Central mediation of the conditioned taste aversion induced in rats by harmaline

The assumption that drugs used as unconditioned stimuli in conditioned taste aversion (CTA) studies act centrally was tested by comparing the effects of systemic and intracerebral injections of harmaline hydrochloride (H) in 340 rats. Intraperitoneal injection of 5–20 mg/kg but not of 2.5 mg/kg H administered 5 min after 15-min saccharin (0.1%) drinking decreased saccharin-water preference in a two-choice retention test, performed 48 h later, from 55% to 20%. Since CTA was not diminished when H (10 mg/kg) was injected into rats anesthetised immediately after saccharin drinking by pentobarbital (40 mg/kg), H (1.7–50 g) was administered intracerebrally to anesthetised rats fixed in the stereotaxic apparatus. Injection of 3–6 g H into the inferior olive elicited CTA comparable to that of systemic injection of 10 mg/kg H. Injections of 6 and 50 g H into cerebellum and bulbar reticular formation elicited weaker CTA while neocortical, hypothalamic and mesencephalic applications were ineffective. CTA could also be elicited when 50 g but not 6 g H was injected into the inferior olive 1 or 2 h after saccharin drinking. This delay-dependent effect and failure of non-contingent H administration to change saccharin preference indicates that the H-induced CTA is not contaminated by a non-specific increase in neophobia. It is concluded that H probably elicits CTA by activation of caudal bulbar structures, including the nucleus of the solitary tract, area postrema and lateral reticular formation.     

The competitive NMDA antagonists CGP 43487 and APV potentiate dopaminergic function

The administration to rats of different doses of the non competitive NMDA receptor blocker MK-801 (0.03–1 mg/kg IP) induced stimulation or reduction of locomotor activity, depending on the dose, whereas the competitive NMDA antagonists CGP 43487 (0.188–6 mg/kg IP) and APV (2.5–20 g/rat ICV) inhibited locomotion at the highest doses. Unlike MK-801 and APV treatment, the administration of CGP 43487 did not induce impairment of rota-rod test performance. Both competitive and non-competitive NMDA antagonists, at doses devoid of any behavioral effect per se, potentiated the responses elicited by apomorphine (0.25 mg/kg SC). In particular, the occurrence of episodes of licking was weakly affected by MK-801 administration, but significantly increased by CGP 43487 and APV treatment; the presence of gnawing was augmented by all the pretreatments; sniffing, locomotion, grooming and rearing occurrence were not affected by the administration of NMDA antagonists. The results suggest that the competitive antagonists which facilitated dopaminergic function without causing motor impairment could be useful supplements in the treatment of Parkinson's disease.     

Safety signal withdrawal: a behavioural paradigm sensitive to both “anxiolytic” and “anxiogenic” drugs under identical experimental conditions

A new method involving the blockade of operant behaviour induced by the withdrawal of a conditioned signal for safety without presentation of a punishment signal has been developed for studying drugs with anxiolytic or anxiogenic properties. For this purpose, rats were trained under two alternating components of a multiple schedule of reinforcement FR8 (food)/FR1 (food) + RR 50% (shocks randomly delivered with 50±15% of the presses). The nonpunished and punished periods were signalled by one cue light above the right lever (safety signal) or the left lever (punishment signal), respectively. On the test session (safety signal withdrawal), the safety signal was turned off at the end of the first nonpunished period, but the punishment signal was not presented (every press was food rewarded and no shocks were delivered). During this period (4 min), rats exhibited a strong blockade of responding that lessened over time. This suppression seemed not to be caused by intervening events such as novelty, temporal conditioning, schedule of food delivery or ambiguity of the signal presented. The behavioural blockade induced by withdrawal of the safety signal was reduced by benzodiazepines: diazepam (0.5–4 mg/kg), chlordiazepoxide (4–8 mg/kg), nitrazepam (0.25–2 mg/kg), alprazolam (0.25–1 mg/kg), and partial agonists at benzodiazepine receptors: bretazenil (0.125–8 mg/kg) and ZK 91296 (32–64 mg/kg). Various 5-HT-related drugs also lessened the behavioural blockade: pCPA (3×150 mg/kg) and the 5-HT1A receptor agonists, buspirone (0.25–2 mg/kg), gepirone (0.25–1 mg/kg) but not 8-OH-DPAT. Compounds that may cause anxiety in humans further enhanced the blockade of lever pressing induced by the safety signal withdrawal at doses that did not modify baseline responding:d-amphetamine (0.125–0.5 mg/kg), caffeine (16 mg/kg) and picrotoxin (1 mg/kg). FG 7142 (8 mg/kg) and CGS 8216 (2–8 mg/kg) decreased responding during both components of the session. Therefore, the present paradigm seems sensitive to both anxiolytic and anxiogenic effects of drugs under identical procedural conditions.     

Effect of nicotine,mecamylamine, and hexamethonium on shock-induced fighting,pain reactivity,and locomotor behaviour in rats

Three series of experiments were performed to evaluate possible nicotinic cholinergic influences on fighting behaviour in rats. Each series consisted of three tests (naive animals in each test); shock-induced fighting, pain threshold estimation and locomotor activity. In the first series, nicotine (0.25–1.00 mg/kg) was found to produce a dose-dependent inhibition of fighting without altering shock thresholds. However, the highest dose used also significantly reduced rearing in the activity test. In the second series, mecamylamine (a centrally active antinicotinic) produced a facilitation of fighting at low doses (2.5 mg/kg) and an inhibition at higher dose (10 mg/kg). Whilst these effects were unrelated to changes in shock thresholds, the high dose resulted in a reduction in both horizontal activity and rearing. Finally, as a control for possible peripheral effects of nicotinic blockade, a third series examined the behavioural effects of hexamethonium. Low doses of this compound (2.25–4.5 mg/kg) had little effect on fighting whilst higher doses (9–18 mg/kg) attenuated these responses. Interestingly, although hexamethonium had no effect on shock thresholds, the highest dose (18 mg/kg) produced a facilitation of horizontal activity. Results are discussed in relation to the hypothesis of central nicotinic cholinergic inhibition of agonistic behaviour.     

The effect of electroconvulsive shock seizures on behaviour induced by dopaminergic agonists and on immobility in the Porsolt test

Male, Wistar rats were given a course of eight electroconvulsive shock seizures (ECS group) or matched handling (control group). They were then tested for locomotion and rearing (7 days post-ECS), for grooming and yawning (9 days post-ECS), and for immobility in the Porsolt test (7, 14 and 21 days post-ECS). Seven days post-seizure, the ECS group showed significantly more locomotion following intraperitoneal administration of apomorphine (0.2 mg/kg), but not following injections of amphetamine (1 mg/kg). Drug-induced rearing was not different in the ECS and control animals. Nine days post-seizure, the ECS group showed significantly more grooming induced by the D-1 dopamine receptor agonist, SKF 38393 (1 mg/kg), but no difference in the yawning induced by the D-2 dopamine receptor agonist, quinpirole (0.05 mg/kg). In the Porsolt test, immobility was decreased in the ECS animals at 7 and 14, but not at 21 days post-ECS. It is concluded that ECS increases activity in the dopaminergic systems of the rat brain for at least 1–2 weeks post-seizure. The beneficial effects of electroconvulsive therapy (ECT) may relate to these dopaminergic alterations.     

Environmental experience produces qualitative changes in the stimulant effects of β-phenylethylamine in rats

The effects of -phenylethylamine (PEA 6.25, 12.5, and 25.0 mg/kg IP) on spontaneous motor activity were examined in rats before (novel situation) and after (familiar situation) they had experience of the test environment, in an undrugged state. In a novel cage, 12.5 mg/kg PEA stimulated rearing and locomotion. A dose of 25.0 mg/kg PEA also increased rearing and produced stereotyped head movements, but did not increase locomotion, in a novel environment. In a familiar cage, both 12.5 and 25.0 mg/kg PEA stimulated locomotion and sniffing, whereas rearing was unaffected by PEA treatment under these conditions. These data provide a striking instance of a qualitative change in the behavioural response to a psychostimulant compound which is associated with the relative familiarity of the animal with the test environment. In addition, the results show that PEA induces stereotypy at high doses and increases locomotor activity at moderate doses, which is a further illustration of the similarity in the unconditioned behavioural effects of PEA and amphetamine.     

Desipramine administration in the olfactory bulbectomized rat: changes in brain beta-adrenoceptor and 5-HT2A binding sites and their relationship to behaviour.

1. The effects of repeated administration of the tricyclic antidepressant drug, desipramine (DMI), on behaviour (locomotor activity and rearing) and the number and affinity of brain beta-adrenoceptor and 5-HT2A receptor binding sites were examined in olfactory bulbectomized (OB) and sham-operated control rats. 2. Locomotor activity and rearing were increased in OB rats compared to sham-operated controls. The effect of various doses of DMI (administered orally twice daily for 21 days) on these behavioural measures was examined. A dose of 7.5 mg kg-1 provided optimal reversal of hyperlocomotion and increased rearing in OB rats, without changing these measures in sham-operated controls. 3. The time course of DMI (7.5 mg kg-1) on behavioural and neurochemical measures was examined. locomotion and rearing in OB rats were not significantly altered after 7 days, were significantly attenuated after 14 days and were normalized after 21 days. 4. After 7 days of DMI administration the number of beta-adrenoceptors was lower in frontal and occipital cortex and hippocampus. This reduction was largely restricted to the beta 1-adrenoceptor subtype. Administration of DMI for 14 or 21 days did not further reduce the number of beta-adrenoceptors. The DMI induced reduction in beta-adrenoceptors did not differ in OB and sham-operated control rats. 5. DMI administration for up to 21 days produced a progressive reduction in the number of 5-HT2A receptors in frontal cortex, without significant alterations in occipital cortex. 6. The time course of the reduction in the number of 5-HT2A receptors was similar to that of the DMI-induced behavioural changes whereas that for the reduction in beta-adrenoceptors was clearly different. 7. The present results suggest that the action of DMI in this animal model is unlikely to be directly related to a reduction in beta-adrenoceptors but may be related to a reduction in frontal cortical 5-HT2A receptors.     

Observational analysis of the effects of kappa opioid agonists on open field behaviour in the rat

An observational analysis of the effects of four kappa-opioid agonists on forward locomotion, rearing and grooming displayed by rats in a novel open field was undertaken. The doses of agonists used corresponded to those previously found to produce changes in food consumption. Ethylketocyclazocine (0.1 and 1 mg/kg), bremazocine (0.01 and 0.1 mg/kg) and tifluadom (0.3 and 3 mg/kg) exerted suppressant effects on all the activities monitored. Grooming behaviour appeared to be particularly sensitive to this action, being virtually abolished by the larger doses of these compounds. In contrast, the selective kappa agonist U-50,488H (0.1–3 mg/kg) only attenuated grooming at the two highest doses tested (1 and 3 mg/kg). None of the agonists tested produced stimulation of open field activity during the 1-h study. Reductions in activity occurred at doses previously found to increase and decrease food intake. It was therefore concluded that the hyperphagia induced by kappa agonists was not part of a more general behavioural activation, whilst reductions in food consumption probably result from a non-specific behavioural depression. Offprint requests to: S.J. Cooper     

Behavioral and biochemical effects of the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT in the rat.

The 5-HT_1A receptor agonists flesinoxan (0.2–3.2 mg kg⁻¹ s.c.) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.025–0.4 mg kg⁻¹ s.c.) produced (1) a dose-dependent facilitation of male rat ejaculatory behavior and (2) characteristic, dose-dependent effects on spontaneous motor activity. Thus, total locomotor activity and rearing activity were decreased. However, forward locomotion and peripheral locomotion were increased relative to the total horizontal activity. Furthermore, (3) 5-HTP accumulation, after inhibition of cerebral decarboxylase, was dose dependency decreased by both compounds in the ventral striatum and in the prefrontal cortex. There was a statistically significant decrease in DOPA accumulation in the ventral striatum after administration of a high dose of flesinoxan (3.2 mg kg⁻¹), and a tendency for 8-OH-DPAT to produce the same effect. The efficacy of the compounds to affect male rat sexual behavior, spontaneous motor activity in the open-field and forebrain 5-HT synthesis was approximately the same, whereas flesinoxan was about an order of magnitude less potent than 8-OH-DPAT.     

Steady-state kinetics of imipramine in patients

Steady-state plasma level kinetics were studied in 76 patients given imipramine (IP) 150 to 225 mg/day for 2–5 weeks. IP was given in three divided doses at 8.00 a.m., 1.00 p.m. and 5.00 p.m. Plasma concentrations of IP and its active metabolite desipramine (DMI) were determined by quantitative in situ thin-layer chromatography. The plasma levels of IP and DMI showed pronounced flucutations throughout the day with a ratio of about 2 between highest and lowest level. Patients with steady-state levels of IP and/or DMI below 50 g/l reached this within 1 week of treatment. Patients with higher steady-state levels reached steady-state concentrations within 2–3 weeks. There were some intraindividual fluctuations in plasma levels from week to week after steady state had been reached (coefficient of variation: 10–20%). Interindividually, the steady-state levels corrected to a dose of 3.5 mg/kg per day varied considerably: IP: 6–356 g/l, DMI: 24–659 g/l and IP+DMI: 58–809 g/l. The steady-state plasma levels showed a skew distribution that became normal by logarithmic transformation. The IP/DMI ratio ranged from 0.07 to 5.5 with a median value of 0.47. Compared to data from amitriptyline treated patients the IP/DMI ratios had significantly lower median value and larger variation than the corresponding plasma level ratios of amitriptyline/nortriptyline. Several statistically significant differences in steady-state levels between age groups were found. For IP: Women aged 30–39 had lower levels than women aged 20–29, 40–49, and 50–59, and men aged 50–59 and 60–65; men aged 30–39 had lower levels than men aged 60–65. For DMI: Women aged 30–39 had lower levels than women aged 50–59.     

LY 171555-induced hyperdefensiveness in the mouse does not implicate benzodiazepine receptors

In naive mice the selective D2 agonist LY171555 dose-dependently (0.5–5 mg/kg) induces defensive responses toward non-aggressive conspecifics. In order to investigate possible anxiogenic properties of the D2 agonist, its behavioural effects were compared with those produced by the benzodiazepine receptor inverse agonist methyl--carboline-3-carboxylate(-CCM) in the elevated plus maze and in social interactions with non-aggressive opponents. When tested in the elevated plus maze, mice injected with LY 171555 (0.005–1 mg/kg) showed no decrease either of the number of entries or of the time spent in the open arms. At 5 mg/kg an actual increase of these two measures was observed. By contrast,-CCM (1–3 mg/kg) dose-dependently decreased both the number of entries and the time spent in the open arms without altering locomotion. The effects of-CCM were antagonized by the benzodiazepine receptor antagonist RO 15-1788 (3 mg/kg) showing a selective involvement of benzodiazepine receptors in their modulation. On the other hand,-CCM, (1–3 mg/kg) did not produce significant effects on defensive behaviour of mice interacting with non-aggressive opponents and the defensive responses of mice treated with 1 mg/kg LY 171555 were not prevented by 5 mg/kg chlordiazepoxide. These results show that DA D2-mediated hyperdefensiveness and anxiety modulated by benzodiazepine receptors are unrelated phenomena and suggest that this behavioural response may represent a model of those forms of fear-related reaction that do not respond to benzodiazepine treatment.     

Effects of 5-HT1A Receptor Agonists on Patterns of Rat Motor Activity in Relation to Effects on Forebrain Monoamine Synthesis

Abstract: The effects of the 5-HT_1A receptor agonists 8-OH-DPAT (0.15–2.5 μmol kg^?1 subcutaneously), flesinoxan (0.6–10.0 μmol kg^?1 subcutaneously) and buspirone (1.9–30.0 μmol kg^?1 subcutaneously) on spontaneous motor activity in male Sprague-Dawley rats was examined in a photocell-equipped open-field arena. Following motor activity observations, the cerebral aromatic L-amino acid decarboxylase inhibitor NSD-1015 (100 mg kg^?1 intraperitoneally) was administered and 30 min. later the animals were decapitated for subsequent analysis of the accumulated forebrain DOPA and 5-HTP levels, as an estimate of the rate of monoamine synthesis. 8-OH-DPAT and flesinoxan produced a similar and characteristic pattern of changes of the spontaneous motor activity in normal animals i.e. a moderate decrease in locomotor activity, a marked suppression of rearing and an increase in the relative amount of forward locomotion and of activity in the periphery of the open-field arena. This behavioural profile was closely related to a decrease in forebrain 5-HTP accumulation, indicating 5-HT receptor stimulation. In agreement with these observations buspirone also produced an increase in peripheral activity and a suppression of rearing. In contrast to effects by 8-OH-DPAT and flesinoxan, however, buspirone produced a further reduction of locomotor activity and reduced the forward locomotion. This difference in behavioural profile between buspirone and the other two compounds is probably explained by its DA receptor blocking properties, as indicated by an increased DOPA accumulation in the neostriatum. At least partially, 8-OH-DPAT, flesinoxan and buspirone, all antagonized reserpine-induced (5 mg kg^?1 subcutaneously – 16 hr) suppression of locomotor activity. This stimulation of locomotor activity in reserpine-treated rats is in all probability related to 5-HT_1A receptor stimulation since concomitant DA D₂ receptor blockade, in the case of buspirone, did not markedly affect this behavioural response.     

Comparison of hyperactivity in adult rats induced by neonatal intraventricular 6-hydroxydopamine following pargyline or desmethylimipramine treatment

The relative roles of norepinephrine (NE) and dopamine (DA) in sustaining neonatal hyperactivity were assessed in rats given 6-hydroxydopamine (6-OHDA) neonatally into the lateral ventricles after pargyline (P) or desmethylimipramine (DMI) pretreatment.On day 5 after birth, male and female rat pups were pretreated with P (50 mg/kg IP) or DMI (25 mg/kg IP) 30 min before receiving bilateral injections of 6-OHDA (200 g/5 l saline containing ascorbic acid 1.0 mg/ml) into the lateral ventricles. Controls were pretreated with P or DMI and then received injections of saline containing the ascorbate.Spontaneous activity was measured in a stabilimeter at ages 30–31, 42–45, 60–63, 75–77, and 120–122 days. Activity in controls and P+6-OHDA animals was also measured at 254 days of age. The sessions lasted 45 min, except those testing activity in the 254-day-old rats which lasted 12 h.Regional assays of catecholamines carried out when the animals were 150 days old revealed that in the P+6-OHDA group the levels of NE were reduced in frontal cortex (7% of control levels), caudate (21%), and hippocampus (14%). The NE levels were unchanged or slightly elevated in hypothalamus, ventral midbrain, and pons. The DA levels in the P+6-OHDA group were depleted in caudate (8%) and ventral midbrain (32%), and unchanged in hypothalamus and pons.In the DMI+6-OHDA group the NE levels were reduced in caudate (25%) and elevated in hippocampus (188%). The DA levels were depleted in caudate (3%) and ventral midbrain (22%).Both treatments resulted in long-term hyperactivity, but the syndrome was of larger magnitude and more permanent in the P+6-OHDA group. The possible biochemical basis of these differential effects is discussed.     

An observational method for quantifying the behavioural effects of dopamine agonists: Contrasting effects of d-Amphetamine and apomorphine

A novel means of measuring and analysing behavioural effects of dopamine agonists is described and illustrated by a comparison of the effects of d-amphetamine and apomorphine in the rat. d-Amphetamine (0–15 mg/kg IP) produced significant dose- and time-dependent changes in responses such as locomotion, rearing and sniffing, but not in licking or gnawing. In contrast, apomorphine (0–5 mg/kg SC) produced significant increases in licking and gnawing, as well as in locomotion and sniffing, but no changes in rearing. The results are discussed in comparison with those obtained by other methods, such as photocell beam interruptions or stereotypy rating scales, and may be of importance in elucidating the functions of the forebrain dopamine projections.     

Behaviour in the novel environment predicts responsiveness to d-amphetamine in the rat: a multivariate approach

The behaviour of rats in a novel environment was studied using a rapid time-sampling observation procedure followed by a principal component analysis (PCA) of the data. This approach revealed that novel environment behaviour can be described by two factors or principal components. The first factor comprised rearing, sniffing-up, ambulation and locomotion (photocell counts), and was termed "Escape". The second factor, which had high positive loadings of sniffing-down and locomotion and a high negative loading of immobility, was termed "Exploration". The scores of individual rats on the "Escape" factor predicted the stimulatory effect of acutely administered d-amphetamine (1.5mg/kg) on unconditioned behaviour. "Escape" high responders (HRs) showed more behavioural stimulation than "Escape" low responders (LRs). However, the locomotor stimulatory response of both groups increased after long-term, periodic administration of d-amphetamine and drug discrimination training, such that the level of drug-induced locomotor activity was now equivalent for the two groups. The same rats were tested twice with various doses of d-amphetamine after being trained to discriminate this drug (0.5mg/kg) from saline. "Escape" HRs were less sensitive than "Escape" LRs to the discriminative effects of 0.125-0.25mg/kg d-amphetamine. In contrast to these findings, "Exploration" HRs and LRs were not different on any of the dependent measures described above. These results are discussed in relation to the possibility that "Escape" factor scores are an indication of an animal's responsivity to novelty-induced stress. If this is the case, then animals which are more susceptible to the effects of novelty stress are more sensitive to the locomotor stimulating effects of acute d-amphetamine, but less sensitive to the cueing properties of low doses of this drug.     

Facilitation of shock-induced fighting following intraventricular 5,7-dihydroxytryptamine and 6-hydroxydopa

Immobilization of albino rats for 2 h showed ambient temperature-dependent changes in rectal temperature, hypothermia at temperatures below 30° C, and hyperthermia at 35° C and above. Adrenalectomized (Adre) rats showed more hypothermia compared to sham operated controls at 25±2° C. The increased hypothermia in adrenalectomized rats was reversed by 10 mg/kg IP or 100 g/rat ICV of hydrocortisone. Groups of rats pretreated with desmethylimipramine (DMI, 25 mg/kg IP) and 6-hydroxydopamine (6-HD, 100 g/rat ICV) or methyl ester of parachlorophenylalanine (ME-PCPA, 100 g/rat ICV for 3 days) or 5,6-dihydroxytryptamine (DHT, 75 g/rat ICV) showed significantly less hypothermia at the end of 2 h of immobilization. Applying analysis of variance test, the hypothermia in Adre, ME-PCPA and DHT groups, was found to be not significantly different from their respective control groups between 0 to 45 min of immobilization but was significantly different between 45 to 120 min of immobilization. DMI-6-HD group however, showed significant difference between 0–45 min only and not between 45–120 min of immobilization. The results suggest that the early phase of immobilization induced hypothermia between 0–45 min is dopamine and the late phase of hypothermia between 45–120 min is 5-hydroxytryptamine mediated.     

Effect of 5-HT1A agonists on stress-induced deficit in open field locomotor activity of rats: evidence that this model identifies anxiolytic-like activity

Deficits in locomotion and exploratory behaviour in an open field were induced in rats by restraint for 2 hr, 23 hr before testing. Diazepam, 0.62 and 1.25 mg/kg, intraperitoneally (i.p.), 15 min before testing, reversed the stress-induced reduction in locomotion; 1.25 mg/kg also attenuated the effect of stress on exploration (rearing and object exploring). Diazepam did not affect the activity of controls. A putative anxiogenic compound, pyrazoloquinoline (CGS 8216, 10 mg/kg administered 30 min before testing), also markedly reduced locomotion and exploration and the effect was reversed by 2.5 mg/kg diazepam, 15 min before testing. Buspirone, 0.1 mg/kg subcutaneously (s.c.) 15 min before testing, significantly attenuated the effect of stress on locomotion and exploration but had no effect in controls. Larger doses (0.5 and 1.0 mg/kg) markedly reduced the behavioural measures in controls and did not modify or enhance the effect of stress. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 0.25 and 0.5 mg/kg (s.c.), 1 hr before testing, significantly attenuated the reduction in locomotion without affecting rearing and object-exploring in stressed rats. At doses from 0.125 to 0.5 mg/kg, 8-OH-DPAT reduced exploration in control rats. Two hr after restraint (corresponding to 21 hr before testing in the open field) 8-OH-DPAT, 0.125 to 2 mg/kg (s.c.), did not modify the open field deficits, caused by stress. In these treatment conditions, 0.5 and 2 mg/kg 8-OH-DPAT reduced locomotion and exploration in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nitrous oxide induces an anxiolytic-like effect in the conditioned defensive burying paradigm,which can be reversed with a benzodiazepine receptor blocker

To investigate the anxiolytic effects of nitrous oxide (N₂O), male hooded rats were tested in the conditioned defensive burying (CDB) test, a paradigm that exploits a propensity of rats to bury objects associated with aversive stimulation. A single, brief electrical shock was delivered to rats upon contact with an electrified prod, before exposure to one of four mixtures of N₂O and oxygen (O₂) (10–40% N₂O) or room air (RA). Compared to RA-exposed animals, rats exposed to N₂O exhibited a concentration-related reduction in duration and height of prod-directed defensive burying with floor bedding material; these measures reached statistical significance at 30% N₂O. Pretreatment with 20 mg/kg of the benzodiazepine receptor blocker flumazenil, which alone had no effect, effectively antagonized a 30% N₂O-induced decrease in burying. Horizontal locomotion and rearing were not significantly affected at concentrations of N₂O that attenuated prod-directed burying. Treatment with the benzodiazepine anxiolytic standard, chlordiazepoxide (2.5–10.0 mg/kg) also resulted in dose-related attenuation of burying behavior. These findings show that N₂O can induce effects similar to those of known anxiolytics in this paradigm and suggest a benzodiazepine mechanism in its mediation.     

Effects of 2, 4-Dichlorophenoxyacetic Acid (2, 4-D) on Open-Field Behaviour and Neurochemical Parameters of Rats *

The effects of the herbicide 2, 4-dichlorophenoxyacetic acid (2, 4-D) on the central nervous system (CNS) were studied in rats. Behavioural and neurochemical studies were performed. Results show that acute and oral administration of dimethylamine 2, 4-D was able to decrease locomotion and rearing frequencies and to increase immobility duration of rats observed in an open-field test. Treatment of rats with p-chlorophenylalanine (PCPA) was unable to change rat's open-field behaviour; 5-hydroxytryptophan (5-HTP) administration not only increased locomotion and rearing frequences but also decreased immobility duration. Pretreatment of the rats with PCPA and 5-HTP decreased and increased dimethylamine 2, 4-D effects, respectively. The herbicide was not able to change the striatal levels of dopamine and homovanilic acid but decreased the striatal levels of serotonin (5-HT), as observed for the doses of 100 and 200 mg/kg and increased those of 5-hydroxyindoleacetic acid (5-HIAA) as measured after the 200 mg/kg dose treatment. When the levels of serotonin and 5-HIAA were measured at the brain stem level, only those of 5-HIAA were modified, being increased by diethylamine 2, 4-D (60; 100 and 200 mg/kg); this increment on 5-HIAA levels was observed even 1 hr after pesticide administration. Further analysis showed that 2, 4-D concentrations chromatographycally detected both in serum and brain of the intoxicated animals were dose-dependent, being found as early as 1 hr after the smaller dose of the herbicide used (10 mg/kg). The results suggest that diethylamine 2, 4-D modify 5-HT functional activity within the CNS. Thus, the effects of the herbicide on open-field behaviour of rats could be attributed to a direct or indirect pesticide action on serotoninergic systems.     

An assessment of the spontaneous activity of rats administered morphine,phencyclidine, or nicotine using automated and observational methods

The effects of morphine, phencyclidine, and nicotine on motor activity in rats were characterized using both observational and automated methods. Activity was scored observationally using a time-sampling method that tabulates discrete response categories (still, locomotion, rearing, sniffing, licking, gnawing, head down, swaying, grooming, falling). Behavior was assessed automatically using an activity monitor that records both the time and activity counts spent in large and small (less than 3 cm) movements, rearing, and resting. The following results using male Sprague-Dawley rats represent significant differences from saline-treated controls. Morphine (1–4 mg/kg SC) increased the incidence of locomotion, sniffing, swaying, and grooming depending on the time after drug injection. These changes corresponded to an increase in large and small movement counts and time as measured by the activity monitor. Phencyclidine (1.25–5 mg/kg SC) caused dose-related increases in the incidence of locomotion, sniffing, swaying, and falling, and induced greater large and small activity movement counts and time especially after the 5 mg/kg dose. Nicotine (0.033–0.33 mg/kg SC) decreased the incidence of rearing and increased the frequency of sniffing and grooming. These changes corresponded to a decrease of rearing activity and to a slight increase in small activity. The present data indicate that morphine, phencyclidine, and nicotine exert dose-related and time-related appearances of various categories of behavior in the rat, and that the data from the automated method complement the findings of the direct observational method.