Single or repeated administration of small doses of apomorphine on water intake and activity in water-deprived rats

Treatment with small doses of apomorphine HCl (15, 60 and 125 μg·kg^?1) was able to stimulate water consumption in thirsty rats, provided it was administered chronically (10 daily injections). Acute administration of apomorphine at the same dose levels did not affect drinking. Simultaneously, apomorphine stimulated locomotor activity, although this action was equally present in both acute and chronically treated animals. Hence, the dipsogenic action of apomorphine which emerged with repeated administration can be distinguished from the stimulant action on locomotor activity, at small dose levels.     

Effects of chronic amphetamine in BALB/cBy mice, a strain that is not stimulated by acute administration of amphetamine

The effects of d-amphetamine and methylphenidate on locomotor activity of BALB/cByJ mice were evaluated. d-Amphetamine had no effect or inhibited locomotor activity at acute doses of up to 10 mg/kg while methylphenidate stimulated locomotor activity at acute doses between 10 and 32 mg/kg. The dose-response curves for methylphenidate and d-amphetamine appeared to be quantal in nature. During a 21-day chronic treatment with 10 mg/kg d-amphetamine no evidence of tolerance to the depressant effects of relatively high doses of d-amphetamine was observed. However, a 3.2 mg/kg dose of d-amphetamine, which acutely inhibited locomotor activity, was found to stimulate locomotor activity following chronic amphetamine treatment. Doses of methylphenidate which acutely stimulated activity were without effect in mice chronically receiving amphetamine. Although the mechanism underlying these behavioral effects has yet to be established, our results indicate that inherent alterations can differentially affect both acute and chronic susceptibility to the behavioral effects of amphetamine and methylphenidate. Use of such altered strains of mice can be especially revealing of subtle behavioral effects brought about by chronic drug treatment which are not readily demonstrated following acute administration of amphetamine.     

Task-dependent development of tolerance to scopolamine

Rats were chronically treated with once daily injections of either 0.5 mg/kg scopolamine hydrochloride or isotonic saline for 21 days. When spontaneous locomotor activity or acquisition of active avoidance in a two-way shuttle box were measured at 48 hours after the cessation of chronic treatment, no differences were observed between the two chronically treated groups. Tolerance to scopolamine's locomotor stimulatory effects was evident as the increase in locomotor activity following acute treatment was smaller in the group which had been chronically treated with scopolamine. On the other hand, acutely administered scopolamine facilitated the acquisition of active avoidance responding to an equal degree in both chronically treated groups. The reasons which may account for this task-dependent tolerance development to scopolamine are discussed.     

The effect of doxepin on the central action of ethanol.

The effect of combined treatment with doxepin and ethanol was tested in mice, rats and rabbits. Doxepin was given in a single dose (5 or 10 mg/kg) or chronically (10 mg/kg/d for 21 days). Doxepin did not affect ethanol toxicity and ethanol-induced impairment of rota-rod performance, but potentiated ethanol-induced hypothermia (only acutely) and prolonged ethanol-induced sleep in mice. Given acutely it potentiated the inhibitory effect of ethanol on locomotor activity in mice, while given chronically it counteracted the ethanol-induced sedation. Doxepin did not interfere with ethanol-induced EEG effects in rabbits, and prevented the development of tolerance to hypothermic, but not to hypnotic effects of ethanol in rats. In general, the interference of doxepin with ethanol was more pronounced after single doses of the drug than after chronic treatment.     

Effects of buspirone and ipsapirone on schedule induced polydipsia: comparison with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and raclopride

In the present experiments, the effects of the azapirone anxiolytics, buspirone and ipsapirone, on excessive drinking induced by a FT-60 schedule of food delivery (schedule induced polydipsia, SIP) were investigated. Because buspirone is known to block dopamine receptors and both buspirone and ipsapirone act as agonists at the 5-HT_1A receptor, their effects on polydipsia were compared to raclopride, an antagonist at D₂ receptors, and 8-OH-DPAT, an agonist at the 5-HT_1A receptor, thus providing information about the relative importance of the serotonergic and/or dopaminergic systems for the maintenance of polydipsia. The effects of all four drugs were investigated both acutely, and following repeated treatment. The doses employed were as follows: buspirone, 1.0, 3.0, and 10.0 mg/kg; raclopride, 0.05, 0.15, and 0.5 mg/kg; 8-OH-DPAT, 0.1, and 1.0 mg/kg and ipsapirone, 1.0, 3.0, 10.0 mg/kg. Administered acutely, the lowest doses of buspirone and raclopride did not alter drinking, whilst the low dose of 8-OH-DPAT significantly reduced polydipsia. These effects were reversed following repeated treatment over 16 successive days. Buspirone 1.0 mg/kg and 0.05 mg/kg raclopride reduced drinking, whilst tolerance developed to the effects of 0.1 mg/kg 8-OH-DPAT. Ipsapirone, at low doses, was without effect on drinking. At high doses, all four drugs reduced drinking both acutely and chronically. Repeated treatment with buspirone (3.0, and 10.0 mg/kg) reduced licking and panel entries, but induced aselective decrease in licking at the low dose (1.0 mg/kg). Similar effects were seen following raclopride treatment, although the effects were less selective. 8-OH-DPAT and ipsapirone, in contrast, reduced licking only at the highest dose, and both drugs increased panel entries as testing continued. The effects of buspirone resembled those of raclopride whereas the effects of ipsapirone resembled those of 8-OH-DPAT. Buspirone appears to act as a dopamine antagonist in this test. The effects of the drugs suggest that SIP depends upon motivational and performance factors which may be more sensitive to drug manipulation than potential underlying psychological factors such as anxiety or stress.     

A comparison of the predictive therapeutic and undesired side-effects of the NMDA receptor antagonist, memantine, in mice

Memantine (1-amino-3,5-dimethyl-adamantane) is the only clinically used NMDA (N-methyl-D-aspartate) glutamate receptor antagonist. The present experiments were carried out to compare the dose-response for memantine's predictive therapeutic and side-effects in a variety of tests in C57BL/6J/Han mice, and to elucidate if tolerance may develop to them. Memantine produced a dose-dependent (2.5-15 mg/kg) antidepressant-like effect in the tail-suspension test (TST); this anti-immobility effect of 15 mg/kg of memantine appeared to persist with its sub-chronic administration (3 days, twice daily). Treatment with the same doses of memantine produced no effects on locomotor activity, and sub-chronic treatment with 15 mg/kg did not affect locomotor activity. Exploratory activity was assessed in the open field. Given acutely 5 min before the test, memantine reduced rearing (1.875-30 mg/kg), ambulation (7.5 and 30 mg/kg) and grooming (30 mg/kg). These effects were more pronounced 35 min after its administration. As measured in three different tests, ataxia and stereotypy appeared only at the single dose of 30 mg/kg, 5 and 35 min after administration. In mice treated sub-chronically with 30 mg/kg, the dose of 30 mg/kg increased ambulation, and continued to decrease rearing and grooming, but no signs of ataxia and stereotypy were detected. The present data indicate that different doses of memantine are required for the purportedly therapeutic and side-effects, and that tolerance may develop to the ataxic, but not anti-immobility actions.     

The cannabinoid agonist HU 210 modifies rat behavioural responses to novelty and stress.

Experiments were performed on groups of rats after acute and sub-chronic treatment (once daily for 9 days) with the cannabinoid agonist HU 210 (25-100 microg kg(-1), i.p.) as well as 24 h and 7 days after the last drug injection. The animals underwent three behavioural tests in novel environments. In the observation cages (Test 1), rat locomotor activity was found to be dose-dependently reduced after acute and sub-chronic treatment at all doses and virtually unchanged during abstinence; grooming was potently inhibited by acute treatment but potentiated by the sub-chronic one at doses of 50 and 100 microg kg(-1), the effect of the higher dose persisting after 24 h and 7 days abstinence. Vocalization in animals in response to a tactile stimulus was highest after HU 210 at 100 microg kg(-1) in all experimental modes except after 7 days abstinence. In the X-maze (Test 2), sub-chronic HU 210 dose- dependently enhanced rat natural aversion for open arms, and this behaviour persisted during abstinence after the highest dose. Grooming in the X-maze was completely absent in rats acutely injected with HU 210 but potentiated in those sub-chronically treated or abstinent. In the swimming test (Test 3) rats sub-chronically treated at 50 and 100 pg kg(-1) displayed relevant wall-hugging and the same occurred 24 h after last injection. On the whole, our results are indicative of an anxiogenic-like effect of sub-chronic HU 210 at high doses and reflect the persistence of enhanced emotional response to novel environments when the treatment is discontinued.     

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.     

Antidepressant-like properties of the anti-Parkinson agent, piribedil, in rodents: mediation by dopamine D2 receptors

The dopamine D2/D3 receptor agonist and alpha2 adrenergic receptor antagonist, piribedil, is used clinically as monotherapy and as an adjunct to L-3,4-dihydroxyphenylalanine in the treatment of Parkinson's disease. As it appears to improve mood, we examined its actions in rodent models of antidepressant properties, in comparison with the prototypical anti-Parkinson agent, apomorphine, the D2/D3 receptor agonist, quinpirole, and the antidepressants, imipramine and fluvoxamine. In the mouse forced-swim test, acute administration of imipramine, fluvoxamine, apomorphine or quinpirole decreased immobility time, actions dose dependently mimicked by piribedil (2.5-10.0 mg/kg, subcutaneously). In rats, acute and subchronic administration of piribedil similarly reduced immobility (0.63-10.0 mg/kg, subcutaneously) and apomorphine, quinpirole and imipramine were also active in this test, whereas fluvoxamine was inactive. Both in mice and in rats, the D2/D3 receptor antagonist, raclopride, and the D2 receptor antagonist, L741,626, dose dependently blocked the antidepressant properties of piribedil, whereas the selective D3 receptor antagonists, S33084 and SB277,011, were ineffective. In a chronic mild stress model in rats, piribedil (2.5-40.0 mg/kg, subcutaneously) restored sucrose intake in stressed animals exerting its actions more rapidly (by week 1) than imipramine. Imipramine, fluvoxamine, apomorphine, quinpirole and piribedil dose dependently (0.63-10.0 mg/kg, subcutaneously) suppressed aggressive and marble-burying behaviour in mice. In the latter procedure, raclopride and L741,626, but not S33084, attenuated the actions of piribedil. Over a dose range (0.63-10.0 mg/kg, subcutaneously) equivalent to those active in models of antidepressant activity, piribedil did not stimulate locomotor behaviour. In conclusion, principally via recruitment of D2 receptors, piribedil exerts robust and specific antidepressant-like actions in diverse rodent models.     

Chronic treatment of guinea pigs with lithium chloride: effects on myenteric plexus preparations and on cyclic AMP levels.

We studied the effects of lithium chloride, given i.p. in doses of 0.05, 1, 2, 4 and 8 mEq/kg twice daily for 14 days, on preparations of guinea pig myenteric plexus. The effects of lithium added to isolated myenteric plexus preparations derived from chronically treated animals showed that relatively low lithium concentrations produced a statistically significant decrease in the force of contraction, this effect being concentration-dependent. 3-Isobutyl-1-methylxanthine (IBMX) induced a statistically significant inhibition, between 30 and 50%, of the lithium effects. cAMP levels in animals treated chronically with lithium were studied, using an isotopic displacement technique. Our results show that only the highest dose of lithium (8 mEq/kg per day) significantly decreased basal levels of cAMP. In the presence of IBMX, low doses of lithium (1 mEq/kg per day) induced a very significant decrease in cAMP levels, but the inhibition remained constant, approximately 30-35%, at doses from 2 mEq/kg per day. In guinea pig myenteric plexus preparations from acutely treated animals, our results show a direct relationship between lithium concentration and inhibition of the cAMP accumulation induced by IBMX.     

The effects of chronic treatment with d-amphetamine on food intake,body weight,locomotor activity and subcellular distribution of the drug in rat brain

Female Wistar rats were treated chronically with d-amphetamine sulphate in drinking water. The concentrations of amphetamine were 0.01%, 0.02%, 0.03%, 0.04% and 0.05% in the 1st, 2nd, 3rd, 4th, and 5th week of treatment. The consumed doses of amphetamine increased from 16 mg/kg on the first day up to 90 mg/kg on the 36th day of treatment. The effects of chronic treatment with amphetamine on food intake, body weight and locomotor activity of rats were determined. The rats developed tolerance to the overall toxicity and to the anorexigenic effect of maphetamine. No tolerance to the effects of the drug on body weight and locomotor activity was observed. The concentration of H³-d-amphetamine in brains of chronically treated rats is significantly higher than in controls. No difference in the pattern of distribution of radioactivity among the subcellular fractions of rat brain was observed between control and chronically treated groups. The relationship between developmen tof tolerance and the concentration of amphetamine in the brain is discussed.     

Behavior “recovery” during chronic reserpine treatment: Effect of dose of reserpine

Summary Various doses of reserpine were administered chronically to rats which were tested for rotarod performance and spontaneous locomotor activity. Doses of 0.0625, 0.125 and 0.25 mg/kg/day produced depression of rotarod performance after varying periods of treatment. No evidence of recovery of performance was observed during treatment with any dose. Doses of 0.125, 0.25 and 0.5 mg/kg/ day produced depression of spontaneous locomotor activity after varying periods of treatment. “Recovery” of activity was observed after the initial depression. A subsequent phase of hyperactivity occurred during treatment with 0.5 and 0.25 mg/kg while activity of the animals treated with 0.125 mg/kg became depressed and remained depressed during another 32 days of treatment. It is suggested that more than one action of reserpine should be considered in the explanation of these results. Supported by USPHS Grant MH 15490-01. Supported by USPHS Grant FR 05404.     

Mecamylamine but not the alpha7 receptor antagonist alpha-bungarotoxin blocks sensitization to the locomotor stimulant effects of nicotine

The involvement of alpha7 receptors in the locomotor stimulant effects of nicotine has been examined by determining the ability of intracerebroventricular (i.c.v.) administration of the alpha7 receptor antagonist alpha-bungarotoxin (alpha-bgt) to modify sensitization to the locomotor activating effects of chronic nicotine. Intracerebroventricular administration of alpha-bgt (0.02 - 8 nmoles) produced a dose dependent increase in convulsive behaviour. At doses less than 1.0 nmole, minimal convulsive behaviour occurred but larger doses evoked convulsions in all rats which displayed a more rapid onset time as the dose increased. The binding distribution of alpha7 receptors 20 min and 3 h following an i.c.v. administration of [(125)I]-alpha-bgt (0.02 nmoles) revealed clear binding in the hippocampus, cingulate cortex and hypothalamus which was more intense after 3 h. Rats chronically treated with nicotine (0.4 mg kg(-1)) and exposed to the locomotor activity apparatus daily acquired an increase in locomotor activity relative to the control group after 3 days of treatment which reached a maximum after 7 days of treatment and was maintained for the 2 week treatment period. Pre-treatment with mecamylamine (1 mg kg(-1)) prevented the expression of the locomotor stimulant effects of nicotine but pre-treatment with i.c.v. alpha-bgt (0.02 nmoles) did not affect nicotine-induced changes in locomotor activity. The results of this study support the conclusion that nicotinic receptors of the alpha4beta2 subtype rather than the alpha7 subtype are important in mediating the expression of the locomotor stimulant effects of nicotine.     

Effects of chronic desipramine treatment on rat brain noradrenergic responses to alpha-adrenergic drugs

It has been previously reported that long-term tricyclic antidepressant treatment in the rat causes a subsensitivity of central beta-receptor-stimulated adenylate cyclase along with alterations of brain norepinephrine (NE) content and metabolism. We have confirmed earlier findings that after one week of desipramine treatment (5.0 mg/kg b.i.d.) brain NE levels decline while NE metabolism is similar to control animals, but is above control after 12 days of treatment. Single cell recordings from noradrenergic neurons of the locus coeruleus (LC) show that after one week of desipramine treatment, neuronal firing rate is lower than in control rats but greater than that seen in response to acutely administered drug. Furthermore, desipramine injection in a dose which profoundly altered LC impulse flow in control rats produced little or no effect on impulse flow in chronically treated rats. Of 25 or 250 microgram/kg doses of clonidine, which are equieffective for decreasing brain NE metabolism in control animals, only the larger dose decreased NE metabolism in 12 day desipramine-treated rats. The postsynaptic alpha-antagonist prazosin (5.0 mg/kg) increased NE metabolism in both groups. These results suggest that presynaptic (alpha 2) adrenoreceptors become subsensitive during long-term desipramine treatment, thus allowing recovery of noradrenergic impulse flow in the presence of NE uptake inhibition.     

Acute and chronic effects of the triazolobenzo-diazepine, alprazolam, on defeat and analgesia evoked by conspecific attack in male mice

Behavioural and pharmacological evidence suggest that non-opioid analgesia in defeated male mice is a consequence of anxiety provoked by ecologically relevant aspects of the stimulus situation. The effects of acute and chronic alprazolam (0.05-2.0mg/kg, i.p.) treatment on basal nociception, defeat behaviour and analgesia evoked by conspecific attack are assessed. Results show that basal nociception (tail-flick assay) was unaffected by acute or chronic drug treatment, and that attack-induced analgesia was unaltered by acute administration of 0.05-0.50mg/kg alprazolam. Higher acute doses (1-2mg/kg) of the compound inhibited locomotor activity, markedly interfered with the display of defeat postures and resulted in the exposure of intruders to higher than normal levels of attack. Though 1mg/kg alprazolam (acute) significantly inhibited the analgesic consequences of conspecific attack, this effect went at a higher dose. Chronic drug administration led to the development of tolerance to the inhibitory effects of higher alprazolam doses on locomotor activity and, over the dose range 0.5-2mg/kg, to the complete inhibition of analgesic consequences of conspecific attack. Nonetheless, mice treated chronically with 0.5-2mg/kg still failed to display defeat within the maximum time allotted for encounters, suggesting that this behavioural effect may be a valid index of anxiolytic activity. Data are discussed in relation to the possible involvement of panic in intruder analgesia.     

Spatial and temporal patterning distinguishes the locomotor activating effects of dizocilpine and phencyclidine in rats

A behavioral pattern monitor was used to assess the effects of dizocilpine (MK-801) and phencyclidine on the spatial and temporal patterns of locomotion and investigatory behavior in rats. The monitor provided both quantitative measures of crossovers, rearings and holepokes and qualitative measurement of the spatial and temporal patterns of locomotion. Dizocilpine (0.004-0.5 mg/kg) and phencyclidine (0.25-5.0 mg/kg) produced similar, dose-dependent increases in locomotor activity. At small doses, dizocilpine and phencyclidine increased investigatory holepokes, while at larger doses, both drugs significantly decreased the number of holepokes. Rearings were reduced similarly by the larger doses of each drug. Both dizocilpine and phencyclidine produced perseverative spatial patterns of locomotion, especially at larger doses. However, the locomotor patterns produced by these drugs were found to be dissimilar in spatial quality. After phencyclidine, animals frequently circled the perimeter of the monitor chamber or moved repetitively in horseshoe or figure-8 patterns. By contrast, rats given dizocilpine completed small rotations about either end of the chamber. Pretreatment with a small dose (0.02 mg/kg) of haloperidol, prior to either dizocilpine (0.5 mg/kg) or phencyclidine (5.0 mg/kg) had no effect on the increase in locomotor activity or the decreases in investigatory holepokes produced by the drugs. However, haloperidol altered the effects of phencyclidine on the spatial and temporal patterns of locomotion, suggesting that sigma receptors or other haloperidol-sensitive binding sites, may influence the quality but not the quantity of phencyclidine-induced hyperactivity.     

Scopolamine and adjunctive drinking in rats

Nine, food-deprived rats were each given daily sessions during which 60 45-mg food pellets were delivered individually at 60-sec intervals, independently of behaviour. Water spouts were available to the animals and the intermittent delivery of food induced high levels of adjunctive drinking. The administration of scopolamine (0.125, 0.25, 0.5, 1.0 mg/kg) produced a dose-related attenuation of this drinking. A dose of physostigmine (0.2 mg/kg) was found to slightly reduce levels of drinking but this dose did not consistently modify the action of scopolamine on this behaviour. Tolerance was found to occur to the action of the highest dose of scopolamine (1.0 mg/kg).     

Hypophysectomy may non-selectively alter pharmacokinetic parameters to enhance the ability of haloperidol to increase striatal dopamine receptor density in the rat

We have investigated the effect of a range of doses of haloperidol (0.625-5.0 mg/kg/day) or saline, administered for 14 days, followed by a 3 day drug washout period, to sham operated or hypophysectomized rats. Haloperidol increased the number of specific striatal 3H-spiperone binding sites (Bmax) in sham-operated animals at doses of 2.5 and 5.0 mg/kg/day, and in hypophysectomized animals at all doses used (0.625-5.0 mg/kg/day). The inhibition of locomotor activity produced by haloperidol was greater in hypophysectomized than sham-operated animals. Plasma and striatal haloperidol levels after equivalent doses were greater in hypophysectomized than in sham-operated animals. We conclude that hypophysectomy may enhance the ability of haloperidol to induce striatal dopamine receptor supersensitivity in the rat, and that this may be due to differences in the pharmacokinetic handling of haloperidol between sham-operated and hypophysectomized animals.     

The detection of subchronic testicular damage using urinary creatine: Studies with 2-methoxyethanol

 We have previously shown that a number of testicular toxicants administered acutely to rats raise urinary creatine. The aim of this study was to determine if this creatinuria was maintained during subchronic testicular damage. Repeated exposure of rats to 2-methoxyethanol for 10 days administered in the drinking water caused significant testicular damage at the highest dose. The urinary creatine:creatinine ratio was significantly increased in the animals receiving the highest dose (220 mg/kg per day) and also those receiving doses of 87 mg/kg per day. Increases in the ratio seen after the lowest dose (43 mg/kg per day) were significant in some cases, but showed more variability. Relative testicular weight was only significantly reduced after the highest dose. Increases in body weight over the time of exposure were only significantly lower after the highest dose of 2-methoxyethanol. The results indicate that urinary creatine may be a useful biomarker for chronic testicular damage. Received: 14 July 1994/Accepted: 7 September 1994     

Effects of nicotine and epibatidine on locomotor activity and conditioned place preference in rats

We studied the effects of nicotine and epibatidine given s.c. acutely and repeatedly, on locomotor activity and conditioned place preference (CPP) in rats. Nicotine at 0.5 mg/kg immediately and at 0.8 mg/kg after a delay increased the locomotor activity and its locomotor stimulant effects were greatly sensitized (about fourfold) when it was given repeatedly. Acute epibatidine at 0.6 and 3.0 microg/kg increased the activity modestly after a delay. When given repeatedly epibatidine's stimulant effects, mainly those at 3.0 microg/kg, were somewhat sensitized (less than twofold). Nicotine at 0.5 and 0.8 mg/kg produced CPP in rats in a biased paradigm. Epibatidine elicited CPP at very low dose (0.1 microg/kg), but at 0.3 or 0.6 microg/kg it induced neither preference nor aversion and at the 3.0 microg/kg dose it was aversive. Both acutely and after the repeated administration, epibatidine enhanced the locomotor activity of rats clearly less than nicotine agreeing with its previously reported lesser effects on accumbal dopamine output. Thus, while nicotine elicits CPP at doses (0.5 and 0.8 mg/kg) equal to those that increase accumbal dopamine output and locomotor activity, epibatidine seems to be aversive at the dose (3.0 microg/kg) that enhances accumbal dopamine output and increases locomotor activity.