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PubMed2003

The pre-clinical behavioural pharmacology of 3,4-methylenedioxymethamphetamine (MDMA).

3,4-Methylenedioxymethamphetamine (MDMA) is a relatively novel drug of abuse and as such little is currently known of its behavioural pharmacology. This review aims to examine whether MDMA represents a novel class of abused drug. MDMA is known as a selective serotonergic neurotoxin in a variety of animal species but acutely it is a potent releaser and/or reuptake inhibitor of presynaptic serotonin, dopamine, noradrenaline, and acetylcholine. Interaction of these effects contributes to its behavioural pharmacology, in particular its effects on body temperature. Drug discrimination studies indicate that MDMA and related drugs produce unique interoceptive effects which have led to their classification as entactogens. This is supported by results from other behavioural paradigms although there is evidence for dose dependency of MDMA-specific effects. MDMA also produces conditioned place preference but is not a potent reinforcer in self-administration studies. These unique behavioural effects probably underlie its current popularity. MDMA is found in the street drug ecstasy but it may not be appropriate to equate the two as other drugs are routinely found in ecstasy tablets

Animals↗

PubMed1992

Stimulus functions of caffeine in humans: relation to dependence potential.

The interoceptive stimulus functions common to drugs of dependence include positive subjective effects, discriminative functions, and reinforcing functions. Data from studies measuring these stimulus functions constitute the objective assessment of a drug's dependence potential. This paper reviews the subjective effects, discriminative stimulus, and reinforcing stimulus functions of caffeine in humans to assess the dependence potential of caffeine. The stimulus effects of caffeine are compared with those of d-amphetamine, a prototypic CNS stimulant that has been studied under similar conditions, to evaluate the relative dependence potential of caffeine. Finally, caffeine's effects are evaluated in terms of generally accepted criteria for defining drug dependence. It is concluded that caffeine partially meets the primary criteria of drug dependence: 1) the majority of caffeine use is highly controlled, but not compulsive; 2) caffeine is psychoactive; and 3) caffeine functions as a reinforcer under certain conditions in humans, but not in animals. Caffeine thus has limited dependence potential. Additionally, although caffeine shares stimulus functions with d-amphetamine, it does so under limited conditions and should be considered to have a relatively lower dependence potential.

Caffeine↗

PubMed2002

Chlorpyrifos shares stimulus properties with pentylenetetrazol as evaluated by an operant drug discrimination task.

Based on previous data from elevated plus-maze tests suggesting a possible anxiogenic effect of the insecticide chlorpyrifos (CPF), the experiment reported here was designed to determine whether this organophosphate (OP) caused an interoceptive discriminative stimulus (IDS) in rats similar to that produced by the anxiogenic drug pentylenetetrazol (PTZ). Rats were trained to discriminate PTZ (20 mg/kg) from saline, using a drug discrimination procedure. When appropriate lever selection was achieved, generalization tests were performed. Tests of various doses of PTZ showed that the drug exerts dose-dependent discriminative control over response. Two more generalization tests were conducted with 250 mg/kg of CPF and 76.8 mg/kg of LiCl for up to 9 days. Results revealed that CPF (250 mg/kg s.c.) produced a PTZ-like IDS that fully substituted for PTZ 24 h after injection and that subjective effects remain for at least 6 days. However, administration of LiCl did not produce any generalization to PTZ on any of the days tested. These results suggest that CPF shares a site of action, and perhaps functional properties, with PTZ that last for several days, are not due to general malaise and should be taken into account in the use of cholinesterase inhibitors in the treatment of different types of dementia.

Animals↗

PubMed1986

Weanlings' transfer of conditioned ethanol aversion from olfaction to ingestion depends on the unconditioned stimulus.

Weanling (21-day-old) rats were exposed to an alcohol odor paired with either an interoceptive (apomorphine-induced illness) or exteroceptive (footshock-induced distress) reinforcer. Twenty-four hours later, ethanol preferences were measured in a locational olfactory test (ethanol vs lemon odor) or an ingestion test (5.6% v/v ethanol vs 0.25% v/v citric acid solution). Weanling rats expressed substantial olfactory aversions, independent of the reinforcer employed in conditioning. During the drinking test, however, only rats that had experienced the ethanol odor paired with internal malaise showed a significant reduction in the intake of the ethanol solution when compared to unpaired controls. Furthermore, rats that had experienced the ethanol odor paired with external distress drank significantly more of the ethanol solution than their controls. These results provide further evidence that olfactory experiences with ethanol can lead to changes in ethanol ingestion, and indicate that the nature of the unconditioned stimulus is critical in establishing the ingestive effect.

Alcohol Drinking↗

PubMed2001

The role of MK-801 in sensitization to stimulants.

Behavioral responses to stimulants can be progressively and persistently enhanced by their repeated administration. This phenomenon, called behavioral sensitization, may underlie substance abuse, psychosis, recurrence in bipolar disorder, or other psychiatric problems. A growing body of work has implicated excitatory amino acid systems in behavioral sensitization. Most of the evidence for a role of excitatory amino acids has come from experiments demonstrating prevention of sensitization by excitatory amino acid antagonists, especially the noncompetitive NMDA receptor antagonist MK-801. Results of studies with MK-801 have varied, however, leading to conflicting interpretations of its relationship to behavioral sensitization. This paper critically discusses the design of experiments that have used MK-801, and interprets data from these experiments in terms of the two leading explanations for the role of MK-801: 1) that sensitization is an example of the family of plastic events that require excitatory amino acid transmission or 2) that interoceptive cues associated with MK-801 lead to state-dependent learning that modifies sensitization because, in essence, the animal does not recognize the stimulant as the same drug if it is given in close association with MK-801. Based on conflicting reports on effects of MK-801, we propose 1) strategies for distinguishing components of MK-801's effects on responses to stimulants, 2) a model that is a hybrid of the two interpretations of its effects on sensitization, and 3) experimental strategies for testing this model.

Amphetamine-Related Disorders↗

PubMed2001

The testosterone metabolite and neurosteroid 3alpha-androstanediol may mediate the effects of testosterone on conditioned place preference.

The abuse of androgens may be related to their ability to produce positive, hedonic interoceptive effects. Conditioned Place Preference (CPP) has been used in many experiments to examine hedonic effects of drugs. This review is focused on studies from our laboratory that utilized CPP to examine potential positive hedonic effects of testosterone (T), and its androgenic metabolite dihydrotestosterone (DHT), and its metabolite 3alpha-androstanediol (3alpha-diol). We hypothesized that administration of a high concentration of 3alpha-diol would produce a CPP, pharmacological concentrations of plasma androgens, and alter androgen receptors (AR) and the function of GABA(A)/benzodiazepine receptor complexes (GBR). In our studies, we observed that systemic 3alpha-diol (1.0 mg/kg) prior to exposure to the non-preferred side of a CPP chamber significantly increased preference for the non-preferred side of the chamber compared to baseline preference and homecage controls. Furthermore, administration of T, DHT, or 3alpha-diol increased levels of these androgens, decreased ARs (decreased seminal vesicle weight and intrahypothalamic AR) and GBR function (decreased GABA-stimulated chloride influx in cortical synaptoneurosomes, and muscimol binding in the hippocampus compared to control groups). With systemic administration of 3alpha-diol that enhanced CPP, concentrations of 3alpha-diol were increased in the nucleus accumbens (NA). Central implants of T, DHT, or 3alpha-diol to the NA also produced a CPP compared to baseline preference and vehicle controls. These data indicate that systemic 3alpha-diol is more effective at enhancing CPP and increasing circulating 3alpha-diol levels than is T or DHT and that central administration of 3alpha-diol to the NA can condition a place preference. These findings indicate that 3alpha-diol produces positive hedonic effects and suggest that T's variable effects on CPP may be due in part to T's metabolism to 3alpha-diol.

Androstane-3,17-diol↗

PubMed2003

Persistent amenorrhoea in weight-recovered anorexics: psychological and biological aspects.

Demographic, psychopathological and hormonal parameters of 22 women with previous anorexia nervosa (AN) presently recovered, in a state of stabilized nutritional normalization for 3 months to 2 years but with persistent amenorrhoea, and of 20 psychophysically healthy age- and sex-matched normally menstruating controls were studied. Body mass index (BMI) values did not differ in patients and controls. Psychological examination, monitored by Eating Disorder Inventory 1, Bulimic Investigation Test Edinburgh, Yale-Brown-Cornell Eating Disorder Scale, and Tridimensional Personality Questionnaire rating scales, showed the persistence of some of the psychopathological symptoms of AN. Hormonal examinations included basal plasma concentrations of follicle stimulating hormone, luteotropic hormone, estrogens (E), progesterone, thyrotropic hormone, FT(3), FT(4) (immunoradiometric assays), leptin (LEP) (enzymatic-linked-immunosorbent assay) and 24 h urinary free cortisol (immunoradiometric assay). Hormone values were the same in patients and controls, except for E and LEP levels, which were significantly lower in patients than in controls. The concentrations of the two hormones were not correlated with the BMI of the patients, but LEP values were correlated negatively with the difference between the present BMI and the preanorexic one. The values of both hormones correlated negatively with some of the psychopathological aspects typical of AN, in particular with high 'body dissatisfaction', 'ineffectiveness', and 'interpersonal distrust' and with low 'interoceptive awareness'.

Adult↗

PubMed2001

The hippocampus and motivation revisited: appetite and activity.

After reviewing the available data regarding the various effects of manipulating (e.g. lesions, chemical or electrical stimulation) the hippocampal formation, Jarrard concluded that this structure likely played a role in motivated behaviors, specifically in general behavioral activation and incentive motivation. Since that time there have been technical advances in lesion techniques and conceptual advances in theories of motivation and learning. Here, we present more recent data that demonstrates the effects of hippocampal lesions on general activity, the utilization of interoceptive state cues, ingestive behaviors, and appetitive responding. We critically evaluate several theories of hippocampal function that have been proposed to explain these data, including the hippocampus as an inhibitor of general activation, as a processor of energy state signals and as a mediator of reward valuation. Finally, we propose that these findings may also be accounted for based on a role for the hippocampus in the learned inhibition of appetitive behaviors. We conclude that, while the specific mechanism of hippocampal involvement may not yet be determined, it is clear that this structure is involved in food-related behaviors and we caution researchers to consider this as a possible confound in studies of learning and memory processes.

Animals↗

PubMed1992

Drug discrimination learning in rats with excitotoxic lesions of nucleus basalis and ventral globus pallidus.

Rats can readily acquire conditional discriminations in which mixtures of drugs serve as compound internal discriminative stimuli. Excitotoxic lesions in the region of the nucleus basalis have been shown to impair the acquisition of conditional discriminations based upon external visual stimuli, but nothing was known about their effects on discrimination of internal stimuli. A baseline of undiscriminated bar-pressing for food reinforcers was established prior to surgery. Lesions were made by infusing either ibotenic or quisqualic acid bilaterally into the basal forebrain (the ibotenate-induced lesions had been shown previously to impair cortical cholinergic function and to produce non-specific damage). After surgery, rats were trained to discriminate effects of drug mixtures using a standard, two-bar operant conditioning procedure. The ibotenate, but not the quisqualate, lesion impaired the acquisition of a discrimination of a mixture of (+)-amphetamine plus pentobarbitone, while neither lesion impaired acquisition with a mixture of (-)-nicotine plus midazolam. The ibotenate lesions also reduced overall rates of responding in both experiments. Thus, the deficit in the acquisition of drug discrimination in rats with ibotenate lesions had some pharmacological specificity, but could not be related easily to disturbances in neocortical cholinergic function. In comparisons with other published data, the results suggest a possible dichotomy in the processing of interoceptive and external information in the basal forebrain, a major target of ventral striatal overflow.

Animals↗

PubMed1998

Differences in heartbeat awareness among males with higher and lower levels of systolic blood pressure.

Recent empirical findings related to the baroreceptor hypothesis indicate that elevated heart rate, pulse pressure, and blood pressure may dampen exteroception and interoception. We thus predicted that persons with elevated systolic blood pressure would be less able to accurately perceive their heartbeats and profit from feedback training. This study examined the plausibility of this hypothesis by exposing 57 male students (11 with elevated SBP levels and 46 with normotensive SBP levels) to the Whitehead heartbeat perception task with, and without, feedback training. Results indicated that participants with elevated SBP levels were more able to accurately perceive their heartbeats prior to, and after, feedback training. Participants with elevated SBP levels also showed a significant increase in heartbeat perception accuracy when they were provided with feedback training while participants with normotensive blood pressure levels did not show a significant response to feedback training. These findings are interpreted in terms of the ballistic perception model of cardiac awareness.

Adult↗

PubMed1996

Carbon dioxide induced panic attack in panic disorder in Japan.

1. The authors investigated the psychological and biochemical factors associated with challenge by 5% CO2-95% O2 inhalation for 20 min. While fifteen healthy people were used as control, thirteen cases who were diagnosed by DSM-III-R as suffering from panic disorder were used as subjects. CO2 inhalation induced panic in 38% of the panic disorder patients, but did not cause panic in any of the control cases (0%). 2. Acute panic inventory (API), heart rate and breathing rate of the panic group increased significantly after CO2 inhalation compared with the values in the control and non-panic groups. 3. Heart rates and systolic blood pressure were significantly higher those in the panic disorder and non-panic groups than in the control group prior to CO2 inhalation. The cortisol values in the panic and non-panic groups also were significantly higher than those in the control group before and after CO2 inhalation. 4. These results suggest elevated activity of the sympathetic nervous system during panic. The significantly higher heart rate, systolic blood pressure and cortisol values of the panic disorder subjects relative to the control before CO2 inhalation may have been due to circumstantial factors. The present findings of convincing evidence for behavioral, physiological, and biochemical hypersensitivity to CO2 in patients with panic disorders are consistent with a model of interoceptive conditioning in these patients.

Acute Disease↗

PubMed1998

A discriminative stimulus produced by 1-(3-chlorophenyl)-piperazine (mCPP) as a putative animal model of anxiety.

1. This study compares behavioral responses to serotonergic (5HT) agonists and pentylenetetrazol (PTZ) in two behavioral paradigms used as animal models of anxiety. PTZ and mCPP were compared for behavioral effects in elevated plus-maze and interoceptive discriminative stimuli they produce. 2. PTZ is a known anxiogenic drug. The discriminative stimuli of mCPP were selected for comparison because this drug produces "anxiety" in human subjects and "anxiety-like" behaviors in rats, and is a potent agonist at 5HT1B/2C receptors and a partial agonist at 5HT2A receptors. 3. In rats trained to discriminate mCPP (1.4 mg/kg, training dose) from saline, PTZ substituted for the mCPP suggesting the "anxiety-like" properties of the mCPP stimulus. The mCPP stimulus was blocked in a dose-related manner by methysergide, a 5HT2A/2C antagonist but not by the anxiolytic diazepam. TFMPP (a 5HT agonist) and DOI (a 5HT2A/2C agonist) substituted for mCPP, but 1-NP (a 5HT1 agonist and 5HT2C/2A antagonist) did not. 4. In animals trained to discriminate PTZ (16 mg/kg) from saline, mCPP and DOI substituted for PTZ, while TFMPP and 1-NP do not. 5. In the elevated plus maze, time spent on the open arms was reduced by mCPP, DOI and PTZ but there was no significant dose effect of TFMPP, or 1-NP. 6. Methysergide blocked the "anxiety-like" behavior in the EPM. 7. These data suggest that the discriminative stimuli produced by mCPP are based upon its selective actions on 5HT receptors and their use in behavioral pharmacology may offer another tool in studying pharmacology of 5HT based anxiogenic and anxiolytic drugs.

Animals↗

PubMed2002

CNS inputs to the suprachiasmatic nucleus of the rat.

The neural circuits that modulate the suprachiasmatic nucleus (SCN) of the rat were studied with the retrograde transneuronal tracer--pseudorabies virus. First-order afferents were also identified using cholera toxin beta subunit. Olfactory processing regions (viz., main olfactory bulb, anterior olfactory nucleus, taenia tecta, endopiriform nucleus, medial amygdaloid nucleus, piriform cortex, and posteriomedial cortical amygdaloid nucleus) were virally labeled. The subfornical organ directly innervates SCN; two other circumventricular organs: organum vasculosum of the lamina terminalis and area postrema provide multisynaptic inputs. Direct limbic afferents arise from lateral septum, bed nucleus of the stria terminalis, amygdalohippocampal zone, and ventral subiculum; multineuronal connections come from the basolateral and basomedial amygdaloid nuclei, ventral hippocampus, amygdalopiriform area, as well as lateral entorhinal, perirhinal, and ectorhinal cortices. Most preoptic regions project directly to SCN. Multisynaptic inputs come from the lateral preoptic region. Hypothalamic inputs originate from the anterior, arcuate, dorsal, dorsomedial, lateral, paraventricular, posterior, periventricular posterior, retrochiasmatic, subparaventricular, ventromedial and tuberomammillary nuclei. Paraventricular thalamic nucleus, intergeniculate leaflet and zona incerta directly innervate SCN. Polyneuronal inputs arise from the subparafascicular parvicellular thalamic nucleus. Brainstem afferents originate from the pretectum, superior colliculus, periaqueductal gray matter, parabrachial nucleus, pedunculopontine nucleus, raphe system, locus coeruleus, nucleus incertus and reticular formation. Nucleus tractus solitarius, C3 catecholamine region, rostral ventrolateral medulla and spinal trigeminal nucleus provide indirect inputs. We propose that the SCN receives feedback primarily from interoceptive systems such as the circumventricular, autonomic, and neuroendocrine systems that are important in the central regulation of glucose metabolism (e.g., insulin and glucocorticoids).

Afferent Pathways↗

PubMed2003

Brainstem prolactin-releasing peptide neurons are sensitive to stress and lactation.

Prolactin-releasing peptide (PrRP) was originally thought to participate in the control of adenohypophyseal prolactin secretion, but its predominant expression in a subset of medullary noradrenergic neurons is more in line with roles in interoceptive and/or somatosensory information processing. To better define functional contexts for this peptide system, immuno- and hybridization histochemical methods were used to monitor the capacity of PrRP neurons to display activational responses to lactation, suckling, acute footshock or hypotensive hemorrhage. PrRP mRNA signal was reduced in the medulla of lactating dams, relative to both male and diestrus female controls, with cell counts revealing 42% and 43% reductions in the number of positively hybridized cells in the nucleus of the solitary tract (NTS) and ventrolateral medulla, respectively. Lactating mothers killed after a 90 min suckling episode (following 4 h pup removal) failed to show induced Fos expression in identified medullary PrRP neurons, despite the fact that responsive neurons were detected in other aspects of the caudal NTS. By contrast, acute exposure to hypotensive (25%) hemorrhage or footshock each activated substantial complements of medullary neurons expressing PrRP mRNA. A substantially greater fraction of the total medullary PrRP population exhibited sensitivity to footshock than hemorrhage (71 versus 39%, respectively). These results suggest that medullary PrRP neurons are negatively regulated by (presumably hormonal) changes in lactation, and are not recruited to activation by suckling stimuli. These populations exhibit differential sensitivity to distinct acute stressors, and may participate in the modulation of adaptive neuroendocrine and autonomic responses to each.

Animals↗

PubMed1997

Effect of the estrous cycle on olfactory bulb response to vaginocervical stimulation in the rat: results from electrophysiology and Fos immunocytochemistry experiments.

To determine whether the stage of the estrous cycle modified the response of olfactory bulb neurons to vaginocervical stimulation, (1) vaginocervical stimulation was applied to animals in proestrus-estrus and metestrus-diestrus and the extracellular electrophysiological response of units in the mitral cell layer of the main olfactory bulb was compared, and (2) the effect of vaginocervical or sham stimulation and the effect of the estrous cycle on the number of neurons stained immunocytochemically for Fos in the main and accessory olfactory bulb was examined. Animals in proestrus-estrus had basal firing rates of 21.8 +/- 1.8 spikes per 5 s and vaginocervical stimulation produced an increase in firing rate. In contrast, animals in metestrus-diestrus had a slower basal firing rate (14.3 +/- 2.3 spikes per 5 s) and vaginocervical stimulation produced a decrease in the firing rate. For animals in proestrus-estrus, vaginocervical stimulation increased the number of Fos-stained cells in the granular cell layer of the accessory olfactory bulb, and in the glomerular and in external plexiform layers of the main olfactory bulb. In contrast, the number of Fos-stained cells decreased in the granular cell layer of the main olfactory bulb after stimulation was applied to animals in proestrus-estrus. The number of Fos-stained cells in the granular layer of the accessory olfactory bulb and the granular and glomerular cell layers of the main olfactory bulb was modulated by the estrous cycle. Therefore, olfactory bulb activity, measured both electrophysiologically and by Fos staining, was affected by the estrous cycle and vaginocervical stimulation, and the two variables interacted. It is likely that integration of interoceptive and environmental stimulation is important for the normal expression of sexual behavior in the female rat.

Animals↗

PubMed1998

Different effects of insulin and 2-deoxy-D-glucose administration on tyrosine hydroxylase gene expression in the locus coeruleus and the adrenal medulla in rats.

The major brain norepinephrinergic nucleus, locus coeruleus, is an important integrating element of extero- and interoceptive stimuli in organisms facing different physiological challenges. We investigated the effects of single and repeated (seven times) exposure to immobilization stress (120 min daily), insulin (5 IU/kg, i.p. daily) or 2-deoxy-D-glucose (500 mg/kg, i.p. daily) administration on tyrosine hydroxylase (TH) mRNA levels, the rate-limiting enzyme in catecholamine biosynthesis, by in situ hybridization in locus coeruleus and by Northern blot analysis in the adrenal medulla of rats. Both the single and repeated immobilization caused a significant increase in TH mRNA levels in the locus coeruleus (1.5-2-fold; p < 0.05) and in the adrenal medulla (about 4-fold; p < 0.05) when compared with unstressed controls. Hypoglycemia induced by a single or repeated insulin administration led to about fourfold (p < 0.01) elevation in adrenal medullary TH mRNA levels, whereas TH mRNA in locus coeruleus remained unchanged when compared with saline-treated controls. In contrast to the effect of insulin-induced hypoglycemia, cellular glucoprivation caused by a single or repeated 2-deoxy-D-glucose administration significantly elevated TH mRNA levels in both the adrenal medulla (fourfold; p < 0.01) and the locus coeruleus (twofold; p < 0.01). Our data suggest that in contrast to immobilization or cellular glucoprivation caused by 2-deoxy-D-glucose administration, insulin-induced hypoglycemia is not a specific or quantitatively sufficient stimulus for induction of TH gene expression in the locus coeruleus, although all these stressors strongly activate the process in the adrenal medulla.

Adrenal Medulla↗

PubMed1982

Discriminative stimulus properties of the vasodilator, hydralazine: differential generalization with alpha 1 and alpha 2 adrenoreceptor drugs.

1. Male albino rats were trained to an operant procedure of lever pressing on an FR-10 schedule of food reinforcement to respond on one lever located on one side of the food cup after an injection of hydralazine (1,25 mg/kg), and to respond on an alternate lever located on the other side of the food cup after an injection of saline. 2. Seven out of ten rats learned the hydralazine-saline discrimination to the rigid criterion of selecting the correct lever for reinforcement on ten consecutive sessions. 3. The elicitation of the discriminative stimulus was dose-dependent (r = 0,98; p less than .001) with 100, 43, and 14% of the subjects selecting the hydralazine lever following hydralazine doses of 1,25; 0,32 and 0,08 mg/kg, respectively (ED50, 0,28 mg/kg). 4. A reduction in response rate and blood pressure was noted only at the 1.25 mg/kg dose. 5. No tolerance to the hypotensive effect of hydralazine was found. 6. In generalization tests, prazosin, an alpha 1 antagonist, was found to produce a dose-dependent generalization to hydralazine (ED50, 1, 25 mg/kg) while clonidine, an alpha 2 agonist, did not generalize. 7. These data indicate that hydralazine produces a discriminable interoceptive stimulus exact site of action of which is not known.

Animals↗

PubMed2003

Principles of drug abuse liability assessment in laboratory animals.

This paper describes the rationale for use of preclinical assessments of abuse liability in laboratory animals, and then discusses "cross-cutting" methodological issues that apply to behavioral evaluations intended to contribute to an abuse liability evaluation package. Issues include use of: (1) positive and negative control conditions; (2) full dose-effect evaluations, (3) multiple dependent measures, (4) pharmacokinetic evaluations to guide choice of dose ranges, (5) a species for which good methodological and comparative data are available to aid interpretation of results, and (6) appropriate methods for the group or single-subject experimental design selected. The remainder of the paper describes basic methodology by which three core pieces of behavioral data required by the Food and Drug Administration for its use in the overall abuse liability analysis can be obtained preclinically. Reinforcing effects are assessed in study of drug self-administration; drug discrimination assesses degree of overlap of interoceptive stimulus effects with relevant comparison drugs; physical dependence potential is determined by assessing whether a withdrawal syndrome occurs after chronic drug administration. Background and methodological issues specific to each procedure are discussed. A key consideration for cross-cutting and specific methodological issues is that choices made enable confident interpretation of both positive and negative results.

Animals↗