Developmental sources of variation in liability to adolescent substance use disorders.

This review provides a synthesis of the literature on the complex sequence of maturational, psychosocial, and neuroadaptive processes that lead to substance use disorders (SUD) in adolescence. A brief overview introduces the concepts of liability to SUD and epigenesis. A theory is presented explaining how affective, cognitive, and behavioral dysregulation in late childhood is exacerbated during early and middle adolescence by family and peer factors, as well as puberty, leading to substance use.

Time-dependent sensitization: the odyssey of a scientific heresy from the laboratory to the door of the clinic.

This review provides both a biological and clinical perspective on Time-Dependent Sensitization (TDS), an ancient amplified memory response to threat manifest in the ability of both drugs and nondrug stressors to induce neuronal and behavioral effects which strengthen entirely as a function of the passage of time following even a single or acute exposure. Evidence is presented to show that TDS may be involved in the development of a spectrum of diseases and how drug regimens based on the principles of TDS could provide a novel and revolutionary means of treating psychiatric and other illnesses.

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.

Low CSF soluble interleukin 2 receptor levels in acute depression. Short communication.

Thirteen patients with DSM-III-R diagnosis of either major depression or bipolar I depression participated in the study. The control group consisted of 10 subjects evaluated for headache or suspected meningitis, none of whom were found to suffer from any organic disease. CSF was withdrawn from all subjects for the measurement of soluble interleukin 2 receptor (sIL-2R).

Cocaine-induced oscillation is conditionable.

We have recently shown that under some circumstances, sensitization produced by a stimulant such as cocaine (COC) can give way, with successive drug administrations, to alternating attenuations and reinstatements of the effect, an outcome that we have termed oscillation. Because sensitization to COC can be conditioned, we inquired whether COC-induced oscillation also was conditionable. The end point used was shock-induced hypoalgesia (paw withdrawal from a hot plate), as we have previously shown that oscillation follows initial sensitization of this measure with one to five pretreatments of 12 mg/kg (IP) of COC spaced at 1-week intervals, with the last COC injection occurring 30 min prior to the footshock.

Time-dependent sensitization--possible implications for clinical psychopharmacology.

Time-dependent sensitization (TDS) has been described in animal models over the past 20 years. It is a phenomenon that occurs in a variety of biological systems, and corresponds to the cellular and systems response to a foreign or stressful stimulus. The exposure to the stimulus triggers the responses typical of that particular biological system, which are progressively amplified with time.

Oscillatory effects of repeated morphine on shock-induced hypoalgesia and beta-endorphin.

Recent research indicates that the sensitization that results from repeated drug or non-drug stress exposure may develop into a pattern of alternating increases and decreases (i.e., oscillation) in response to each subsequent stressor exposure.

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.

Oscillatory-sensitization model of repeated drug exposure: cocaine's effects on shock-induced hypoalgesia.

1. The authors have recently proposed that the sensitization produced by repeated exposure to drugs or stress may give way to an alternating pattern of increases and decreases in the response to each subsequent exposure (i.e.

Clinical application of time-dependent sensitization to antidepressant therapy.

1. A number of animal studies have shown that the actions of numerous drugs can grow or sensitize with the passage of time following even a single treatment, to achieve results equal to or greater than those seen after chronic administration. 2.

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.

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.

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.

Time-dependent sensitization in animals: a possible model of multiple chemical sensitivity in humans.

It often happens in science that clues to the nature of a problem under study come from a completely different, seemingly unrelated, line of investigation. This may be the case with MCS and Time-Dependent Sensitization (TDS), a phenomenon we discovered in rats in the late 1970s and later named. TDS refers to the ability of mild stressors--whether pharmacological or environmental--to induce physiological and behavioral effects which then progress, i.

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.

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.

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.

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.

Conditioned tolerance to the anorectic and corticosterone-elevating effects of nicotine.

We have shown that tolerance to the behavioral effects of nicotine is partially dependent on conditioned environmental cues that predict drug delivery. The present research extends this finding to physiological effects of nicotine by assessing both the appetite-suppressing and adrenocortical-activating effects of nicotine, as measured by plasma corticosterone (CORT). In the first study, male rats on a 22-h food deprivation schedule were injected daily with 0.

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.