Biomedical subjects

R M Zacharko

Publications and source records attributed to R M Zacharko.

At least 37 records · Page 2Linked to original sources

PubMed1990

Multiple neurochemical and behavioral consequences of stressors: implications for depression.

Animal models of clinical depression have frequently focused on the contribution of stressors to the induction of behavioral impairments and pharmacological intervention in the amelioration of these disturbances. Stressors provoke various behavioral disturbances and influence the activity of central neurotransmitters implicated in depression. It is our contention that those variables which favor the provocation of amine depletions or prevent the development of a neurochemical adaptation will increase vulnerability to behavioral disturbances. It is essential to consider, however, that marked interindividual and interstrain differences exist in the behavioral and neurochemical response to stressors, and in the effectiveness of antidepressant treatments.

Animals↗

PubMed1990

Stressor-induced behavioral alterations in intracranial self-stimulation from the ventral tegmental area: evidence for regional variations.

Exposure to uncontrollable footshock reduced responding for electrical brain stimulation (ICSS) from the ventral tegmental area (VTA) of the CD-1 mouse. Such an effect, however, varied with electrode position in the tegmental field. In both a rate-dependent and a current intensity paradigm, ICSS from the dorsal VTA was reduced immediately, 24 hr and 168 hr following exposure to acute uncontrollable footshock. In contrast, ICSS from the ventral VTA was unaffected by the stressor regimen. These data are consistent with the suggestion that a stressor may reduce the rewarding value ordinarily derived from ICSS. Inasmuch as the stressor differentially affected ICSS from the dorsal and ventral tegmentum, these data provide evidence for a functional differentiation within the midbrain tegmental area.

Animals↗

PubMed1987

Strain-specific effects of inescapable shock on intracranial self-stimulation from the nucleus accumbens.

Responding for electrical stimulation from the nucleus accumbens was assessed in 3 inbred strains of mice (DBA/2J, C57BL/6J and BALB/cByJ) following exposure to uncontrollable footshock. While the operant response was most readily acquired in the DBA/2J strain, exposure to inescapable shock in this strain induced a marked deterioration of self-stimulation responding, which tended to dissipate over a 168-h period. In contrast to these mice, the stressor did not affect self-stimulation responding in the C57BL/6J strain, and produced a transient enhancement of responding in BALB/cByJ mice. It appears that although uncontrollable aversive events may engender an anhedonic effect, such an outcome is strain-dependent. These data suggest the importance of considering individual and genetic differences in the development of animal models of depression.

Animals↗

PubMed1987

Variations of norepinephrine concentrations following chronic stressor application.

Exposure to acute uncontrollable footshock increased utilization of central norepinephrine (NE), and in some brain regions, most notably the hypothalamus, a decline in amine concentrations was induced. Utilization of NE was likewise increased in mice exposed to footshock on 14 consecutive days, but the NE reduction was not evident, suggesting that the chronic stressor provoked a compensatory increase of amine synthesis. In mice that were decapitated 24 hr after the chronic shock regimen, NE concentrations exceeded those of nonshocked animals or mice decapitated immediately after the last shock session, possibly reflecting a sustained increase of amine synthesis. The altered NE utilization and concentrations associated with chronic footshock were evident irrespective of whether the stressor was applied on a predictable schedule or on an intermittent basis, although the former treatment was somewhat more effective in increasing concentrations and utilization.

Animals↗

PubMed1987

Evaluation of stressor effects on intracranial self-stimulation from the nucleus accumbens and the substantia nigra in a current intensity paradigm.

The effect of uncontrollable footshock was evaluated in animals responding for intracranial self-stimulation from the nucleus accumbens and the substantia nigra (pars compacta) in a descending current intensity paradigm. Responding for brain stimulation from the nucleus accumbens was found to be affected by the stressor at the upper end of the rate-intensity curve. In contrast, responding for brain stimulation from the substantia nigra was unaffected by the stressor at any of the current intensities employed. The variations of responding for self-stimulation from the nucleus accumbens were unrelated to alterations of locomotor activity or rearing. It is suggested that stressor-provoked reductions of responding for intracranial self-stimulation are not a result of the brain stimulation taking on aversive properties, but rather reflect a reduction in the reinforcing or motivational value associated with the stimulation.

Animals↗

PubMed1986

Amphetamine withdrawal: a behavioral evaluation.

The effects of withdrawal from long-term amphetamine treatment of intracranial self-stimulation, forced swim-induced immobility, shuttle escape performance, acoustic startle and locomotor activity were evaluated. Mice implanted with stimulating electrodes in the lateral hypothalamus demonstrated stable and reliable rates of self-stimulation responding. After exposure to a chronic schedule of amphetamine treatment response rates were severely depressed. In addition to modifying intracranial self-stimulation responding, amphetamine withdrawal increased the duration of immobility in a forced-swim situation. Although chronic amphetamine exposure induced pronounced behavioral changes in the intracranial self-stimulation and forced swim tasks, drug withdrawal had little effect on shuttle escape performance, acoustic startle and locomotor activity. Based on these findings it was suggested that the development of post-amphetamine depression in the self-stimulation and forced swim paradigms was not related to variations in motoric or arousal mechanisms resulting from amphetamine withdrawal, but rather involved drug-induced changes in motivational processes.

Acoustic Stimulation↗

PubMed1986

Influence of p-chloroamphetamine and methysergide on the escape deficits provoked by inescapable shock.

The effects of serotonergic manipulations on the escape interference engendered by exposure to inescapable shock were assessed. Consistent with the view that the behavioral interference was related to reductions of serotonin (5-HT), treatment with the 5-HT receptor blocker methysergide mimicked the effects of inescapable shock in that it increased escape latencies. Conversely, acute treatment with a moderate dose of the 5-HT releasing agent p-chloroamphetamine (PCA) effectively antagonized the escape interference ordinarily provoked by inescapable shock. The effects of PCA were behaviorally distinguishable from the previously observed effects of catecholamine stimulants. Whereas catecholamine stimulants applied prior to either inescapable shock or escape testing eliminated the interference, PCA antagonized the behavioral disruption only if it was administered before testing. It is suggested that catecholamine alterations may be fundamental in the provocation of the interference, whereas 5-HT variations may contribute to the expression of the behavioral disturbance.

Amphetamines↗

PubMed1986

Alterations of amphetamine elicited perseveration and locomotor excitation following acute and repeated stressor application.

The effects of acute and repeated stressor application on amphetamine-induced Y-maze perseveration and locomotor activity were assessed. When the stimulus context associated with an acute stressor (restraint or restraint plus shock) was distinctively different from that in which an amphetamine test was conducted 72 hr afterward, neither perseveration nor locomotor excitation were augmented. However, following three restraint sessions the amphetamine elicited perseveration was enhanced. With a more protracted regimen applied over 15 days the augmented perseveration was absent, whereas the amphetamine-provoked motor excitation was increased. While stimulus factors have been shown to be fundamental, it is provisionally suggested that the stressor induced enhancement of amphetamine-elicited perseveration is influenced by sensitization processes. However, the sensitization is apparent only under some stress regimens, and the behavioral expression of the sensitization may be obfuscated if the stressor is too severe. Furthermore, it appears that the mechanisms operative in enhancing the stressor provoked amphetamine motor excitation are independent of those which subserve the augmented perseveration.

Amphetamine↗

PubMed1986

Central norepinephrine and plasma corticosterone following acute and chronic stressors: influence of social isolation and handling.

Exposure to acute inescapable shock resulted in a decline of hypothalamic norepinephrine (NE), and an increase of plasma corticosterone concentrations. With repeated application of the stressor over 15 successive days the reduction of NE was eliminated and concentrations of the amine actually exceeded those of control animals. In contrast to the NE variations, plasma corticosterone concentrations were elevated irrespective of whether mice received a single or repeated sessions of inescapable footshock. Moreover, unlike NE concentrations, handling mice on successive days in the absence of the shock treatment was sufficient to provoke a modest, but reliable increase of corticosterone concentrations. It is suggested that the hypothalamic NE and plasma corticosterone changes may be reflective of different attributes of the stressor or are subserved by different mechanisms. It is suggested that variations in both these systems represent adaptive changes to meet environmental demands.

Animals↗

PubMed1986

Behavioral and neurochemical consequences associated with stressors.

A series of neurochemical changes occur in response to stressors that may permit the organism to contend with environmental demands. When the organism is exposed to a stressor the utilization and synthesis of brain NE and DA increases. Under conditions where utilization exceeds synthesis, owing either to the nature of the stressor (uncontrollability), experiential factors (e.g., prior exposure to acute stressors), or organismic variables (e.g., strain, age), reductions of the amine may be incurred. It is suggested that the reduced amine concentrations leave the organism less well prepared to deal with the demands placed upon it, and ultimately increase vulnerability to psychological disturbances. It follows that the more persistent the amine reduction, the greater the probability of pathology being engendered. In effect, in our analyses of stressor effects it is not sufficient merely to determine whether amine reductions occur, but also to assess the ability of the system to re-establish adequate levels and turnover. Additionally, since stressors may result in the conditioning or sensitization of neurochemical processes, it is essential not only to assess the immediate impact of the stressor, but also the neurochemical variations that occur upon re-exposure to stressors or cues associated with the stressor. In considering the consequences of stressors and the potential implications for human pathology, it is important to consider the impact of chronic stressors. After all, many stressors encountered by humans are chronic in nature, particularly if one considers ruminations associated with the aversive event. It seems that with repeated stressor application a further series of adaptive neurochemical changes occur. The activity of tyrosine hydroxylase is increased, and concentrations of NE and DA approach those of nonstressed animals. Indeed, it appears that after stressor termination the increased amine synthesis may persist for some time leading to a further increase of amine concentrations, which may enable the organism to deal with environmental demands. In addition, receptor variations may occur, including down-regulation of beta-NE receptors, and possibly alterations of alpha-1 and alpha-2 receptors as well. It is believed that the receptor variations may be the essential element in maintaining the integrity of the organism. It is our contention that where such adaptive changes do not occur or are slow in occurring, pharmacological intervention may be necessary to engender such neuronal variations.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1985

Differential effects of pimozide on response-rate and choice accuracy in a self-stimulation paradigm in mice.

Intracranial self-stimulation (ICSS) from the dopamine (DA) A9 cell grouping was evaluated in mice following pimozide administration in both a one hole head dipping task and a two hole discrimination paradigm. While pimozide reliably decreased response rates, choice accuracy in the discrimination paradigm was unaffected by the drug treatment. The data were taken to suggest that neuroleptics influence response rate owing to motoric disturbances, without influencing the effectiveness of cues that previously had been associated with primary reinforcement.

Animals↗

PubMed1985

Stressor invoked exacerbation of amphetamine-elicited perseveration.

The provocation of stimulus preservation induced by amphetamine in a Y-maze was appreciably enhanced in animals that had been exposed to uncontrollable shock, whereas controllable shock did not influence performance. The enhancement of the stimulus perseveration was evident irrespective of whether the stressor was applied immediately or 72 hr prior to the perseveration test, provided that the stimulus complex in which shock was delivered was similar to that in which the perseveration test was conducted. When the two environments were distinctively different from one another the enhancement of stimulus perseveration was evident immediately after shock exposure, but not 72 hr after shock. It is suggested that stressors may have long-term effects of amphetamine-elicited perseveration, but the expression of such an effect is dependent upon the stimulus context in which the behavior is examined. Moreover, it is suggested that evaluation of amphetamine-induced behavioral changes, and possibly amphetamine-elicited and idiopathic psychosis, should consider the stress history of the organism.

Amphetamine↗

PubMed1984

Prevention of stressor-induced disturbances of self-stimulation by desmethylimipramine.

Following exposure to uncontrollable footshock mice displayed a pronounced reduction of responding for electrical brain stimulation from the nucleus accumbens. In mice that received repeated treatment with the tricyclic antidepressant, desmethylimipramine, the shock induced reduction of responding was attenuated. It was suggested that, among other things, uncontrollable stressors result in disturbances of motivational/reward processes, which are antagonized by repeated treatment with desmethylimipramine.

Animals↗

PubMed1984

Effects of inescapable shock and norepinephrine depletion induced by DSP4 on escape performance.

The potential contribution of dorsal bundle norepinephrine (NE) in the induction of escape disturbances engendered by inescapable shock was evaluated following administration of the NE neurotoxin, DSP4. Treatment with DSP4 produced marked NE reductions in the hippocampus and cortex, a moderate reduction of NE in the locus coeruleus, but only small effects on hypothalamic NE. In contrast to the effect of inescapable shock, DSP4 was found not to influence escape behavior among naive mice or mice that had received inescapable shock. Moreover, DSP4 was without effect on escape performance irrespective of whether animals were individually or group housed, a treatment that has been shown to be sensitive to manipulations that influence escape performance. Treatment with DSP4 was found not to influence the escape interference ordinarily provoked by either haloperidol or alpha-MpT. Interestingly, the escape interference ordinarily engendered by the dopamine-beta-hydroxylase inhibitor, FLA-63, was eliminated among mice that had been pretreated with DSP4. The interference effect induced by inescapable shock is probably not attributable to NE alterations in the hippocampus and locus coeruleus. Serial or parallel effects of shock on more than a single transmitter system are likely to be responsible for the behavioral interference.

Amines↗

PubMed1984

Amphetamine-induced perseverative behavior in a radial arm maze following DSP4 or 6-OHDA pretreatment.

Mice permitted to explore an 8-arm radial maze tended to visit those arms least recently entered. Treatment with D-amphetamine engendered a perseverative tendency, wherein mice repeatedly visited two arms of the maze. Administration of the norepinephrine (NE) neurotoxin, N-2-chloroethyl-N-ethyl-2-bromo-benzylamine (DSP4), appreciably reduced NE in the hippocampus and cortex, moderately reduced NE in the locus coeruleus, and had only a small effect on hypothalamic NE. The DSP4 treatment resulted in a decrease of locomotor activity among amphetamine-treated mice, coupled with an increase of stereotyped response patterns. Although the NE depletion did not affect the pattern of exploration that mice ordinarily displayed, DSP4 appreciably increased the perseverative tendency provoked by amphetamine. Reduction of dopamine (DA) and NE by intraventricular administration of the catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA), antagonized the effects of amphetamine, such that the frequency of alternation responses was increased and the proportion of perseverative responses was reduced. The effectiveness of the 6-OHDA treatment in antagonizing the amphetamine-induced perseveration was not reduced among mice that were pretreated with desmethylimipramine, which resulted in partial prevention of the NE reduction by 6-OHDA administration. It is suggested that DA neuronal activity contributes to the amphetamine -provoked perseveration , whereas NE stimulation modifies the perseverative tendency by influencing exploration or habituation.

Amines↗

PubMed1984

Responding for brain stimulation: stress and desmethylimipramine.

Stressors influence the activity of biogenic amines and provoke a variety of behavioral disturbances which have been considered as models of human depression. To evaluate the effects of stressors on reward processes, responding for electrical brain stimulation was assessed after acute or chronic shock, and the modification of performance by desmethylimipramine was determined. While escapable shock did not affect performance, inescapable shock reduced responding from the nucleus accumbens and medial forebrain bundle, but not from the substantia nigra. These deficits were were antagonized by repeated stressor application or by desmethylimipramine. Uncontrollable stressors may influence motivational processes subserved by some brain regions, and may thus influence affective state. Chronic stress or desmethylimipramine may induce adaptive neurochemical changes, thereby preventing the behavioral disturbances otherwise produced by stressors.

Adaptation, Psychological↗

PubMed1983

Alteration of exploration and the response to food associated cues after treatment with pimozide.

A series of experiments assessed the effects of pimozide on spontaneous alternation in a Y- and 8-arm radial maze, and on approach to food or cues that had previously been associated with food. Mice treated with pimozide (0.2, 0.4 and 0.8 mg/kg) displayed a dose dependent reduction of alternation performance, without engendering a perseverative tendency and apparently without affecting the course of habituation. When food deprived mice entered an arm of the maze that was baited with a food pellet they consumed the food and remained in the vicinity of the food cup. Moreover, upon retesting in the non-drug state mice still exhibited a preference for cues that had been associated with food. It seems that although pimozide at the doses tested produced a haphazard pattern of exploration, the drug did not alter the rewarding value of secondary reinforcers. Contrary to an anhedonic hypothesis, it is suggested that higher doses of pimozide may actually increase, rather than decrease, the saliency of biologically significant stimuli.

Animals↗

PubMed1983

Region-specific reductions of intracranial self-stimulation after uncontrollable stress: possible effects on reward processes.

Rates of responding for intracranial self-stimulation from the medial forebrain bundle, nucleus accumbens and substantia nigra were evaluated in mice that had been exposed to either escapable shock, yoked inescapable shock or no shock treatment. Whereas performance was unaffected by escapable shock, marked reductions of responding from the medial forebrain bundle and nucleus accumbens were evident following the uncontrollable shock treatment. Responding from the substantia nigra was unaffected by the stress treatment. Uncontrollable shock is thought to reduce the rewarding value of responding for electrical brain stimulation from those brain regions in which stressors are known to influence dopamine activity.

Animals↗