO4 or saline. At 1 and 5 days following treatment they were tested for maternally-directed behaviors which are mediated in large part by olfactory cues. At 1 day following treatment the pups treated with ZnSO4 solutions had significant deficits in their odor-directed behavior. By 5 days however, most pups treated with 1% ZnSO4 had recovered to control levels, while the pups treated with 5% ZnSO4 continued to exhibit profound behavioral deficits. Following the behavioral testing, the pups were tested using the 2-deoxyglucose method for amyl acetate odor-induced metabolic activity in their olfactory bulbs. Control pups had large regions of high focal activity in their anterolateral and caudomedial olfactory bulbs. The 1% ZnSO4 pups had smaller foci which were confined primarily to the medial olfactory bulb. The 5% ZnSO4 pups had very little focal uptake in their olfactory bulbs. There was a clear correlation between intact olfactory nerve and glomerular layers and sites of increased functional activity. The results of this study demonstrate that there is a relationship between the degree of behavioral deficit and the extent of odor-induced functional activity in the olfactory bulb.

Animals↗
PubMed1982

Effects of apomorphine on appetitive conditioning in 6-hydroxydopamine treated rat pups.

Rat pups were treated on postnatal day 5 either with the combination of desmethylimipramine (DMI) and 6-hydroxydopamine (6-OHDA) to produce depletion of brain dopamine, or with control injections of saline. Two days later they were presented a novel anise odor paired with intraoral baby formula, and on the next day were tested for preference for the novel odor. Before conditioning and testing, animals were treated with either apomorphine (0.05 mg/kg) or isotonic saline. Performance of the conditioned appetitive response was impaired in dopamine depleted animals. In DMI/6-OHDA treated pups, apomorphine administration prior to conditioning produced an improvement in performance, but drug treatment prior to testing had no effect. In normal pups, apomorphine administration either before conditioning or testing produced impaired performance at testing.

Animals↗
PubMed1981

Effects of bromocriptine in developing rat pups after 6-hydroxydopamine.

The effects of low (0.5 mg/kg) and high (2.0 mg/kg) doses of bromocriptine (BCR) on activity and escape performance were examined during the first month of postnatal life in normal developing rat pups and littermates treated at 5 days of age with a combination of desmethylimipramine and 6-hydroxydopamine (6-OHDA). Such a procedure resulted in significant reductions in brain dopamine to concentrations 10-20% of vehicle controls while norepinephrine was unaffected. BCR increased general motor activity in vehicle pups at 13 and 19 days but had little effect on more mature animals. Pups who had not received BCR exhibited a decline in activity over the hour long observation period (habituation of activity) but this decline was abolished by both low (0.5 mg/kg) and high (2.0 mg/kg) doses of the agent. Stereotyped activity, particularly at 19 days was increased by BCR in 6-OHDA pups but not in vehicle animals, an effect suggesting denervation supersensitivity. Head dips in a hole box at 30 days of age were not influenced by BCR in vehicle pups but significantly reduced by BCR in 6-OHDA pups, suggesting that BCR might be acting to stimulate inhibitory dopaminergic mechanisms. Escape learning in a T-maze at 20 days and shuttle box at 28 days was disrupted by high doses of BCR in vehicle pups and both doses of BCR in 6-OHDA animals. The similarity with the behaviors observed in the clinical syndrome of attention deficit disorder with hyperactivity prompted a number of investigative groups including our own to suggest that the 6-OHDA model might serve as a useful and convenient paradigm to evaluate pharmacological agents that offer potential in the treatment of this most common disorder. From this perspective we would predict that BCR would have little clinical utility since it both failed to attenuate 6-OHDA induced hyperactivity and tended to disrupt performance in an avoidance learning task.

Animals↗
PubMed1981

Differential effects of maternal and sibling presence of hyperactivity of 6-hydroxydopamine-treated developing rats.

The influence of test environment on the expression of hyperactivity produced by neonatal 6-hydroxydopamine (6-OHDA) administration was assessed in rat pups at 15, 19, and 22 days of age. The 6-OHDA pups and an equal number of controls were tested in one of five different social circumstances: (a) isolation, (b) mixed groupings of two treated and two control pups, (c) mixed groupings with their anesthetized mothers, (d) mixed groupings with an anesthetized sibling, and (e) homogeneous groupings of all treated and all control siblings. Social factors had striking differential effects on activity, particularly at 19 days of age. The 6-OHDA pups were hyperactive relative to controls in isolation. Both treated and control pups were equally active in the mixed grouping, and they were hyperactive relative to control isolation levels. The addition of an anesthetized mother sharply attenuated the activity of both types of pups, whereas the addition of an anesthetized sibling attenuated the activity of the controls only. Pups in both types of homogeneous groupings were less active than pups in mixed groupings, and under homogeneous test conditions the treated pups were even less active than the controls. Thus, social factors strongly influence the behavior of rat pups with whole brain dopamine depletion produced by 6-OHDA and, within the confines of this animal model of hyperactivity, exert greater attenuating effects on their activity than previously observed with stimulant medication.

Animals↗