Long-term oscillation of corticosterone following intermittent cocaine.

We have shown that repeated administration of cocaine, as well as other drugs and nondrug stressors, can induce alternating increases and decreases in several neurotransmitter and endocrine endpoints, which we call oscillation. Oscillation studies have typically used 3-4 pretreatments with cocaine or other agents, raising the question of whether oscillation lasts beyond this point. Using plasma corticosterone as our endpoint measure, we therefore inquired whether oscillation would persist across eight administrations of cocaine over a 28-day period.

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.

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.

One brief exposure to a psychological stressor induces long-lasting, time-dependent sensitization of both the cataleptic and neurochemical responses to haloperidol.

Rats were exposed for 10 minutes to one of several enclosures graded in novelty. In one experiment they were then simply sacrificed and plasma corticosterone determinations made in order to obtain an index of the relative stressfulness of these enclosures. In a second experiment the animals received haloperidol and were tested for catalepsy, 2 hours or two weeks following the novel experience.

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.

One experience with 'lower' or 'higher' intensity stressors, respectively enhances or diminishes responsiveness to haloperidol weeks later: implications for understanding drug variability.

This laboratory has previously shown that acute exposure to a variety of brief stressful events can have a very long-lasting influence on subsequent responsiveness to pharmacological and non-pharmacological stressors. In some cases the response to these agents is enhanced, while in others it is diminished: the common denominator being that in each instance the influence of the initial stressor grows stronger with the passage of time. Here, we identify one factor that determines which time-dependent effect is manifest.

Immobilization 12 days (but not one hour) earlier enhanced 2-deoxy-D-glucose-induced immunosuppression: evidence for stressor-induced time-dependent sensitization of the immune system.

1. Prior exposure to a stressor can either increase or decrease subsequent behavioral, neurochemical, and endocrine reactivity to stress, depending on the pattern of stress exposure. 2.

Anticonvulsant and other effects of diazepam grow with time after a single treatment.

The hypothesis was tested that some of the effects in rats of the prototypical benzodiazepine, diazepam, would grow (i.e., sensitize) with the passage of time after acute administration as we had previously observed following stimulants, antidepressants, neuroleptics and other compounds.

A single exposure to cocaine or immobilization stress provides extremely long-lasting, selective protection against sudden cardiac death from tetracaine.

Exposure of rats to one injection of cocaine (35 mg/kg, i.p.) or a single four-hour period of immobilization protected them from the virtually instantaneous death but not from the later, seizure-related death seen in untreated controls following administration of the local anesthetic, tetracaine, 1-4 weeks later.

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.

One stressful event blocks multiple actions of diazepam for up to at least a month.

Based on recent findings of this laboratory, the hypothesis was tested that a single stressful encounter might have a persistent antidiazepam influence. Our results indicate that one exposure to a brief stressful event up to at least one month earlier prevented completely the effect of diazepam on pentylenetetrazole-induced changes in dopamine in the rat frontal cortex, elevations of plasma corticosterone levels and seizures.

Behavioral effects of a single neuroleptic treatment grow with the passage of time.

The principal finding of this manuscript is that the incidence of catalepsy observed in the rat after a single administration of low, clinically relevant doses of the dopamine receptor antagonists and antipsychotic agents, haloperidol and fluphenazine hydrochloride, grows over time such that one re-exposure to the same compound up to 8 weeks later results in a marked enhancement (i.e. sensitization) of this response.

Amitriptyline sensitization of a serotonin-mediated behavior depends on the passage of time and not repeated treatment.

Daily treatment for 10 days with either amitriptyline or the tricyclic muscle relaxant, cyclobenzaprine, increased the incidence of head-twitch behavior in response to 5-hydroxytryptophan (5-HTP) when this was examined two days later. Only one day of amitriptyline treatment followed by an 11-day hiatus before administration of 5-HTP also sensitized the head-twitch response whereas similar amitriptyline treatment followed by 5-HTP one hour later failed to do so. These data provide the first evidence for time-dependent sensitization of brain serotonin systems.

Differences among 'serotonergic' anorectics in a cross-tolerance paradigm: do they all act on serotonin systems?

Rats on a 4 hr/day feeding schedule showed anorexia after i.p. injections of several 'serotonergic' agents.

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.