Donna Kocan

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. This phenomenon appears to be independent of pharmacokinetic or conditioning factors as well as alterations in dopamine or dihydroxyphenylacetic acid. It suggests that the antidopaminergic influence of acute exposure to a neuroleptic not only persists but continues to sensitize for extraordinary periods of time even after the drug is no longer detectable in the system. Our findings may hold the key to understanding the apparent paradox that although neuroleptics presumably induce their therapeutic actions in disorders such as Tourette syndrome and schizophrenia as well as their parkinsonian effects by blocking dopamine receptors, this antagonism occurs immediately while behavioral changes often require weeks for maximal development.

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/kgd-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.

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.

Elevated Water Intake in Rats Treated Chronically with Amphetamine: Drinking in Excess of Need?

Daily injection of amphetamine (4mg/kg) induces drinking in rats. The present experiments further investigate this new phenomenon, and suggest that the induced drinking is in excess of need. First, we show that rats may be induced to drink unpalatable 2.7% NaCl solution in addition to water after repeated amphetamine injection. Second, the induced drinking persists in the absence of food, occurs between two and six hours after the injection, and is composed of numerous small drafts. Third, desalivate rats also exhibit increased drinking, ruling out oral thirst after amphetamine. Fourth, body fluid loss, which is completely accounted for by increased urine output, can account for about 6 ml of drinking; however, many of the drinking responses are greatly in excess of 6 ml. Finally, the renin-angiotensin system does not seem to play a role in the induced drinking, since neither β-adrenergic nor angiotensin receptor blockers affect the amount drunk. We propose this may be a model paradigm of need-free drinking.

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.

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 organisms 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.

Stress and Enhanced Dopamine Utilization in the Frontal Cortex: The Myth and the Reality

Fashions are seen in science as they are in other arenas of society. Some findings, as certain areas of research, are “in” and others are not. Unfortunately, those results that fit in with the zeitgeist are often subject to less scrutiny than they might otherwise be and perhaps than they ought to be. One such example relates to the currently fashionable and widespread belief that mild stress causes a “selective activation of the mesocortical dopaminergic system.”’ There is no question that there have been a number of reports suggesting an increase in dopamine (DA) utilization in the frontal cortical terminal region of the mescortical DA pathway following several different stressors.l-lo However, questions can and should be raised regarding the issues of (1) whether this is true of all stressors, (2) whether the stressors employed to induce this effect can truly be considered “mild,” and (3) whether the effects of stressors are selective for the mesocortical DA system. Interest in some of these issues began as a result of experiments designed to determine whether prior exposure to a benzodiazepine (BZD) could sensitize the response to a subsequent encounter with the same agent. Our initial finding was that the ability of diazepam (0.5 mg/kg, ip) to antagonize convulsions induced by pentylenetetrazole (PTZ) was significantly enhanced when the same dose of this BZD had been administered once, weeks earlier.I1 We next inquired whether the demonstrated antistress effects of diazepam on DA metabolism in the nucleus accumben~~ and frontal and would show similar evidence of sensitization over tirne.l3 Since PTZ produces stresslike effects, including anxiogenic actions in rats”

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. Our principal findings indicate that: 1) A single pretreatment with 0.5 mg/kg of diazepam significantly enhances the anticonvulsant effect of this same dose administered again two weeks later. 2) One injection of 2.5 mg/kg of diazepam significantly sensitizes the catalepsy and ptosis observed following the administration of haloperidol two weeks but not two hours later. These data provide the first evidence for time-dependent sensitization after benzodiazepines and perhaps by implication, of GABA neurons. They may also suggest that acute stimulation of GABA neurons triggers the progressive development of a long-term, antidopaminergic influence. Finally, they raise the question of whether the progressive anxiolytic influence seen during the first week or so of benzodiazepine therapy depends on the passage of time rather than repeated drug treatment.

Immobilization 12 days (but not one hour) earlier enhanced 2-deoxy-d-glucose-induced immunosuppression: Evidence for stressorinduced 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. Massed or frequent exposures typically induce a reduction in reactivity whereas intermittent or widely spaced exposures increase subsequent reactivity. 3. In the present study, the authors examined whether a single presentation of a temporally remote stressor would increase the immunosuppressive effects of a subsequent stressor. Specifically, the authors investigated the effectiveness of 2-deoxy-D-glucose (2-DG) in suppressing the responsiveness of splenic lymphocytes in male, Sprague-Dawley rats that received either no prior treatment, or immobilization either one hour or 12 days earlier. 4. Splenic lymphocyte responsiveness to the T-cell mitogens, Concanavalin A (Con-A) and phytohemagglutinin (PHA) was suppressed following a single injection of 2-DG. 5. The group exposed to the stress of immobilization one hour prior to 2-DG demonstrated a comparable level of immune suppression. 6. In contrast, animals immobilized 12 days prior to the administration of 2-DG showed a more pronounced suppression of immune responsiveness which was significantly greater than the other groups injected with 2-DG. 7. Neither the stress-induced elevation in corticosterone, nor the suppression of blood lymphocyte reactivity to Con-A and PHA was enhanced by prior immobilization. 8. The results indicate that the immunosuppressive effects of an acute stressor can sensitize with the passage of time.

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. These data suggest that when appropriately timed, strong sympathomimetic stimulation--whether generated by an environmental stressor or a drug--can provide long-lasting protection against the sudden cardiac death potential of local anesthetics. As such, they provide a means for understanding why the incidence of sudden cardiac arrest from one such agent--cocaine itself--is not higher and suggest that an individuals stress history may play a key role in determining vulnerability to the cardiotoxic effect of this compound.