Drug-induced Behavior Research Articles

The description of rat drug-induced behavior: Kinematics versus response categories

The study of rat drug-induced locomotor behavior is largely based on the assumption that behavior consists of a sequence of response categories performed by the whole animal one at a time. By analysing this behavior under (+)-amphetamine (5 mg/kg), we illustrate how even a precise definition of such categories may not be sufficient for the establishment of behavioral variables that have a "physiological reality." We describe the changes of relation between the parts of the rat's body in reference to selected coordinate systems, and show that a great variety of locomotor patterns observed under amphetamine can be reduced to as few as 3 descriptive component-variables. These continuous and relatively independent variables, which behave predictably in the course of drug action, operate simultaneously. Variations in their relative timing of onset and termination account for the apparent variability in observed behavior. The economy and generality of a description based on these variables suggest the existence of corresponding central mechanisms of control.

Effects of anxiety drugs on the modification of the acoustic startle reflex by noise gaps

The acoustic startle reflex was modified by presenting gaps (0–30 ms) in a continuous noise (70 dB) before the startle eliciting stimulus. The effects of midazolam (0.4–1.8 mg/kg, IP), DMCM (0.1–0.4 mg/kg, IP), buspirone (5–20 mg/kg, PO), 8-OH-DPAT (0.5–8 mg/kg, IP), and clonidine (0.009–0.08 mg/kg, IP) on startle amplitudes (reflecting sensorimotor reactivity) on the one hand, and on gap inhibition of the startle reflex (a measure of temporal acuity) on the other hand, were investigated. The results showed that midazolam and clonidine attenuated sensorimotor reactivity dose-dependently. DMCM had no systematic effect on sensorimotor reactivity. Buspirone and 8-OH-DPAT increased sensorimotor reactivity dose dependently. Furthermore, midazolam and clonidine did not affect the neuronal systems underlying inhibition of the startle reflex. In contrast, DMCM and buspirone increased inhibition dose-dependently, and 8-OH-DPAT first increased and than decreased inhibition of the startle reflex. The possibility that drug-induced behavior affected the startle reflex was discussed.

Asymmetries in thigmotactic scanning: evidence for a role of dopaminergic mechanisms

In two experiments, the influence of spontaneous asymmetries in thigmotactic scanning was analyzed on spontaneous and drug-induced behavior in the rat. The side of the face with which an animal performed more scanning in a baseline test was defined as the dominant vibrissae side. In experiment 1, repeated testing of either spontaneous thigmotactic scanning, or scanning after apomorphine or amphetamine, yielded no evidence that rats would preferably use one side of the face for scanning, when re-exposed to the same environment. However, an asymmetry in turning was observed both under apomorphine and amphetamine, that is, turning away from the dominant vibrissae side. In experiment 2, an influence of spontaneous asymmetries in scanning was found on behavioral asymmetries induced by unilateral vibrissae removal. Only animals, in which the vibrissae of the non-dominant side had been removed, showed more scanning with the intact vibrissae side, both undrugged and after apomorphine. Turning under apomorphine was more pronounced in animals in which the vibrissae on the dominant side had been removed. These animals showed an asymmetry in turning towards the intact vibrissae side. Furthermore, in both experiments we found evidence for left/right differences in turning or scanning. The results are discussed with respect to possible endogenous substrates of asymmetry, such as within the mesostriatal dopamine system.

Drug-induced purposeless chewing: animal model of dyskinesia or nausea?

Drug-induced purposeless chewing movements in rodents are often considered to represent movement disorders or dyskinesias. We have compared the ability of drugs to induce chewing and retching or emesis in squirrel monkeys; such studies are not possible in rodents, which do not vomit. Acute administration of oxotremorine (3.3-33 micrograms/kg IM), SKF38393 (1-30 mg/kg SC) or ipecacuanha (0.5-0.75 mg/kg PO) caused dose-related increases in purposeless chewing which was frequently associated with retching and emesis. Treatment with haloperidol (0.015-0.06 mg/kg IM) did not induce chewing. Rather, haloperidol decreased spontaneous chewing at doses of 0.03 and 0.06 mg/kg. Our findings indicate that at least some drug-induced oral behaviours in rodents may reflect nausea rather than dyskinesia.

The Potential for Mental Status Changes Associated with Systemic Absorption of Anticholinergic Ophthalmic Medications: Concerns in the Elderly

Several cases have been reported of anticholinergic toxicity following the administration of commonly used parasympatholytic cycloplegics and mydriatics. Cases have been reported in children, adults, and the elderly. The risk of developing mental status changes secondary to anticholinergic ophthalmic medications is of particular concern in the elderly. Drug-induced mental status or behavior changes should not be mistaken for exacerbation of an underlying disorder or the onset of a new disease (e.g., Alzheimer's disease, dementia). Clinicians should be aware of these potential complications, monitor for changes in mental status, and take appropriate action.

Enhancement of apomorphine and l-amphetamine-induced behaviors by magnesium

The behavioral effects of magnesium suggest that this divalent cation has psychomotor stimulant-like properties. Because deficiencies of this cation lead to reductions in drug-induced behaviors dependent on the levels of norepinephrine and dopamine, and numerous in vitro studies have demonstrated a relationship between magnesium and catecholamine activity, the present experiments investigate whether administration of magnesium will lead to increases in stereotyped and locomotor behaviors induced by apomorphine and l-amphetamine. Such changes would suggest that magnesium is increasing the activity of catecholamines in vivo. The results demonstrate that magnesium dose dependently increases the potency of these drugs by producing greater behavioral effects at certain drug doses, by producing shifts to the left in dose-response functions, and by producing decreases in the ED 50 as dose of magnesium increases.

A different look at measurement and interpretation of drug-induced stereotyped behavior

Stereotyped behavior is a term used widely to describe behavior induced by psychostimulant drugs. However, a historical examination of what is meant by this term shows that different researchers use it to label different behavioral manifestations of the drug-induced syndrome. Moreover, the drug-induced syndrome has not been described adequately. We suggest that to do so requires a morphogenetic approach that will reveal the structure of the behavior as it unfolds during the course of the drug’s action. This can be accomplished by decomposing the observed motor activity into independent kinematic variables. Using this approach, we have identified three kinematic variables (snout contact, progression, and turning) whose coupling explains much of the structure of behavior under apomorphine. Moreover, these variables can help us to understand the topography of drug-induced behavior in different environments and enhance the use of behavior to measure drug action.

Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: immunological aspects, spontaneous and drug-induced behaviour, and dopamine release.

We have used a rat model of Parkinson's disease (PD) to address issues of importance for a future clinical application of dopamine (DA) neuron grafting in patients with PD. Human mesencephalic DA neurons, obtained from 6.5-8 week old fetuses, were found to survive intracerebral cell suspension xenografting to the striatum of rats immunosuppressed with Cyclosporin A. The grafts produced an extensive new DA-containing terminal network in the previously denervated caudate-putamen, and they normalized amphetamine-induced, apomorphine-induced and spontaneous motor asymmetry in rats with unilateral lesions of the mesostriatal DA pathway. Grafts from an 11.5-week old donor exhibited a lower survival rate and smaller functional effects. As assessed with the intracerebral dialysis technique the grafted DA neurons were found to restore spontaneous DA release in the reinnervated host striatum to normal levels. The neurons responded with large increases in extracellular striatal DA levels after the intrastriatal administration of the DA-releasing agent d-amphetamine and the DA-reuptake blocker nomifensine, although not to the same extent as seen in striata with an intact mesostriatal DA system. DA fiber outgrowth from the grafts was dependent on the localization of the graft tissue. Thus, grafts located within the striatum gave rise to an extensive axonal network throughout the whole host striatum, whereas grafted DA neurons localized in the neocortex had their outgrowing fibers confined within the grafts themselves. In contrast to the good graft survival and behavioural effects obtained in immunosuppressed rats, there was no survival, or behavioural effects, of human DA neurons implanted in rats that did not receive immunosuppression. In addition, we found that all the graft recipients were immunized, having formed antibodies against antigens present on human T-cells. This supports the notion that the human neurons grafted to the non-immunosuppressed rats underwent immunological rejection. Based on an estimation of the survival rate and extent of fiber outgrowth from the grafted human fetal DA neurons, we suggest that DA neurons that can be obtained from one fetus may be sufficient to restore significant DA neurotransmission unilaterally, in one putamen, in an immunosuppressed PD patient.

C3a anaphylatoxin in the rat hypothalamus potentiates drug-induced behaviors and is antagonized by the desarginated derivative C3ai

C3a anaphylatoxin in the rat hypothalamus potentiates drug-induced behaviors and is antagonized by the desarginated derivative C3ai

A behavioral analysis of the effects of amphetamine on play and locomotor activity in the post-weaning rat.

Amphetamine has been shown to canalize or direct the activity of a young rat towards ethologically relevant stimuli. In the five-day-old, amphetamine increases the speed of approach to the nipple of an anesthetized dam; in the 15-day-old, amphetamine increases motor activity and directs it toward an anesthetized adult, however, in the juvenile rat amphetamine reportedly disrupts species-specific behaviors such as huddling and play. The present experiments further assessed the effects of amphetamine in the post-weaning rat by measuring drug-induced behaviors in the presence of an alert and anesthetized companion. In Experiment 1, subjects were videotaped in the presence of an alert non-treated, same-age rat and components of play, a predominant behavior of the post-weaning rat, were recorded. Results confirmed previous reports that low doses of amphetamine (0.5 mg/kg) disrupt play behavior, however, in the present experiment higher doses of amphetamine (1.0 mg/kg) did not disrupt the percentage of time spent in play. Further analysis of drug-induced behavior revealed that the 1.0 mg/kg amphetamine-injected rat engaged in play with the companion, although the drug-treated animal did exhibit marked alterations in the flexibility of its motor patterns. The second experiment confirmed that amphetamine did not disrupt the amount of time a juvenile rat spent with an anesthetized age-mate. In fact, amphetamine-induced activity was directed towards the anesthesized same-age rat. Following amphetamine treatment, all subjects were active nearly 100% of the observation period whether they were tested alone or in the presence of an anesthetized same-age rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Enigma of drug-induced altered states of consciousness among the !kung bushmen of the kalahari desert

This article examines data presented in Katz' book, Boiling Energy: Community Healing among the Kalahari Kung, particularly with regard to plant drugs present in the community during the 1968 visit. The author argues that the similarity of the Bushman trance state, kia and that of drug-induced altered states of consciousness has been paid too little attention in the research, and that an enigma currently exists with regard to the degree to which plant drugs may have influenced the !Kung trance phenomenon and healing beliefs. The author discusses the existing evidence for plant drug use based on Katz' research and the specimens currently on hand at the Harvard Botanical Museum herbarium, and presents a Table which contrasts drug-induced behaviors and ideologies of societies known or suspected to have used mind-altering drugs with similar behavior/beliefs of the!Kung. It is suggested that the influence of a number of psychoactive drugs may have played a much more pivotal role in Bushman behavior and belief than is generally acknowledged.

Spontaneous and drug-induced locomotor activity after partial dopamine denervation of the ventral striatum.

Spontaneous and drug-induced locomotor behavior was investigated in rats subjected to lesions of the ventral striatum, using the neurotoxin 6-hydroxydopamine to produce selective depletions of dopamine. Locomotor activity changed with time after lesion. At 2 weeks postoperative less spontaneous rearings were observed compared to controls, a reduced response to 1.0 mg/kg amphetamine and an increased response to 0.1 mg/kg apomorphine. These changes were not observed 9 weeks postoperative; that is, spontaneous locomotor activity and the response to amphetamine were not different from those of controls, and the rearing response to apomorphine was now reduced. The neurochemical assays of the lesioned ventral striate showed equivalent dopamine depletions of about 48% in both lesion groups relative to controls.

The role of afferents from the parafascicular-centromedian complex in the excitatory striatal neuronal response to dexamphetamine in freely moving animals

1. The striatal neuronal response to dexamphetamine, 2.5 mg/kg, was studied in normal freely moving animals and in freely moving animals with unilateral lesions of the parafascicular-centromedian complex. 2. Whereas dexamphetamine produced predominantly excitation of striatal neurons in control animals, the predominant response in lesioned animals was inhibition. 3. In lesioned animals dexamphetamine-induced behavioral activation was unchanged. 4. It is concluded that the PF-CM complex plays an important role In the striatal neuronal response to dexamphetamine in freely moving animals and may be one of the neural substrates conveying sensory feedback from drug-Induced behavior to the striatum.

The time and space machine: continuous measurement of drug-induced behavior patterns in the rat.

Because of the increasing demand for refined techniques to record drug-induced motoric changes, we designed and evaluated a computer monitoring system with continuous measurement of different parameters of rat motor activity. This system is particularly useful for chronic drug studies because it can characterize patterns of behavior and combines the residential and experimental environments, thus enabling automated behavioral measurement without experimenter intervention. Behavioral responses are detected by a capacitance-sensing device that generates bipolar analog voltages representing the location of the rat in its home cage. These voltages are first transduced, then amplified, and finally converted to digital signals in a computer that processes the input using algorithms to define specific responses. The technique pinpoints the exact location of the rat and identifies many kinds of responses simultaneously (e.g., rearing, circling) by tracking the path of movement or setting threshold limits. Some threshold values (representing rearing, gross movements, fine movements) were validated against stereotypy rating scales for amphetamine, apomorphine, and beta-phenylethylamine. Among these drugs, quantitatively distinct response profiles were obtained. The system has wide applications for studies of biological rhythms, sleep, aging, and drug toxicology.

Calcitonin depresses amphetamine-induced locomotor activity

Synthetic salmon calcitonin (sCT), given subcutaneously (6.4 micrograms/kg) or intracerebroventricularly (ICV, 30-600 ng), depressed amphetamine-induced locomotor activity in rats by more than 50%. ICV injection of sCT, either three hours or immediately before intraperitoneal amphetamine (1-3 mg/kg), significantly reduced the amphetamine-induced activity. In the absence of amphetamine, sCT had no effect on locomotor activity during the first 100 minutes after treatment. These results show sCT can act centrally to modify drug-induced behavior and may be related to reports of calcitonin receptors and calcitonin-like peptides in the brain.

Effect of age, clonidine or propranolol on behavioral toxicity induced with digitoxin in mice

In three experiments, behavioral toxicity induced by 5 different dose levels of digitoxin was investigated in mice that were treated with either clonidine or propranolol or were either young (70–140 days), middle aged (240–260) or old (450–600). Observed on four drug-induced behavior categories, it was found that both clonidine and propranolol attenuated the toxic effects of relatively low dose levels of digitoxin, while at higher digitoxin dose levels only propranolol was able to reduce significantly the ED 50 and the LD 50. The results were discussed in terms of adrenergic mechanisms mediating digitoxin toxicity. Aged mice were found to be the least and middle aged the most resistant to the toxic effects of digitoxin.

Use of a programmable protocol timer and data logger in the monitoring of animal behavior

The quantitative assessment of animal behavior by continuous or intermittent observation often requires much time and intense concentration. We have developed an accurate and convenient system which allows one observer to monitor up to four animals and record two types of behavior simultaneously. The system uses an inexpensive portable microcomputer including keyboard, video monitor, and cassette recorder. A program written in BASIC generates timed visible and audible cues, and tabulates data entered through the keyboard. The total number of occurences of a particular behavior (e.g., “wet dog” shakes) and the frequency of a second behavior (e.g., grooming) may be measured. Frequency data, based on intermittent observations, is processed for histogram display. The results may be copied from the video display or recorded on tape for further statistical analysis. The system has provided a convenient way to time experiments and collect data on drug-induced behavior in over 800 rats.

Gonadectomy attenuates turning behavior produced by electrical stimulation of the nigrostriatal dopamine system in female but not male rats

Rotational behavior induced by electrical stimulation of ascending dopamine neurons is used as a behavioral model to investigate gender and hormonal influences on extra-hypothalamic dopamine systems. Steroid hormones influence the metabolism of many dopaminergic drugs, and therefore this approach avoids the complications inherent in drug-induced behavior models of dopamine activity. We found that gonadectomy of female, but not male, rats severely attenuates electrical stimulation-induced rotational behavior. This suggests that some female gonadal steroid hormone(s) may modulate the activity of ascending dopamine neurons, while male gonadal hormones do not.

Studies on possible mechanisms of action of electroconvulsive therapy; effects of repeated electrically induced seizures on rat brain receptors for monoamines and other neurotransmitters.

There is evidence that repeated electroconvulsive shocks (ECS) in rats potentiate dopamine (DA)-, serotonin (5HT)- and alpha-noradrenergic (alpha-NA)-mediated drug-induced behaviour and reduce opiate-induced behaviours. These studies suggest changes at the level of the receptor or beyond. However, high affinity in vitro 3H-ligand binding studies in brain membranes from ECS-treated control rats failed to demonstrate generalized ECS-induced changes in 5HT, DA, alpha-NA or opiate receptor binding. Binding of the beta-receptor ligand dihydroalprenolol (3H-DHA) was significantly reduced in ECS-treated rat brain membranes. This may be secondary to effects on NA neurones since ECS-induced reduction of 3H-DHA binding did not occur in animals with 6-hydroxydopamine-induced depletion of cortical noradrenaline. In conjunction with other studies, the results suggest that electroconvulsive therapy may have a noradrenergic mechanism of action.

The effect of amygdala kindling on spontaneous and cocaine-induced motor activity and lidocaine seizures.

Interactions of amygdala kindling and drug effects were explored in two experiments. Pretreatment with cocaine (40 mg/kg, IP) for 10 days did not significantly affect the rate of amygdala kindling compared to saline or non-kindled controls. In contrast, daily amygdala kindling with 200 microA for 0.5 s for 20 days substantially altered subsequent behavioral responses in a long-lasting fashion. Animals showed decreased spontaneous vertical rearing activity, as well as decreased cocaine-induced vertical activity. In contrast, they were more reactive to the direct dopamine receptor agonist apomorphine. Eighteen days following completion of amygdala kindling, kindled animals were more sensitive to lidocaine-induced convulsions; 88% of kindled animals, but only 24% of the implanted sham-stimulated controls, had seizures. These data suggest that amygdala kindling may produce long-lasting changes in selected spontaneous and drug-induced behaviors, as well as convulsive thresholds. Possible physiological and neurological changes underlying this altered responsivity are discussed.