James L. Howard

Chronic low-level lead toxicity in the rat: II. Effects on postnatal physical and behavioral development

Abstract This report is the second in a series dealing with the chronic exposure of rats to lead (Pb) in drinking water. Weanling female CD rats were provided semipurified diets and deionized water containing 0, 0.5, 5, 25, 50, or 250 ppm Pb (as lead acetate). Following exposure for 6–7 weeks, females were mated with unexposed males and exposure continued throughout pregnancy and lactation. At 21 days of age, offspring were weaned onto the same concentration their mothers had been given, and exposure continued until sacrifice at 6 or 9 months of age. Significant depressions in body weight were seen at most time points for offspring exposed to 50 and 250 ppm Pb. Clinical signs of respiratory infection, as well as poor fur condition, tail-tip necrosis, and sialodacryoadenitis were noted to occur at 250 ppm. Highly significant delays in age at vaginal opening were noted in 25-, 50-, and 250-ppm females. Surface righting and air righting were delayed in 50- and 250-ppm animals. Locomotor development was unaffected except for an increase in pivoting in 250-ppm animals at Day 14 of age. Postweaning activity levels were unaltered when measured in either the open field or the circular photocell activity cage and evaluations of motor coordination using the rotorod test showed no effects of Pb. Food and water consumption based on body weight were essentially unchanged. Overall, the “lowest effect level” for Pb using chronic oral exposure was 25 ppm, a level associated with alterations in reproductive development. In other reports from this study, immune function and performance of an operant task in adults were altered at 25 ppm (blood Pb, 20–40 μg/dl), and renal morphology after 9 months of exposure was altered at 5 ppm (blood Pb, 10–16 μg/dl). The importance of reporting blood and tissue Pb concentrations for comparing Pb dose-effect among studies is emphasized.

Alteration of avoidance and ingestive behavior after destruction of central catecholamine pathways with 6-hydroxydopamine

Abstract Alterations of shuttle-box avoidance acquisition, ingestive behavior, and catecholamine content in 4 different parts of brain were determined following bilateral infusion of 6-hydroxydopamine into the ventral tegmental area containing A-10 dopamine cell bodies, the tegmental segment of the ascending norepinephrine pathways, the globus pallidum, or the caudate-putamen. The maximum antagonism of active avoidance acquisition occurred following placement of 6-hydroxydopamine into the ventral tegmental and caudate areas. No effect on either avoidance or ingestive behavioral measures occurred after infusion of 6-hydroxydopamine into the norepinephrine pathways. Factor analysis of behavioral and biochemical data suggested that only striatal dopamine content bore a high relationship to avoidance behavior, while ingestive behavioral measures were highly related to both striatal and limbic dopamine content. Results suggest a functional—anatomical differentiation of dopamine pathways in brain.

Effect of central catecholamine alterations by 6-hydroxydopamine on shuttle box avoidance acquistion

Abstract Rats treated intracisternally with multiple doses of 6-hydroxydopamine (2 × 200 μg) in combination with pargyline, which depleted both brain norepinephrine and dopamine, showed no evidence of acquisition of an avoidance response in the shuttle box. Mean intertrial interval (ITI) crosses were not significantly different from control. Treatment with 2 × 250 μg of 6-hydroxydopamine without pargyline also retarded acquisition of avoidance, but to a lesser extent. ITI crosses for this latter group were significantly increased. Preferential depletion of norepinephrine facilitated acquistion of avoidance and increased the number of ITI crosses. The rate of acquisiton of the avoidance response by rats in which dopamine was preferentially reduced was not significantly different from control animals even though ITI crossing was significantly increased. These results are discussed in relation to views concerning the role of brain catecholamines in avoidance responding.

Enhanced behavioral depressant effects of reserpine and α-methyltyrosine after 6-hydroxydopamine treatment

The effects of 6-hydroxydopamine treatment on behavioral performance in an operant, shuttle-box and a T-maze task were examined. In spite of marked depletions of brain catecholamines, 6-hydroxydopamine-treated rats showed no significant reductions in performance level in these tasks. However, administration of 1 mg/kg of reserpine which had no effect in control subjects was found to cause severe disruption of bar press responding on a CRF schedule in 6-hydroxydopamine-treated rats. Similarly, low doses of α-MPT which also had no observable effect in control rats produced a severe depression of performance of not only CRF responding but also responding in the shuttle-box avoidance and T-maze tasks in centrally-sympathectomized subjects. The relationship of these findings to the proposal that catecholamines are important to the maintenance of behavioral responding and to possible mechanisms involved in the behavioral effects of 6-hydroxydopamine are discussed.

Cardiac-somatic changes during a simple reaction time task: A developmental study.

Abstract The relationship during a simple reaction time task between heart rate and four measures of task irrelevant somatic activity was evaluated in four age groups of children, i.e., 4-, 5-, 8-, and 10-year-olds and young adults, in order to evaluate further a hypothesized coupling of cardiac and somatic activity. At all age levels, phasic decreases in both heart rate and somatic activity coincident with performance were found with the magnitude of the effect increasing with age only on three somatic measures. However, tonic levels of both heart rate and somatic activity decreased with age. Performance on the reaction task was found to be inversely related to the age-related phasic somatic effects as well as age-related tonic heart rate and somatic activity.

Blood pressure and cardiac changes during signalled and unsignalled avoidance in dogs

Alterations in blood pressure (BP) during two aversive behavioral tasks were studied in five chronically-prepared dogs. During a signalled-avoidance task, BP levels were not altered, although heart rate (HR) increased. While propranolol (0.3 mg/kg, IA) led to slight increases in resting pressure, and phenoxybenzamine (1.0 mg/kg) reductions, the tachycardia at avoidance onset was not affected. Exposure to an unsignalled-avoidance task led to elevated diastolic BP levels during a preavoidance period and to increases in systolic BP, HR and aortic dP/dt at the inception of the avoidance session. Again, neither drug affected the tachycardia during avoidance, but both agents precluded BP and aortic dP/dt increases. Patterns of intercorrelations among cardiovascular variables were similar for both tasks, and suggested that the basis of the BP maintenance shifted from vasomotor to cardiac control during the avoidance periods. The differential cardiovascular adjustments during these tasks could not be accounted for in terms of differences in response rate. Rather, the critical variable seemed to be the amount of feedback the animal received for responding.

Physiological and behavioral effects of centrally-administered 6-hydroxydopamine in cats ☆

Abstract Intraventricular injections of 6-hydroxydopamine (6-OHDA) into cats produced a greater reduction of brain norepinephrine than dopamine content while producing no change in brain serotonin. The effects immediately after the first injection of 6-OHDA included hypothermia, increase in respiratory rate, and in the presence of pargyline, sham rage. Following the first injection, a prolonged period of hypophagia and hypodipsia occurred. Subsequent injections produced less hypothermia and greater increases in respiratory rate. Measurement of sleep-wake ratios indicated that paradoxical sleep was initially reduced by 6-OHDA administration, but eventually recovered to occupy its normal percentage of the cycle. However, wake time was increased and slow-wave sleep time decreased. Animals treated with 6-OHDA had lower baseline heart rates and showed no evidence for acquiring a conditioned heart rate response, although heart rate response to shock was potentiated.

Cardiovascular changes following DOCA/NaCl or conditioning in 6-hydroxydopamine-treated rats

Abstract Two intracisternal injections of 200 μg 6-hydroxydopamine reduced brain catecholamine levels 90% and significantly lowered resting heart rate and blood pressure. In a classical aversive conditioning paradigm, 6-hydroxydopamine-treated rats displayed little or no conditioned heart rate response in anticipation of shock, but a potentiated unconditioned response to shock itself. The alteration in heart rate responses may have been due in part to alterations in general activity. Although 6-hydroxydopamine treatment did not abolish the hypertension caused by DOCA/NaCl treatment following uninephrectomy, the increase in blood pressure was significantly less than the blood pressure increase in control rats receiving this treatment. The 6-hydroxydopamine treatment, however, concomitantly reduced the amount of NaCl consumed after DOCA. Since peripheral tyrosine hydroxylase activity and amine levels were not significantly altered by 6-hydroxydopamine treatment, the alterations in cardiovascular responses following 6-hydroxydopamine must result from its central actions. Although 6-hydroxydopamine administration markedly altered the cardiovascular responses to conditioned stimuli, shock, and DOCA/NaCl treatment, it is difficult to ascribe these alterations to ablation of central catecholamine fibers participating directly in cardiovascular control. The link between destruction of catecholamine fibers and changes in cardiovascular responses may be secondary to changes in activity or ingestive behavior.

An improved respiratory system for curarized rats

A respiratory system is described in which peak expired CO2 is continuously monitored from curarized rats. Another alteration from previous systems is that an endotracheal tube is used to minimize dead air space. The adequacy of the system was tested by maintaining curarized rats at one level of peak expired CO2 for varying periods of time and by keeping rats at different peak expired CO2 levels for a fixed period of time. Results of blood gas analyses indicated that values obtained with this system are similar to values in noncurarized rats, and that manipulation of expired CO2 is an effective means of altering blood gas values.

Classical aversive conditioning of heart rate in curarized rats at different blood gas levels

In an effort to examine whether normal blood gas tensions were essential for conditioning, paralyzed rats received a classical aversive heart rate (HR) conditioning session while respirated at different peak expired CO3 values. After the session, arterial blood was drawn for analysis. That peak expired CO2 was effective in manipulating Pco2 was indicated by a significant correlation (r = 0.594, df = 17, P < 0.05). In addition, only rats with blood gas values similar to those of anesthetized controls displayed a discriminated HR CR. These animals also had lower baseline HRs and greater HR variability. Further, 7 of the 9 rats with normal blood gas values were respirated at peak expired CO2 values from 5.0–5.1 per cent, and no animal ventilated within this range displayed abnormal values. These findings suggest that previous difficulties in obtaining classical and operant conditioning in paralyzed animals may, in part, be attributable to inadequate ventilation.