Biomedical subjects

I M White

Publications and source records attributed to I M White.

18 recordsLinked to original sources

PubMed2001

Neuronal activity in dorsomedial frontal cortex and prefrontal cortex reflecting irrelevant stimulus dimensions.

Previous studies of the dorsomedial frontal cortex (DMF) and the prefrontal cortex (PF) have shown that, when monkeys respond to nonspatial features of a discriminative stimulus (e.g., color) and the stimulus appears at a place unrelated to the movement target, neurons nevertheless encode stimulus location. This observation could support the idea that these neurons always encode stimulus location, regardless of its relevance to an instrumentally conditioned behavior. Past studies, however, leave open the possibility that activity observed during one operant task might reflect the contingencies of a different task, performed at different times. To test these alternatives, we examined the activity of DMF and PF neurons in two rhesus monkeys conditioned to perform an operant eye-movement task in which only the color and shape of visual stimuli served as salient discriminative features. Each of eight stimuli was associated with a response to a different eye-movement target. The location of these stimuli varied from trial to trial but was of no behavioral relevance, and the monkeys did not perform any operant task in which stimulus location controlled behavior. A substantial minority of neurons in both DMF and PF nevertheless encoded stimulus location, which indicates that this property does not depend on its relevance in an instrumentally conditioned behavior.

Action Potentials↗

PubMed2000

Effects of MK801 and neuroleptics on prepulse inhibition: re-examination in two strains of rats.

Disruption of prepulse inhibition (PPI) induced by NMDA receptor antagonists, such as MK801, has been used as an animal model of positive and negative symptoms of schizophrenia. Previous studies suggested that atypical, but not typical, neuroleptics can selectively restore MK801-induced PPI disruption and that such selectivity may depend on strain differences. The present study re-examined PPI disruption by systemic MK801 in Wistar (WS) and Sprague-Dawley (SD) strains, and addressed the issue whether clozapine (atypical), compared to haloperidol (typical), effectively antagonizes MK801-induced PPI disruption. In addition, we tested the effects of bilateral microinfusion of MK801 into the ventral hippocampus in WS. Systemic MK801 disrupted PPI in both strains. Neither clozapine nor haloperidol antagonized MK801-induced PPI in either strain. Our clozapine data do not agree with previous reports of clozapine's ability to antagonize MK801-induced PPI disruption. Similar to previous results with SD, MK801 infusion into the ventral hippocampus failed to affect PPI in WS. In our view, the selective ability of atypical neuroleptics to restore PPI disruption by NMDA antagonists, and to serve as a tool for identifying possible atypical neuroleptics, requires further examination. PPI disruption with systemic MK801 may be due to the blockade of NMDA receptors in multiple brain sites.

Animals↗

PubMed2000

Effects of administering cocaine at the same versus varying times of day on circadian activity patterns and sensitization in rats.

The effects of different schedules of cocaine administration on circadian activity patterns and locomotor sensitization were studied. Rats received intraperitoneal injections of either saline or 20 mg/kg cocaine at either 24- or 33-hr intervals for 8 cycles (development). After a 2-day withdrawal, they were given a cocaine challenge in a novel environment. Rats given cocaine at 24-hr intervals were hypoactive 4 to 9 hr postinjection during development and, during cocaine challenge, showed sensitization of locomotor activity. Rats given cocaine at 33-hr intervals did not show these effects. On the 33-hr-period schedule, activity was enhanced beginning 24 hr after drug receipt. Different intermittent schedules of cocaine receipt may alter the vulnerability to cocaine, and altered vulnerability may be more likely when a subsequent cocaine injection interacts with a distal state of sensitivity produced by a prior injection.

Animals↗

PubMed2000

A link function approach to model heterogeneity of residual variances over time in lactation curve analyses.

Several studies with test-day models for the lactation curve show heterogeneity of residual variance over time. The most common approach is to divide the lactation length into subclasses, assuming homogeneity within these classes and heterogeneity between them. The main drawbacks of this approach are that it can lead to many parameters being estimated and that classes have to be arbitrarily defined, whereas the residual variance changes continuously over time. A methodology that overcomes these drawbacks is proposed here. A structural model on the residual variance is assumed in which the covariates are parametric functions of time. In this model, only a few parameters need to be estimated, and the residual variance is then a continuous function of time. The analysis of a sample data set illustrates this methodology.

Analysis of Variance↗

PubMed1999

Rule-dependent neuronal activity in the prefrontal cortex.

We studied single-neuron activity in the prefrontal cortex (PF) while a monkey performed a task according to two different rules, termed conditional and spatial. The monkey viewed a video screen, and its task required a hand movement in response to the dimming of a light spot. There were four light spots on the screen: right, left, up, and down from the center. Only one of the four spots dimmed, and the degree of dimming was slight. Accordingly, the monkey needed to foveate the "correct" light spot to detect the dimming. A visual cue indicated which of the four light spots would be deemed correct and, thus, would dim on each trial. The sequence of events was as follows: a fixation spot appeared at the center of the screen; then, a cue appeared twice at one of the four potential target locations; then, the four target spots appeared; and, finally, one of them dimmed. Except for the color of an initial fixation point, the cues, their locations, and other events were identical for the conditional and spatial rules. The rules differed in one essential way. For the conditional rule, nonspatial attributes of the visual cue indicated which of the four light spots would dim, and the cue's location was irrelevant. For the spatial rule, the cue's location determined the correct target on that trial. The light spot at the location of the cue always dimmed, regardless of which cue appeared there. Our sample included 221 PF neurons showing significant task-related activity modulation, distributed among dorsal, dorsolateral, and ventral PF regions. Between one-third and one-half of the sample in each of those regions showed statistically significant activity differences that could be attributed to the rule. Selectivity for cues and/or their locations was common. However, there was no significant regional segregation of such selectivity. These data support the hypothesis that PF plays a role in the guidance of behavior according to previously learned rules.

Animals↗

PubMed1999

Genetic and environmental smoothing of lactation curves with cubic splines.

Most approaches to modeling lactation curves involve parametric curves with fixed or random coefficients. In either case, the resulting models require the specification on an underlying parametric curve. The fitting of splines represents a semiparametric approach to the problem. In the context of animal breeding, cubic smoothing splines are particularly convenient because they can be incorporated into a suitably constructed mixed model. The potential for the use of splines in modeling lactation curves is explored with a simple example, and the results are compared with those using a random regression model. The spline model provides greater flexibility at the cost of additional computation. Splines are shown to be capable of picking up features of the lactation curve that are missed by the random regression model.

Animals↗

PubMed1998

Cocaine-induced activation of striatal neurons during focused stereotypy in rats.

As psychomotor stimulants, both amphetamine and cocaine elicit episodes of repetitive motor activation (focused stereotypy) known to involve the mesostriatal dopamine system. During amphetamine-induced focused stereotypy, motor-related neurons in the striatum respond with either an excitation or inhibition, depending on dose and behavioral pattern, whereas nonmotor-related units are inhibited. To assess striatal activity during the focused stereotypy induced by cocaine, both types of striatal units were recorded in ambulant rats. Either 20 or 40 mg/kg cocaine caused highly focused sniffing and head bobbing, which occurred in conjunction with activation of both motor- and nonmotor-related neurons. The activation of motor-related units was evident even when firing rate was compared during periods of matched pre- and post-drug behavior, arguing against movement as the sole basis for the drug-induced neuronal excitation. Subsequent administration of haloperidol (1.0 mg/kg) reversed but did not completely block the neuronal activation, while the behavioral response shifted away from focused stereotypy toward an increase in ambulation. Thus, the level of activation of both motor- and nonmotor-related striatal neurons may play a critical role in the behavioral response pattern induced by cocaine.

Amphetamine↗

PubMed1997

Quinpirole inhibits striatal and excites pallidal neurons in freely moving rats.

The activity of single neurons in the striatum of freely moving rats was recorded in response to systemic administration of dopamine agonists selective for either the D1 or D2 family of receptors. At a dose that induced behavioral activation, SKF-38393 (5.0 mg/kg s.c.), a D1 agonist, had no consistent effect on striatal activity, whereas quinpirole (1.0-5.0 mg/kg s.c.), a D2 agonist, inhibited the great majority of striatal neurons. In addition, quinpirole (1.0 mg/kg s.c.) excited neurons of the globus pallidus, which receives an inhibitory projection from the striatum. These results are consistent with models of the basal ganglia in which dopamine, via D2 receptors, inhibits striatopallidal activity, resulting in a disinhibition of neurons in globus pallidus.

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

PubMed1997

Responses of neurons in dorsal striatum during amphetamine-induced focused stereotypy.

The phase of highly focused, repetitive behavior (stereotypy) induced by amphetamine in rats emerges after an initial period of locomotor activation. To assess the neuronal correlates of this behavioral transition, single-unit activity was recorded from the dorsal striatum of awake, unrestrained rats. Units were first characterized in terms of their responsiveness to spontaneous movement. Various types of motor-related neurons were identified. Some increased activity above resting baseline during specific movements such as forward locomotion or turning of the head, while others were excited during periods of general behavioral activation. Neurons that showed no consistent change in firing rate during overt movement were classified separately. Administration of 5.0 mg/kg d-amphetamine caused a steady increase in the overall neuronal response through both the locomotor and stereotypy phases. An analysis of specific neuronal types, however, revealed distinct, phase-related shifts in firing rate. Locomotor-related neurons discharged rapidly during the early phase of the amphetamine response and then declined toward baseline as focused stereotypy emerged. Cells found to be excited primarily during head movements showed relatively small changes shortly after drug administration but increased markedly in conjunction with intense head-movement activity associated with focused stereotypy. Other neurons, which increased activity nonselectively to a wide range of movements, showed progressive increases in firing rate during both behavioral phases elicited by the drug. Subsequent administration of 1.0 mg/kg haloperidol typically reversed the neuronal changes and blocked amphetamine-induced focused stereotypy. Nonmotor-related cells responded inconsistently to amphetamine, showing an inhibition, excitation, or no change in rate. Previous assessments of neuron-behavior relationships have shown that changes in motor-related neuronal activity are not secondary to amphetamine-induced behavioral changes, though this finding may not apply in all cases. At doses capable of eliciting focused stereotypy, therefore, amphetamine appears to trigger a complex pattern of striatal activity that governs the behavioral response. This conclusion supports steadily increasing evidence that the role of striatal neurons in amphetamine-induced focused stereotypy is shaped by multiple synaptic mechanisms.

Amphetamine↗

PubMed1996

Localization of motor- and nonmotor-related neurons within the matrix-striosome organization of rat striatum.

Striatal neurons can be classified as movement- and nonmovement-related depending on their ability to change firing rate in close temporal association with spontaneous movement in an open-field arena. The present study assessed the location of these cell types within the compartmental organization of the striatum by combining single-unit recording techniques in freely moving rats with calbindin immunohistochemistry. Movement-related neurons were found predominately either in the matrix or along the matrix-striosome border. Most of these neurons were nonselective in that they increased activity whenever the animals changed from a quiet resting posture to any form of behavioral activation (e.g., grooming, locomotion, rearing). The remaining neurons in this group responded exclusively to movements of the head. Nonselective units discharged at a significantly slower rate than head-movement units during both quiet rest and periods of actual movement. Nonmovement-related neurons, which failed to show a reliable change in activity to overt behavior, comprised a relatively small portion of the neuronal sample but were also located in either the matrix or along the matrix-striosome border. Collectively, these results suggest that even though striatal neurons can be distinguished on the basis of their responsiveness to ongoing behavior in an open-field paradigm, such distinctions are not clearly linked to sites within the matrix or its striosomal borders.

Animals↗

PubMed1995

Phencyclidine-induced increases in striatal neuron firing in behaving rats: reversal by haloperidol and clozapine.

Amphetamine and related drugs of abuse facilitate dopamine transmission in the striatum. This action is believed to underlie the increase in firing of striatal motor-related neurons after amphetamine administration in behaving rats. The present study extended this electrophysiological investigation to phencyclidine (PCP), a nonamphetamine psychomotor stimulant that acts primarily as a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors. Like amphetamine, PCP (1.0, 2.5, or 5.0 mg/kg) increased the activity of striatal motor-related neurons concomitant with behavioral activation. These effects were blocked by subsequent administration of either 1.0 mg/kg haloperidol or 20.0 mg/kg clozapine, typical and atypical neuroleptics, respectively. Dizocilpine (MK- 801), another noncompetitive NMDA antagonist, mimicked the effect of PCP. Collectively, these results indicate that amphetamine and NMDA antagonists exert comparable effects on striatal motor-related neurons, suggesting that the response of these cells to psychomotor stimulants is regulated by a dopaminergic-glutamatergic influence.

Animals↗

PubMed1995

Amphetamine, cocaine, and dizocilpine enhance performance on a lever-release, conditioned avoidance response task in rats.

A lever-release version of the conditioned avoidance response (CAR) task was used to assess the behavioral effects of several psychomotor stimulants in rats. The indirect dopamine agonists, d-amphetamine (0.1 and 0.25 mg/kg) and cocaine (7.5 and 15 mg/kg), enhanced performance on this task. Both drugs increased percent avoidance responses and decreased avoidance latency. A higher dose of amphetamine (0.5 mg/kg) also decreased avoidance latency but failed to improve percent avoidance. Similar effects were seen at low (0.01 and 0.025 mg/kg) and high (0.05 mg/kg) doses of dizocilpine (MK-801), a stimulant that acts as a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors. When combined with haloperidol (0.1 mg/kg), a dopamine antagonist, amphetamine (0.25 mg/kg) and dizocilpine (0.025 mg/kg) had differential effects on the lever-release CAR task. Thus, amphetamine-haloperidol was significantly better than haloperidol alone on percent avoidance but not on avoidance latency, whereas dizocilpine-haloperidol had the opposite effect: significantly better than haloperidol alone on avoidance latency but not on percent avoidance. Taken together, these results provide further support for dopaminergic mechanisms in CAR performance but suggest an opposing glutamatergic influence.

Amphetamine↗

PubMed1994

Performance on a lever-release, conditioned avoidance response task involves both dopamine D1 and D2 receptors.

SCH-23390 (0.01 and 0.05 mg/kg s.c.), a dopamine D1 receptor antagonist, or eticlopride (0.01 and 0.05 mg/kg s.c.), a dopamine D2 receptor antagonist, dose-dependently impaired performance on a lever-release conditioned avoidance response (CAR) task by decreasing percent avoidance responses and increasing avoidance latency. When combined, these drugs impaired CAR performance in an additive fashion. Lever-release CAR performance, therefore, requires activation of both dopamine D1 and D2 receptors.

Animals↗

PubMed1994

Neuronal activity in rabbit neostriatum during classical eyelid conditioning.

Extracellular multiple- and single-unit recordings were made from the neostriatum of rabbits during classical eyelid conditioning. Neostriatal neurons processed information regarding the conditioned auditory stimulus (CS) and conditioned eyelid response (CR) as well as the unconditioned stimulus/response (US/UR). These data are consistent with previous reports that neostriatal neurons respond to movement and movement-related sensory stimuli. In most cases, neostriatal neurons increased activity to the US during the early phase of training, but to the CR as training progressed. A close temporal correlation was found between neuronal activity and CR onset with unit discharges typically preceding CR onset by 10-50 ms. The activity of some multiple and single units was monitored after injection of haloperidol, a neuroleptic and dopamine antagonist known to disrupt neostriatal function. Interestingly, haloperidol caused a greater disruption of CRs at low-intensity than at high-intensity CSs, but conditioning-related neuronal activity was disrupted equally at both intensities. These data are discussed in terms of a possible role for the neostriatum in eyelid conditioning.

Animals↗

PubMed1993

Responses of rat striatal neurons during performance of a lever-release version of the conditioned avoidance response task.

Neural activity was recorded from 218 sites in the striatum (caudate-putamen and nucleus accumbens) of rats trained on a lever-release version of the conditioned avoidance response (CAR) task, in which an auditory signal elicits a short-latency, forelimb withdrawal. > 80% of these recording sites showed task-related activity, including neurons that responded to the auditory stimulus (signal-related cells), the lever-release (response-related cells), or both of these events (signal/response-related cells). Histological analysis revealed a predominance of signal-related neurons in medial striatum, whereas lateral recording sites mainly showed response-related activity. Haloperidol (0.1 mg/kg s.c.), a widely used neuroleptic that impairs CAR performance, significantly attenuated task-related neural activity without altering the latency of the neural response or spontaneous firing rate. Collectively, these results, which demonstrate the usefulness of the lever-release CAR paradigm for assessing striatal function, suggest that the sensory and motor aspects of the CAR task are processed by different striatal regions. Moreover, haloperidol appears to disrupt the striatal processing of both sensory and motor information.

Acoustic Stimulation↗

PubMed1993

Striatal single-unit responses to amphetamine and neuroleptics in freely moving rats.

Single-unit recordings from 50 striatal neurons in freely moving rats revealed generally low activity (< 3 spikes/sec) during resting behavior and movement-related excitations in most (n = 36) neurons. While activating behavior, d-amphetamine (1.0 mg/kg, sc) usually excited and inhibited motor- and nonmotor-related neurons, respectively, relative to resting baseline firing rates. A behavioral clamping analysis, which controlled for neuronal effects secondary to behavior, yielded results suggesting a primary, amphetamine-induced excitation of striatal motor-related neurons. Haloperidol (0.1-1.0 mg/kg) strongly inhibited behavior and neuronal activity when injected 30 min after amphetamine. Clozapine (5.0-30.0 mg/kg) inhibited only selected behaviors, but reliably produced haloperidol-like reversals of amphetamine-induced neuronal excitations. A literature review revealed that the neuronal results in behaving animals differ markedly from the inhibitory striatal responses to amphetamine and the excitatory responses to dopamine antagonists often found in immobilized or anesthetized rat preparations. These contrasting, preparation-dependent results support a model based on drug interactions with a proposed neuromodulatory function of striatal dopamine, which is to facilitate or attenuate the activity of neurons receiving, respectively, substantial, or little excitatory afferent input.

Amphetamine↗

PubMed1992

A lever-release version of the conditioned avoidance response paradigm: effects of haloperidol, clozapine, sulpiride, and BMY-14802.

Rats trained on a lever-release version of the conditioned avoidance response (CAR) task were used to test the behavioral effects of established and putative antipsychotic drugs. Baseline CAR latencies decreased as the conditioned-unconditioned stimulus interval was shortened from 500 to 250 ms. Haloperidol, clozapine, and BMY-14802 decreased successful avoidance responses and increased avoidance latencies in a dose-dependent manner without affecting the latency of escape responses. In contrast, sulpiride failed to affect either successful avoidance response rates or avoidance latency. Sulpiride, however, significantly attenuated d-amphetamine-induced locomotion and rearing compared to vehicle-treated controls. Similar effects of these antipsychotics have been reported on shuttlebox avoidance, and these results now are confirmed in a CAR paradigm that achieves greater control over behavior. Because this paradigm elicits a discrete forelimb response without activating numerous muscle groups, it is potentially useful as a tool for examining neuronal mechanisms underlying the behavioral effects of antipsychotic drugs.

Animals↗

PubMed1977

Pitfalls to avoid: the Australian experience.

In this paper the major health problems facing Australia's Aboriginal population are reviewed and an attempt is made to assess the genetic and environmental, social and cultural factors to which they may be attributed. Among Aborigines living in remote areas under semi-tribal conditions, recent improvements in health, though considerable, have not been commensurate with the greatly increased expenditure on health and welfare services. This disappointing outcome is due partly to loss of control by Aborigines over their own lives, including matters concerning health, and partly to failure of white medical and welfare personnel to communicate with people holding different beliefs about health and disease. The bad health of Aborigines living in cities and rural areas can be attributed largely to their poverty, which in turn stems from discrimination in employment, housing and community services. In both the remote and the settled areas health services for Aborigines are increasingly coming under the control of Aborigines themselves and producing encouraging results.

Adult↗