Tail pinch induces eating in sated rats which appears to depend on nigrostriatal dopamine.

Mild tail pinch reliably and rapidly induced eating, gnawing, or licking behavior in all animals tested. Eating was by far the predominant response. Pharmacological analysis of the involvement of the brain catecholamines in tail-pinch behavior suggests that it is critically dependent on the nigrostriatal dopamine system.

Electroconvulsive shock: progressive dopamine autoreceptor subsensitivity independent of repeated treatment.

Repeated electroconvulsive shock, applied to rats, induces a subsensitivity of dopamine autoreceptors located in the substantia nigra as indexed by single-unit electrophysiological techniques. This reduced sensitivity is time-dependent, since effects similar to those seen with repeated treatment were also observed when single electroconvulsive shock was followed by an appropriate treatment-free interval. These data, coupled with identical results after the repeated administration of tricyclic antidepressants, raise the possibility that a reduction of dopamine autoreceptor sensitivity could underlie both electroconvulsive shock and pharmacological treatment of depression.

Norepinephrine-dopamine interactions and behavior.

The proposed hypothesis is directed toward explaining a number of disparate findings in terms of a stress-related interaction between the NE- and DA-containing systems in the brain. The deleterious behavioral effects of decreased DA activity, for example, may be counterbalanced by a similar decrease occurring in NE activity, such compensation being most likely to occur under conditions of stress. This hypothesis may have application to the understanding of neurological and mental disorders such as Parkinson's disease and schizophrenia.

Stress-induced hyperphagia and obesity in rats: a possible model for understanding human obesity.

Mild tail pinch administered to rats several times daily in the presence of sweetened mild induced immediate hyperphagia and led to considerable gain in body weight. Parallels are drawn with stress-induced hyperhagia and altered affective states in obese humans.

Interchangeability of stress and amphetamine in sensitization.

In view of similarities between the behavioral, biochemical, and electrophysiological effects of amphetamine and stress, we tested the hypothesis that presentation of a stressor, mild tail pressure, can sensitize an animal to the later effects of amphetamine, and vice versa. Our findings supported this hypothesis and suggest that amphetamine and at least some stressors may be interchangeable in their ability to induce a sensitization. The data raise the possibility that stress might be a common variable contributing to both amphetamine psychosis and some forms of schizophrenia.

Criteria for rationally evaluating animal models of posttraumatic stress disorder.

Animal models of stress have the potential to provide information about the course and etiology of posttraumatic stress disorder (PTSD). To date, however, there have been no systematic approaches for evaluating the relevance of animal models of stress to PTSD. It has been established in the animal literature that different types of stress paradigms lead to different biobehavioral consequences and that many different factors contribute to differential responsivity to stress. It becomes important therefore to differentiate between factors that are essential to the induction of PTSD-like symptoms and those that influence their manifestations. In the present commentary, we present five criteria that must be fulfilled by animal models of stress for them to be useful to understanding the induction of PTSD. We then evaluate two potential animal models of stress--inescapable shock-learned helplessness and time-dependent sensitization--to illustrate how to more successfully pair animal models of stress with the specific clinical syndrome of PTSD.

Neurochemical and physiological effects of cocaine oscillate with sequential drug treatment: possibly a major factor in drug variability.

Variability in response to drug treatment is a poorly understood problem with severe consequences for both the individual and the health care delivery system. Our data suggest that one source of variability may be inherent in the way physiological systems normally respond to repeated drug exposures. We report that for a wide array of endpoints-amphetamine-evoked, in vitro striatal dopamine efflux, amphetamine and K(+)-evoked efflux of heart norepinephrine and nonevoked plasma levels of corticosterone and glucose-repeated, in vivo cocaine (15 mg/kg IP) administration to male rats precipitated successive oscillations in the magnitude or direction of the organism's responsiveness to subsequent cocaine administration. This capacity of cocaine to produce oscillations in response to successive administrations appears to be due to its foreign/stressful aspect rather than its specific pharmacological properties.

The effects of ethanol on striatal dopamine and frontal cortical D-[3H]aspartate efflux oscillate with repeated treatment. Relevance to individual differences in drug responsiveness.

Numerous inconsistencies in the reported effects of drugs that can be found in both the human clinical and animal experimental literatures have prompted attempts to identify the basis of this variability. Our data suggest that one source may derive from the tendency of many systems to oscillate in their response to repeated drug or stress exposure. In the first experiment a single administration of ethanol to male rats, either 2 or 30 minutes or 2 weeks before sacrifice suppressed amphetamine-induced dopamine efflux from striatal slices. However, when ethanol was given both 2 weeks and 30 minutes before sacrifice, the two treatments significantly attenuate each other's effects. In Experiment 2, the stress of a novel environment (black box) 30 minutes before sacrifice decreased fractional D-[3H]aspartate efflux from the medial frontal cortex. When a single injection of ethanol 1 week earlier was added to black box exposure, it depressed efflux still further. However, adding a third treatment (ethanol at 2 weeks and 1 week + black box at 30 minutes) significantly reversed the effects of the two treatments (ethanol + black box). When a four-treatment chain was used (ethanol at 3, 2, and 1 week + black box at 30 minutes), the attenuation of efflux was reinstated. These data complement other findings from this laboratory showing that repeated stress or drug exposure can lead to an oscillatory pattern of change in the effects of future exposures and, in this way, contribute to variability in drug responsiveness.

Immunological effects of acute and chronic nicotine administration in rats.

We previously demonstrated that acute nicotine administration decreased the response of rat blood leukocytes (PBL) to concanavalin A (ConA). We now extend those findings to a comparison between the effects of acute and prolonged nicotine exposure (ten daily injections), on PBL and splenocytes (SL). A single injection suppressed the PBL response to ConA and phytohemagglutinin (PHA); tolerance developed by ten injections. In contrast, acute nicotine did not affect SL response to ConA and reduced the PHA response only at the highest concentration. Ten nicotine injections enhanced SL responsiveness to PHA. The only change in PBL subsets was an increase in CD8+ cells following ten injections.

Oscillation follows drug sensitization: implications.

This paper begins with the question of whether physiological systems can sensitize indefinitely or whether, at some point, countervailing mechanisms are activated in the organism's attempt to maintain homeostasis. The question is addressed by the review and presentation of considerable data encompassing a host of systems showing that when they reach or approach their biological limits, unidirectional sensitization gives way to oscillation. The implications of this evolution to an oscillatory pattern of response are discussed with regard to cyclic disorders, addictive behavior, and the marked individual differences that characterize drug sensitization.

The role of corticosteroids in nicotine's physiological and behavioral effects.

This paper reviews evidence indicating that adrenal corticosteroids modulate the responsiveness of mice and rats to nicotine. Adrenalectomy increases, and both acute and chronic corticosteroid administration decrease, some of the physiological and behavioral effects of nicotine. One function of adrenal steroids may be to regulate stress-induced changes in nicotine sensitivity. Another is to mediate the development of chronic tolerance when nicotine is given intermittently, and when the resulting tolerance has a learned component. A role of glucocorticoids in the development of tolerance to nicotine is suggested by the findings that a conditioned elevation of plasma corticosterone, which anticipates nicotine delivery, accompanies the development of chronic tolerance and that environmental cues evoke a conditioned corticosterone response, but only after they have become associated with nicotine delivery. The mechanisms by which adrenal steroids modulate nicotine sensitivity are not known, although recent in vitro evidence suggests that steroids can rapidly and reversibly reduce nicotinic receptor function. While most of the data are consistent with the hypothesis that corticosteroids reduce nicotine responsiveness, and thus promote a learned form of tolerance, there are new findings that corticosteroids increase the development of sensitization to the locomotor-activating effects of nicotine. These data suggest that formulations postulating a unidirectional effect of corticosteroids on nicotine's actions (e.g. decreased sensitivity) must be revised to take into account interacting variables such as the specific nicotine effect being studied and whether that effect normally exhibits tolerance or sensitization. Finally, research is presented which indicates that the corticosterone-elevating effects of nicotine, previously reported for experimenter-administered drug, are also produced when nicotine administration is contingent on an operant response, and at a dose which sustains the development of nicotine self-administration in rats. These findings highlight the feasibility of using self-administration models in future explorations of the relationship between adrenal steroids and nicotine function.

Amphetamine stereotypy is not a homogeneous phenomenon: sniffing and licking show distinct profiles of sensitization and tolerance.

Sniffing and licking components of amphetamine-induced stereotypy were studied separately during chronic drug treatment. Sniffing showed a gradual increase, or sensitization, in intensity and duration. By contrast, licking developed tolerance for approximately the first 21 days, followed by a progressive increase. Stereotypy is therefore not a homogeneous phenomenon, and sniffing and licking are probably subserved by distinct neuroanatomic substrates. The sensitization of sniffing behavior may be related to the induction of amphetamine-induced paranoid psychosis in humans.

Persistent sensitization of clonidine-induced hypokinesia following one exposure to a stressor: possible relevance to panic disorder and its treatment.

Based on previous findings of this laboratory that a single exposure to a stressful stimulus can induce a very long-lasting, sensitizing influence on the actions of drugs of multiple clinical and structural classes, the hypothesis was tested that a single stressful event might exert such an action on the alpha-2 norepinephrine agonist clonidine. Male rats received a single injection of the highly stressful convulsant stimulant pentylenetetrazole (PTZ; 40 mg/kg, IP) and were tested for locomotion after treatment with clonidine (25 micrograms/kg, IP) 1 h, 1 week or 2 weeks later. As expected, clonidine itself induced the hypokinesia typically associated with low doses of this compound. More importantly, all groups pretreated with PTZ showed a significant enhancement of this effect. The influence of PTZ 1 or 2 weeks prior to clonidine cannot be explained as simply due to a lingering impairment of locomotion by PTZ, since no hypokinesia was observed when activity in these groups was examined immediately prior to clonidine administration. Such impairment appears, however, to have been a factor in the heightened hypokinesia observed in the group receiving PTZ only 1 h before clonidine. Mass spectrometric analysis of norepinephrine and 3-methoxy-4-hydroxyphenylglycol levels in hippocampus and cortical areas failed to reveal any changes which could explain the persistent behavioral sensitization we observed. Plasma corticosterone determinations confirmed the stressful nature of PTZ but similarly failed to provide an explanation for the observed behavioral sensitization. The major finding of a long-term sensitizing influence on clonidine of an acute stressful experience is consistent with what is known of the precipitants and treatment of panic disorder.

Prior stress attenuates the analgesic response but sensitizes the corticosterone and cortical dopamine responses to stress 10 days later.

This study demonstrates that pre-exposure to stress influences subsequent effects of stress on pain sensitivity (stress-induced analgesia) and on plasma corticosterone and brain catecholamine activity. Animals exposed to a 30 min shock session (S1 = 8, 5.0 s shocks) 10 days earlier showed a significant attenuation of shock-induced analgesia, as measured by increased latency of tail withdrawal from a hot water bath immediately after a 40 s, 1.6 mA footshock (S2). Animals exposed to shock 10 days before testing also exhibited a higher plasma corticosterone response to testing than did all other groups. Norepinephrine (NE) levels in the frontal cortex and dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels in the frontal cortex and nucleus accumbens were not altered in any group. However, the DOPAC/DA ratio in the frontal cortex was increased by analgesia testing, and this increase was enhanced only by the combination of shock 10 days before testing and shock immediately before the test (S1 + S2). These results are consistent with previous reports from this laboratory which indicate that an animal's acute response to stress is strongly influenced by its past history of stress.

Amphetamine or haloperidol 2 weeks earlier antagonized the plasma corticosterone response to amphetamine; evidence for the stressful/foreign nature of drugs.

We inquired whether a single exposure to amphetamine (AM) or haloperidol (HALO) could modify the plasma corticosterone (CORT) response to a second injection of AM 2 weeks later. Male rats were injected with 4 mg/kg d-AM sulfate and tested for water intake for 5 h before sacrifice. Overall, AM induced water intake but none of the pretreatments altered this effect. By contrast, preexposure to AM, HALO or its vehicle 2 weeks earlier prevented the elevation of plasma CORT obtained when AM was administered without pretreatment. A combined pretreatment of HALO or its vehicle with AM produced an even greater blockade of AM-induced CORT elevation. Manipulations which prevented AM-induced drinking reduced the effectiveness of AM pretreatment in attenuating AM-induced elevation in CORT, suggesting that the pretreatment may have been sensitizing the effectiveness of a coping response--drinking--in reducing the CORT effect. Our findings also indicate that a dopamine agonist (AM), a dopamine antagonist (HALO) and a nonspecific stressor (acidic vehicle) can all induce the same, long-lasting action on CORT. This strongly suggests that the effects of AM and HALO in this instance cannot be explained in terms of their pharmacological actions, which are opposite to one another, but instead relate to their properties as stressful/foreign agents to the organism.

Acute stress or corticosterone administration reduces responsiveness to nicotine: implications for a mechanism of conditioned tolerance.

We have shown that conditioned tolerance develops to some of the behavioral and endocrine effects of nicotine in rats. Other investigators have suggested that tolerance to multiple nicotine injections in mice may be due, in part, to elevated plasma corticosterone (CORT) levels, since repeated nicotine injections are associated with elevated CORT, chronically elevated CORT reduces nicotine responsiveness and adrenalectomy disrupts nicotine tolerance. Three experiments tested the feasibility of this hypothesis, as a mechanism for conditioned nicotine tolerance in rats, by determining whether acute administration of CORT or manipulations that increase adrenocortical activity reduce nicotine responsiveness. In experiment 1, male rats were injected IP with CORT (1 mg/kg), vehicle (ETOH + distilled water) or no injection 10 min before nicotine (0.75 mg/kg, SC) and tested for nicotine-induced analgesia every other day for 10 days. A significant reduction in withdrawal latencies was obtained for CORT pretreated rats compared to animals given only nicotine. A similar reduction was produced by the vehicle pretreatment, which itself induced an elevation of endogenous CORT. Experiments 2 and 3 established that similar effects could be produced by doses of CORT as low as 0.125 mg/kg or by exposure to a novel environment which also elevated CORT levels. Results also suggest that a conditioned release of endogenous CORT was triggered by stimuli associated with nicotine delivery. These data are consistent with the hypothesis that a conditioned release of CORT could contribute to the development of tolerance to some of nicotine's effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Cortical beta-adrenergic subsensitivity after desmethylimipramine may depend on the passage of time rather than daily treatment.

Earlier data from our laboratory indicated that the effects of antidepressants on dopamine autoreceptors are dependent on the passage of time rather than repeated treatment. The present study inquired whether the same might be true of cortical beta-adrenergic receptors. Our findings indicate that beta-adrenergic subsensitivity is obtained whether rats were treated with desmethylimipramine daily for 17 days or only on day 1 and day 17. These data suggest that antidepressant-induced changes in beta-receptor sensitivity may, like those in dopamine autoreceptors, also depend on the passage of time.

Tail pinch-induced eating, gnawing and licking behavior in rats: dependence on the nigrostriatal dopamine system.

Mild-tail-pinch induces a syndrome of eating, gnawing and licking behavior in rats in the presence of food. Detailed behavioral, pharmacological and biochemical analyses of this phenomenon resulted in the following conclusions. (1) This is an unusually reliable phenomenon, demonstrable in each of more than 200 animals tested. (2) Eating is by far the predominant response to tail-pinch. (3) Tail-pinch behavior is critically dependent on the nigrostriatal dopamine system. (4) There are striking pharmacological parallels between tail-pinch behavior and schizophrenia.