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Biomedical subjects

G Mittleman

Publications and source records attributed to G Mittleman.

At least 19 recordsLinked to original sources
PubMed1994

Polydipsia and dopamine: behavioral effects of dopamine D1 and D2 receptor agonists and antagonists.

Substantial evidence implicates dopaminergic neural systems in the occurrence of polydipsia in both animals and humans. Two experiments were conducted in order to specify the behavioral mechanisms whereby manipulation of dopaminergic neural transmission can affect scheduled-induced polydipsia (SIP). The role of dopamine D1 and D2 receptors was investigated by comparing the behavioral effects of dopamine D1 agonists (SKF 38393 and SKF 82958) and antagonists (SCH 23390 and SKF 83566) to those of a dopamine D2 agonist (quinpirole) and antagonist (haloperidol) by using an animal model of excessive water consumption, drinking evoked in the SIP paradigm. Additionally, the behavioral effects of these relatively specific compounds were compared to those of the indirect agonist d-amphetamine sulfate and the nondopaminergic drug, diazepam. All of the drugs produced dose-related decreases in SIP. With the exception of SKF 38393 and SCH 23390, the decreased drinking appeared to be a behaviorally nonspecific drug effect in that changes in activity consistently preceded or accompanied reductions in water consumption. Some of the drugs tested, including quinpirole, haloperidol and SKF 83566, also produced changes in behavior consistent with decreased hunger, which may have also contributed to the reductions in SIP. These results are generally suggestive that dopamine neural systems are involved mainly in the motor or performance aspects of established SIP and that disruptions in established SIP produced by dopamine agonists or antagonists may result from a change in the balance of activation of dopamine D1 and D2 receptors. These results may be relevant to understanding the factors influencing polydipsia in humans.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Enhancement of amphetamine-induced locomotor activity and dopamine release in nucleus accumbens following excitotoxic lesions of the hippocampus.

This study tested the hypothesis that the hippocampus modulates dopamine-dependent function of the nucleus accumbens using behavioural and neurochemical evidence. Rats with bilateral lesions of the hippocampus induced by colchicine and kainic acid exhibited equivalent levels of spontaneous locomotor activity but a potentiation of the hyperactivity produced, dose-dependently, by D-amphetamine measured in photo-cell activity cages. The same rats subsequently received unilateral implantations of a microdialysis probe aimed at the nucleus accumbens and showed elevated levels of extracellular dopamine in response to D-amphetamine but no significant difference in basal values in comparison with sham-operated controls. The results are discussed in terms of functional interactions between the hippocampus and nucleus accumbens involving the control of mesolimbic dopamine release.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Relationship between schedule-induced polydipsia and amphetamine intravenous self-administration. Individual differences and role of experience.

It has been suggested that drug abuse belongs to a larger class of addictive behaviors, including smoking, eating or gambling, which are mediated by common processes. Since laboratory animals can be induced to develop drug self-administration as well as indulge in compulsive eating or drinking, the present experiments were designed to find out if the same animals were susceptible to both behaviors. Only certain rats develop amphetamine intravenous self-administration (SA), and this susceptibility can be predicted from their enhanced locomotor response in a novel environment. Furthermore, excessive, non-regulatory drinking, referred to as schedule-induced polydipsia (SIP), in response to the periodic delivery of small amounts of food is only observed in certain rats. Since the propensity to SA has been shown to be influenced by experimental factors and testing for SIP was found to modify behavioral and biological parameters related to the propensity for drug-seeking, we also investigated whether experience of SIP influenced the subsequent development of SA. In Expt. 1, the rats that developed SA also acquired SIP, and had a higher locomotor response to novelty. The results of Expt. 2 showed that testing for SIP influenced the predisposition to develop amphetamine SA. When animals were tested for SIP first, the polydipsic rats subsequently failed to acquire SA, and had a reduced locomotor response to novelty. These changes seemed to be specific to the experience of SIP, as individual differences in the locomotor response to novelty were unchanged when animals were housed in standard laboratory conditions over a period of one month between the two tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Psychological↗
PubMed1993

The role of D1 and D2 receptors in the heightened locomotion induced by direct and indirect dopamine agonists in rats with hippocampal damage: an animal analogue of schizophrenia.

Rats with limbic system damage display increases in responsivity to sensory stimulation and changes in the sensitivity to amphetamine, suggesting that their condition may parallel that of human schizophrenia. This experiment examined locomotion and stereotyped behavior in mature, male rats that had received aspirative lesions of the hippocampus, control lesions of the overlying parietal cortex, or were unoperated controls. Locomotion, measured as photocell beam breaks, was recorded during 2- or 3-h test sessions. Behavioral stereotypy was simultaneously rated. Hippocampal lesioned rats exhibited a selective enhancement in locomotion following D-amphetamine (0.0-5.6 mg/kg) when compared to animals in the control groups. Similar results were observed following injections of apomorphine (0.0-0.25 mg/kg), a mixed D1 and D2 agonist. In order to determine if D1 or D2 receptors were involved in this increased locomotion, the D1 agonist SKF 38393 (0.0-15 mg/kg) and the D2 agonist quinpirole (0.0-0.5 mg/kg) were tested alone and in combination. Hippocampal-ablated rats showed significantly increased locomotion only in response to quinpirole, suggesting that these lesion-induced increases were largely mediated by D2 receptors. When both drugs were administered together, SKF 38393 further enhanced the locomotor stimulating effects of quinpirole in hippocampal lesioned rats, indicating a synergistic interaction between D1 and D2 receptors in the modulation of locomotion. These findings provide further evidence of hippocampal modulation of locomotion and suggest that dopaminergic mechanisms in the nucleus accumbens, probably involving changes in receptor sensitivity, are involved. The results are discussed in relation to the functional roles of the nucleus accumbens and in terms of their implications for mental diseases including schizophrenia.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Interactions between chronic haloperidol treatment and cocaine in rats: an animal model of intermittent cocaine use in neuroleptic treated populations.

This experiment investigated the possibility that rats maintained on chronic haloperidol treatment would show increased behavioral responsiveness to cocaine, similar to that observed in human stimulant abusers who are chronically treated with neuroleptics. Thus, the effects on locomotion and stereotyped behavior of intermittent injections of cocaine were investigated in female rats receiving chronic haloperidol treatment. Daily injections of haloperidol (0.2 mg/kg, IP) or vehicle were administered for 6, 12 or 18 days prior to the start of testing with cocaine and were then continued throughout cocaine testing. All rats received four doses of cocaine (0.0, 3.0, 7.5, or 15.0 mg/kg, IP) in random order with an intervening vehicle day between successive drug days. The four dose sequence of cocaine was repeated a total of four times. Initial cocaine administration produced dose dependent increases in locomotion and stereotyped behavior. When the sequence of cocaine doses was repeated, differences among treatment groups emerged. Groups treated with haloperidol exhibited heightened locomotion in response to cocaine and with repeated injections, showed a higher rate of behavioral sensitization than control animals. These differences in the behavioral response to cocaine were maintained for at least 2 months following termination of daily haloperidol treatment. In order to examine the mechanisms underlying this heightened responsiveness to cocaine, apomorphine-induced locomotion (dose range, 0-250 micrograms/kg, SC) was determined. Regardless of dose, rats treated with haloperidol showed different temporal patterns of locomotion in response to apomorphine suggesting that the increased response to cocaine was related to changes in dopaminergic receptor sensitivity.

Animals↗
PubMed1993

Effects of phenylpropanolamine on regulatory and nonregulatory ingestion in adult rats.

This experiment examined the effects of phenylpropanolamine (0.0, 5.0, 10.0, 20.0 mg/kg PPA) on regulatory (RG) and nonregulatory (NRG) eating and drinking in rats using a within-subjects design. Administration of PPA produced dose-dependent reductions in eating in animals deprived to 80-85% of baseline weight, and reduced drinking after 23.5-h of water deprivation. Nonregulatory eating, elicited by tail pinch in nondeprived animals, was similarly inhibited. Nonregulatory drinking was elicited in the schedule-induced polydipsia (SIP) paradigm. Water consumption, locomotion, licking, lick efficiency (licks/ml water), and entries into the food magazine were simultaneously measured. At the lowest dose, only locomotion was significantly reduced. At 10.0 mg/kg, lick efficiency and entries into the food magazine were also significantly reduced, while all measured behaviors, including licking and water consumption, were decreased by the highest dose of PPA. The reduction in lick efficiency suggested a PPA-induced motor impairment in the capacity for licking. Considered together, these results indicated that the observed decreases in regulatory and nonregulatory eating and drinking could be at least partially accounted for by the drug's effects on behaviors contributing to ingestion, as well as apparent motor impairments in ingestive behavior at higher doses.

Animals↗
PubMed1993

Effects of phenylpropanolamine infusion and withdrawal on body weight and dietary composition in male and female rats.

Male and female rats with ad lib access to separate sources of carbohydrate, fat, and protein were implanted with minipumps providing one of three dosages (0.0, 40.0, or 80.0 mg/kg/day) of phenylpropanolamine (PPA) for 2 weeks. Body weight, macronutrient intake, and water consumption were measured daily before, during, and after PPA treatment. Phenylpropanolamine lowered body weight and caloric intake in males and females, and water consumption in females, but did not alter dietary composition in either sex. After PPA termination, caloric intake returned to control levels in both males and females. However, body weight returned to control levels in males only, while PPA-treated females continued to weigh less than controls. Phenylpropanolamine termination was associated with significant increases in water consumption and the percentage of total calories consumed from protein and reductions in the percentage of calories from carbohydrate in males. In contrast, water and macronutrient consumption was similar comparing PPA-treated females to controls after drug termination. These results suggest there are sex differences in the effects of PPA termination on water and macronutrient consumption that result in differential weight gain in males and females.

Animals↗
PubMed1993

Lack of involvement of 4-hydroxynorephedrine in phenylpropanolamine-induced anorexia in rats.

The anorexic effects of phenylpropanolamine (PPA) appear to be qualitatively different in humans and rats. One factor that may account for these differences is that PPA is excreted essentially unchanged in humans, while nearly 30% is metabolized into 4-hydroxynorephedrine (4-OHN) in rats. To investigate the contribution of 4-OHN to the anorexic properties of PPA, this experiment compared the effects of equal doses (0.0-20.0 mg/kg, IP) of both drugs on eating and drinking during restricted feeding trials in the same group of food-deprived, female rats. Both 15.0 and 20.0 mg/kg of PPA significantly decreased eating when compared to saline vehicle, while 5.0-20.0 mg/kg of the drug reduced prandial drinking. In comparison, only the highest dose of 4-OHN (20.0 mg/kg) significantly suppressed food and water intake. When the percentage of reduction produced by corresponding doses of the two drugs was compared, PPA proved to be more than twice as potent as 4-OHN. It is concluded that, at the doses used, 4-OHN is unlikely to significantly contribute to reductions in deprivation-induced eating produced by the acute administration of PPA.

Animals↗
PubMed1992

Do forebrain structures compete for behavioral expression? Evidence from amphetamine-induced behavior, microdialysis, and caudate-accumbens lesions in medial frontal cortex damaged rats.

The neurochemical basis of behavioral changes following medial frontal cortex damage were investigated. Experiment 1 examined locomotion in response to D-amphetamine (1.5 and 5 mg/kg) in rats that had received bilateral aspirative lesions of the medial frontal cortex alone or in combination with 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens or caudate-putamen. Relative to controls, medial frontal cortex rats were initially hypoactive (day 1 postoperative) but rapidly became hyperactive (days 5-15 postoperative). Locomotor-time profiles and stereotypy ratings showed that amphetamine produced a selective enhancement of locomotion at the expense of stereotyped behavior. Nucleus accumbens lesions blocked the locomotion but enhanced stereotyped behavior in the medial frontal cortex damaged rats, suggesting that amphetamine-enhanced locomotion is dependent upon the integrity of the nucleus accumbens. In Experiment 2, intracerebral microdialysis was used to examine whether alterations in dopamine (DA) or monoamine metabolites in the nucleus accumbens or caudate-putamen accompanied the lesion-induced changes in locomotion. There were no differences in extracellular DA or monoamine levels between control rats and medial frontal cortex rats when tested on day 1 or day 15 postsurgery, either when they were at rest, while they walked on a motor-driven belt, or after amphetamine treatment. Therefore, it seems unlikely that changes in amphetamine-induced locomotion following medial frontal cortex lesions are related to underlying modifications in dopaminergic activity in the nucleus accumbens. It is suggested that neural structures compete for behavioral expression and that postlesion behavioral alterations reveal the competitive advantage of remaining intact neural systems.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Pituitary-adrenal and dopaminergic modulation of schedule-induced polydipsia: behavioral and neurochemical evidence.

Five experiments investigated in rats the effects of increasing or decreasing plasma corticosterone levels on schedule-induced polydipsia and dopamine efflux in the nucleus accumbens. The results indicate that the acquisition of schedule-induced polydipsia could be decreased by adrenalectomy, blockade of corticosterone synthesis, or administration of corticosterone. Performance of established schedule-induced polydipsia was also decreased by adrenalectomy. The effects of corticosterone administration on established schedule-induced polydipsia depended on the level of performance. High levels of drinking were enhanced by a high dose of corticosterone, whereas low rates of drinking were increased by a low dose. Similar injections of corticosterone also significantly increased dopamine efflux. The relative involvement of pituitary-adrenal activity and dopamine neurotransmission in the nucleus accumbens in the acquisition and performance of SIP is discussed and related to contemporary hypotheses of schedule-induced behavior.

Animals↗
PubMed1991

Sensitization of amphetamine-stereotypy reduces plasma corticosterone: implications for stereotypy as a coping response.

The potential coping functions of amphetamine-induced stereotypy were investigated using a physiological index of stress or arousal, plasma corticosterone level. A series of five injections of d-amphetamine was used to enhance stereotyped behavior in control animals as well as in rats with bilateral dopamine-depleting lesions of the caudate-putamen. This regimen of amphetamine injections significantly increased stereotyped behavior and also reduced the normal elevation in corticosterone produced by treatment with d-amphetamine. This effect was apparent in both control and lesioned animals. These results support the hypothesis that amphetamine-induced stereotyped behavior functions to reduce stress or arousal and additionally suggest that this effect is largely independent of underlying dopaminergic mechanisms.

Adaptation, Psychological↗
PubMed1991

Hippocampal modulation of nucleus accumbens: behavioral evidence from amphetamine-induced activity profiles.

The experiments examined amphetamine-induced locomotion and stereotyped behavior in hippocampal-ablated and control rats for 30 days following surgery. Locomotor counts, stereotypy ratings, and locomotor-time profiles showed that d-amphetamine sulfate produced a selective enhancement of locomotion (cage crosses) at the expense of stereotyped behavior in hippocampal rats relative to normal control rats. This enhancement emerged over the first 2 weeks postsurgery. To examine the role of the striatum in this amphetamine-induced effect, combined hippocampal damage and 6-hydroxydopamine-induced damage of the nucleus accumbens or caudate-putamen were used. These results suggested that amphetamine-enhanced locomotion of hippocampal rats is dependent upon the integrity of the nucleus accumbens and may reflect a change of nucleus accumbens activity relative to caudate-putamen activity. Together these findings suggest that the hippocampus may participate in the control of locomotion by projections that modulate the activity of the nucleus accumbens.

Animals↗
PubMed1990

Cortical, hippocampal, and striatal mediation of schedule-induced behaviors.

The sequential occurrence of licking, locomotor activity, entries into the food magazine (panel pressing), and nonreenforced lever pressing engendered by a periodic schedule of food presentation were measured in each 60-s interreenforcement interval in normal and brain-damaged rats. The development of these responses was measured over 20 days in different groups of food-deprived rats that had received aspirations of the hippocampus, small lesions of the cortex overlying the hippocampus (hippocampal-operated control group), decortication, or 6-hydroxy-dopamine lesions of the caudate nucleus or nucleus accumbens. All lesions produced distinctive patterns of change in the measured behaviors, and dissociations as well as similarities in their effects were evident. These results are discussed with respect to dissociations in the motor and motivational effects of the various lesions and in terms of contemporary hypotheses of schedule-induced behavior.

Animals↗
PubMed1990

Physiological correlates of schedule-induced activities in rats.

Oxygen consumption and heart rate as well as a range of behavior variables were tracked continuously as rats adapted to a schedule of food delivery. Over 15 days of observation a majority of the subjects developed characteristic patterns of schedule-induced polydipsia (SIP) in which bouts of drinking reliably followed food delivery. Variations in food tray entries, oxygen consumption, heart rate, and, in the final stage of the experiment, rates of general activity were also time locked to food delivery in both rats exhibiting SIP and nondrinkers. However, the patterns of variation in these measures differed consistently between these two groups. Oxygen consumption varied over a wider range and reached higher levels in drinkers than nondrinkers. Additionally, heart rate was lower in the drinkers, which, in the final stage of the experiment, also exhibited depressed rates of food tray entries and general activity relative to the nondrinkers. Each of these between-subject differences was paralleled by differences within the drinking group between trials on which drinking occurred and trials on which it did not occur. The implications of these results on the utility of unidimensional energetic constructs are discussed.

Animals↗
PubMed1989

Training-dependent decay in performance produced by the neuroleptic cis(Z)-flupentixol on spatial navigation by rats in a swimming pool.

Rats were trained on place or cue spatial navigation tasks in a swimming pool and then given the neuroleptic, alpha-flupentixol. Initial experiments showed that regardless of testing schedule, including blocks of trials given concurrently or separated by 7 or 30 days, drugged rats showed a trial-by-trial decay in latency and accuracy of responding although they continued to swim. The rate of decay increased with increases in drug dosage. Further experiments showed that: 1) Performance decay was specifically related to conditioned components of the test environment. Animals required to swim in a different test, or to struggle, showed less decay than rats exposed to the test platform only or required to perform all aspects of the task. 2) Decay was not due to nonspecific effects of neuroleptic treatment because rats injected and replaced in their home cage, and then subsequently reinjected and tested performed like rats treated and tested for the first time. 3) A trial-dependent decay of performance was also obtained in hippocampectomized and decorticate rats, suggesting that at least part of the major action of the drug is on subcortical systems. The results are discussed with respect to hypotheses of neuroleptic action and with respect to their possible relevance to experience-dependent changes in animal analogues of Parkinson's disease. Finally, it is suggested that behavior may be organized in subsystems, which when active, become selectively sensitive to neuroleptics.

Animals↗
PubMed1989

Attenuation of amphetamine-stereotypy by mesostriatal dopamine depletion enhances plasma corticosterone: implications for stereotypy as a coping response.

The relationship between amphetamine-induced stereotyped behavior and a neuroendocrine index of arousal, plasma corticosterone (CCS), was investigated. 6-Hydroxydopamine lesions of the caudate-putamen, which produced dopamine depletions of 60%, blocked stereotypy and prolonged the elevation in corticosterone associated with d-amphetamine treatment (5 mg/kg). Similar dopamine depleting lesions of the nucleus accumbens, which attenuated the locomotor, but not the stereotypic, response to AMPH did not have this effect on CCS. This pattern of results supports the hypothesis that stereotypy has a coping function which may serve to alter arousal and further suggests important differences between the nigrostriatal and mesolimbic dopamine projections in modulating the responsiveness of the neuroendocrine system. These results have implications for understanding the function of behavioral stereotypies common to a number of psychopathological conditions, including schizophrenia and childhood autism.

Adaptation, Psychological↗
PubMed1988

Cortical lateralization of function in rats in a visual reaction time task.

Rats were trained to orient to a visual cue presented in either visual field. An asymmetry in reaction time showed that they used one eye to control responses to both visual fields. Cortical removal contralateral to this dominant eye produced a severe and permanent response deficit. Cortical removal ipsilateral to the dominant eye caused a mild and temporary change. Thus, in the rat, there is a functional lateralization that is similar to that seen in humans.

Animals↗