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. Continued exacerbation of the three components of dysregulation by drug and non-drug stressors during late adolescence is posited to result in neuroadaptations that increase the likelihood of developing SUD, particularly in high-risk individuals. Implications for etiologic research as well as clinical and preventive interventions are discussed.

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. We report oscillation of corticosterone levels persisting across all eight cocaine groups. Our data also indicate that the degree of oscillation increases with the intertreatment interval.

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). CSF sIL-2R levels were found to be lower in patients as compared to controls (df = 1, 20; F = 84; p<0.000001).

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. Experiment 1 indicated that a conditioned stimulus (CS)--a distinctive environment--which repeatedly had been paired with COC, would substitute for the last COC injection in sustaining the oscillatory effect. Experiment 2 showed that a previously established CS successfully substituted for all COC injections in first inducing sensitization that was then followed by oscillation. These findings strongly suggest that COC-induced oscillation shares with COC-induced sensitization, the property that both can be conditioned.

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. Oscillation, with or without prior sensitization, has been observed for a number of drug and non-drug stressors, and for various neurochemical and endocrine endpoints. The present studies investigated whether oscillation also occurs in the behavioral and endocrine effects of repeated morphine treatment and if a drug that normalizes the mood swings of bipolar disorder in humans will also attenuate drug oscillation in this animal model. In the first experiment, rats were given 1-5 pretreatments with morphine (15 mg/kg, i.p.), separated by 1-week intervals with the last injection occurring 1 hour prior to being tested for stressor-induced (i.e., 5 seconds, 2-mA electric footshock) hypoalgesia, as measured by latency to paw-lift or jump from a hot-plate. Plasma beta-endorphin also was measured. The second experiment replicated the behavioral findings of the first study and, in addition, assessed the effect of continuous lithium chloride, in the drinking water, on morphine-induced oscillation. Caffeine was used as a partial control for the lithium. The results were that one injection of morphine enhanced stress-induced hypoalgesia and subsequent morphine administrations resulted in oscillation. Beta-endorphin exhibited sensitization but not oscillation, suggesting that it did not mediate oscillation of the behavioral response. In addition, lithium, but not caffeine, eliminated oscillations of the behavioral response without affecting its initial enhancement.

The effects of lithium on a potential cycling model of bipolar disorder.

1. Although bipolar disorder constitutes a major public health problem, with a high risk of suicide and an economic cost exceeding that of unipolar depression, it has received comparatively little attention, particularly at the basic science level. Perhaps as a result of this neglect, there is currently no animal model able to simulate the cyclicity which is its defining characteristic. 2. Consequently, drug development in this area is meager and has proceeded serendipitously rather than empirically. 3. The authors have recently reported that repeated exposure to cocaine and other stressors can induce an oscillation or cycling in a host of neurochemical and physiological systems. 4. In order to test whether such cycling might be of potential relevance to bipolar disorder, the authors examined whether cocaine-induced cyclicity of amphetamine-evoked efflux of dopamine from slices of rat nucleus accumbens and striatum and/or cocaine induced oscillation of a behavior, stress-induced hypoalgesia, could be prevented by lithium, the agent of choice in treating this disease. 5. The authors report that prophylactic treatment with lithium, completely and specifically prevented oscillations in each instance. This may represent an important initial step toward the development of the first cycling model of bipolar disorder.

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., oscillate), as the limits of the physiological system are approached. 2. Evidence for oscillation has been obtained for 6 drug/non-drug stressors and 9 neurochemical or endocrine endpoints. This paper extends the model to a behavioral outcome. 3. In the first experiment, rats were given 0, 1, 2 or 3 pretreatments with cocaine hydrochloride (COC; 12 mg/kg i.p.), separated by 1-week intervals, and then were tested for footshock-induced hypoalgesia (5-sec, 2-mA), as measured by withdrawal latencies from a hot-plate. 4. The second experiment replicated the first and extended the pretreatment sequence to 5 COC injections. 5. In both experiments, shock significantly increased latencies over the no-shock controls. COC enhanced shock-induced hypoalgesia and this sensitization reached its maximum after 2 COC pretreatments. Thereafter, oscillation developed such that the sensitization was attenuated by 3 as compared to 2 COC injections, enhanced by 4 injections, and reattenuated after 5 COC pretreatments. 6. These data complement other findings by demonstrating that the oscillation model extends to a stress-induced behavioral outcome.

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.

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. Our laboratory earlier proposed that this principle might be applied to the treatment of human disorders. It was suggested that the same results might be achieved by giving drugs once every one or two weeks rather than daily, or, even more likely, several-times-daily. 3. Here the authors review the clinical literature relevant to that hypothesis, as it relates to antidepressant therapies. 4. The evidence uniformly supports our earlier thesis that the therapeutic influence of antidepressants would grow with the passage of time, even as their pharmacokinetic actions are declining.

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. This phenomenon has potential major implications for clinical pharmacology. Some human studies have investigated this phenomenon to date. Antidepressant action, with its typical lag in the onset of effects, may be a fruitful paradigm to understand the relevance of TDS for psychopharmacological treatment. In this paper we review these emerging findings, and suggest that clinical pharmacology research should investigate this process further in expanded human studies.

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.

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. 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.

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.e., get stronger, entirely as a function of the passage of time since stressor presentation. This strengthening is revealed when the organism is later exposed to either the original or another stressor. The characteristics of TDS bear a remarkable resemblance to the features of MCS and that similarity is the subject of this manuscript.

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.

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.

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)