Showing papers in "Pharmacology, Biochemistry and Behavior in 1994"
TL;DR: Behavioral categories were measured in rats left on an elevated plus-maze for 5 min, in addition to the traditional measures, and four independent factors emerged from a factor analysis, seemingly related with anxiety.
Abstract: Behavioral categories were measured in rats left on an elevated plus-maze for 5 min, in addition to the traditional measures. Four independent factors emerged from a factor analysis. The variables that loaded highly and positively on Factor 1, seemingly related with anxiety, were: number of entries onto open arms, time spent on open arms, percentage of open/total arm entries, percentage of time on open arms, scanning over the edge of an open arm, and open arm end-exploring. The time spent on enclosed arms loaded highly, but negatively on the same factor. Risk-assessment from an enclosed arm also loaded negatively on Factor 1. Number of enclosed arm entries, total number of arm entries and rearing loaded highly on Factor 2, probably related to motor activity. However, the total number of entries also loaded on Factor 1, being thus a mixed index. Similarly, the number of open arm entries loaded on both Factors 1 and 2. As expected, the variables having high loads on Factor 1 were changed to one direction by administration of two anxiolytics (nitrazepam and midazolam) and to the opposite direction by two anxiogenic drugs (pentylenetetrazol and FG 7142). Such pattern of drug effects was not observed with the remaining variables.
798 citations
TL;DR: The data suggest that chrysin possesses anxiolytic actions without inducing sedation and muscle relaxation, and postulate that this natural monoflavonoid is a partial agonist of the central BDZ receptors.
Abstract: The pharmacological effects of 5,7-dihydroxyflavone (chrysin), a naturally occurring monoflavonoid that displaces [3H]flunitrazepam binding to the central benzodiazepine (BDZ) receptors, were examined in mice. In the elevated plus-maze test of anxiety, diazepam (DZ, 0.3-0.6 mg/kg) or chrysin (1 mg/kg) induced increases in the number of entries into the open arms and in the time spent on the open arms, consistent with an anxiolytic action of both compounds. The effects of chrysin on the elevated plus-maze was abolished by pretreatment with the specific BDZ receptor antagonist Ro 15-1788 (3 mg/kg). In the holeboard, diazepam (1 mg/kg) and chrysin (3 mg/kg) increased the time spent head-dipping. In contrast, high doses of DZ (6 mg/kg) but not of chrysin produced a decrease in the number of head dips and in the time spent head-dipping. In the horizontal wire test, diazepam (6 mg/kg) had a myorelaxant action. In contrast, chrysin (0.6-30 mg/kg) produced no effects in this test. These data suggest that chrysin possesses anxiolytic actions without inducing sedation and muscle relaxation. We postulate that this natural monoflavonoid is a partial agonist of the central BDZ receptors.
350 citations
TL;DR: The results suggest that regional patterns of brain DA and 5-HT activation after physical and psychological stress depend on the intensity of that stress, although there are some differences between these stress; and that the more widespread activation of DA and5-HT after more severe stress might relate to behavioral changes that reflect the augmentation of fear.
Abstract: The present study examined whether regional patterns of brain dopamine (DA) and serotonin (5-HT) activation after physical and psychological stress depend on the intensity of that stress. Monoamine concentrations (DA, 5-HT, and their metabolites) were measured using high-performance liquid chromatography with electrochemical detection in eight brain regions of rats exposed to two different intensities of foot shock stress for 30 min (1.5 mA or 2.5 mA) or conditioned fear stress (CFS, after single or repeated foot shock). A low level of foot shock selectively increased the DA metabolism in the medial prefrontal cortex (mPFC), whereas a high level of foot shock increased it in most of the brain regions examined in the present study. A low level of foot shock did not increase the 5-HT metabolism in any regions, but a high-intensity shock increased the 5-HT metabolism in the mPFC, nucleus accumbens, and lateral hypothalamus. Rats that received high-intensity shock displayed more freezing than those that received low-intensity shock in a conditioned fear paradigm (24 h after receiving foot shock, the animals were placed in a shock chamber without being given shock), indicating an augmentation of conditioned fear. The increased DA and 5-HT metabolism were especially marked in the mPFC after CFS following a single foot shock session (2.5 mA). Rats that were repeatedly exposed to 2.5 mA foot shock for a period of 10 days displayed a greater degree of freezing induced by CFS than those given only one foot shock session, indicating an augmentation of fear and stress intensity. CFS after repeated foot shock, like foot shock per se, increased the DA metabolism in most of the brain regions except for the striatum and increased the 5-HT metabolism in the mPFC, nucleus accumbens, and amygdala. These results suggest that regional patterns of brain DA and 5-HT activation after physical and psychological stress depend on the intensity of that stress, although there are some differences between these stress; and that the more widespread activation of DA and 5-HT after more severe stress might relate to behavioral changes that reflect the augmentation of fear.
260 citations
TL;DR: A spectrum of effects caused by oxytocin was similar to that of midazolam but different from that induced by raclopride, and the behavior gradually returned to normal within 24 h.
Abstract: The aim of the present investigation was to explore dose relationships for effects of oxytocin on spontaneous motor activity in the rat. Oxytocin in doses from 1-1000 micrograms/kg was given SC to male Sprague-Dawley rats, and spontaneous motor behavior was measured by means of photocell-operated open-field observations. In the rats treated with low doses of oxytocin (1-4 micrograms/kg), there was a decrease in peripheral locomotor activity. With increasing doses (250-1000 micrograms/kg), there were clear signs of sedative effects as indicated by a suppression of locomotor activity and rearing. The time course for the effect of oxytocin on peripheral activity (1 microgram/kg) and rearing (1 mg/kg) was tested. A maximal effect was obtained within 1 h and, thereafter, the behavior gradually returned to normal within 24 h. This spectrum of effects caused by oxytocin was similar to that of midazolam but different from that induced by raclopride.
256 citations
TL;DR: Inhibitory avoidance remained impaired 3 days later in the rats treated with 1-4 mg/kg DZP, indicating anterograde amnesia, and dose-response curves were determined for the benzodiazepine anxiolytic and amnestic agent diazepam (DZP), as well as for ipsapirone (IPS, 0.25-2mg/kg).
Abstract: In an attempt to analyze different types of anxiety, and at the same time assess memory, a new experimental model was developed. The apparatus, named the elevated T-maze, consisted of three arms of equal dimensions (50 × 10 cm) elevated 50 cm from the ground. One arm, enclosed by 40-cm high walls, was perpendicular to two open arms. The first experimental session was conducted 25 min after IP injection of either drug or saline. To assess inhibitory (passive) avoidance, the rat was placed at the end of the enclosed arm and the time taken to withdraw from this arm was recorded three times in succession. Soon afterwards, the rat was placed at the end of one of the open arms and the time taken to withdraw from this arm was measured, thus estimating one-way escape. To assess memory, inhibitory avoidance and escape were measured again 3 days later, without drug. Dose-response curves were determined for the benzodiazepine anxiolytic and amnestic agent diazepam (DZP, 0.5–4 mg/kg), as well as for ipsapirone (IPS, 0.25–2 mg/kg), an azapirone anxiolytic that is devoid of clinically significant amnestic effects. The doses of 1, 2, and 4 mg/kg DZP and of 1 and 2 mg/kg IPS impaired inhibitory avoidance, an effect that may be viewed as anxiolytic. Inhibitory avoidance remained impaired 3 days later in the rats treated with 1–4 mg/kg DZP, indicating anterograde amnesia. This effect was not due to state-dependent learning, because rats injected both at pretraining and pretesting with 2 mg/kg DZP still showed complete amnesia. In contrast, the doses of 1 and 2 mg/kg IPS did not significantly affect memory, indicating a dissociation between the drug effects on anxiety and memory. Neither the performance of escape nor its memory was affected by DZP or IPS. Therefore, the two aversive tasks studied are likely to generate distinct types of fear/anxiety and memory, which may correlate with different classes of psychiatric disorders. The present results also warrant further exploration of the elevated T-maze as a potential model for the combined study of anxiety and memory.
211 citations
TL;DR: It is demonstrated that performance of lever pressing behavior is accompanied by an increase in Accumbens DA release and metabolism, and that DA release in nucleus accumbens is more closely related to the performance of highly active instrumental responses than it is to consumption of large quantities of food.
Abstract: This experiment was undertaken to investigate the role of nucleus accumbens dopamine (DA) in instrumental and consummatory responses for food. In vivo microdialysis methods were used to study DA release and metabolism in the nucleus accumbens of behaving rats. Four behavioral conditions were used: performance on a fixed ratio 5 (FR 5) schedule of food reinforcement, consumption of Bioserve food pellets, consumption of laboratory chow, and food deprivation control. Groups of rats that were previously exposed to these conditions were implanted with dialysis probes in the nucleus accumbens and tested the day after implantation. The rats that pressed a lever on a FR 5 schedule showed significant increases in extracellular DA and DA metabolites compared to food-deprived control rats. In further analyses, rats that responded on the FR5 schedule were divided into three groups based upon their response rates. The rats with low response rates did not significantly differ from control rats, whereas rats with medium and high rates of responding showed significant increases in DA release relative to the control group. Rats that received massed presentation of food pellets or laboratory chow consumed large quantities of food, but showed no significant increases in DA release. This experiment demonstrated that performance of lever pressing behavior is accompanied by an increase in accumbens DA release and metabolism, and that DA release in nucleus accumbens is more closely related to the performance of highly active instrumental responses that it is to consumption of large quantities of food.
207 citations
TL;DR: It is suggested that PMD treatment leads rats to be insensitive to environmental stimuli in adulthood.
Abstract: The effects of periodic maternal deprivation (PMD) treatment on the adrenocortical stress response and on open-field behavior in adult offspring were investigated. Sprague-Dawley rat pups were deprived of mothers daily for 4.5 h during the first 3 weeks of life. PMD treatment resulted in lower corticosterone levels during restraint stress later in life. The result of dexamethasone suppression test indicated that PMD treatment caused a potentiation of the negative feedback function of adrenocortical response. These effects of PMD were not accompanied by an increased density of the hippocampal glucocorticoid receptor which has been reported to be induced in neonatal handling treatment (brief 15-min maternal deprivation). Serotonin (5-HT)-2 and beta-adrenergic binding sites were also examined in cerebral cortex and no change of binding capacities were induced by PMD treatment. In the open-field test, PMD treatment decreased the number of ambulations and rearings but did not affect a frequency of defecation. From these results, it is suggested that PMD treatment leads rats to be insensitive to environmental stimuli in adulthood.
195 citations
TL;DR: The inhibition of NMDA and AMPA receptors by agents acting at different recognition sites produces qualitatively different behavioral consequences.
Abstract: Locomotor activity, ataxia, and stereotypy were assessed in the open field after administration of NMDA and AMPA antagonists acting by different mechanisms. The interaction with glutamatergic receptors was confirmed in the binding assay. (+)MK-801 and phencyclidine (PCP) produced similar changes in horizontal activity, i.e., a strong increase from the begining of the test. Ketamine, and to a lesser extent, memantine, enhanced horizontal activity at the later observation periods only. Amantadine and NBQX produced a slight inhibition, while GYKI-52466, d -cycloserine, (+R)-HA-966, CGP-37849, and dextromethorphan were ineffective. Vertical activity (rearings) were inhibited by most agents except GYKI-52466 and gly-B partial agonists. At higher doses ataxia was seen after: MK-801, PCP, ketamine, memantine, amantadine, CGP-37849, dextromethorphan, and GYKI-52466. Hence, the inhibition of NMDA and AMPA receptors by agents acting at different recognition sites produces qualitatively different behavioral consequences.
184 citations
TL;DR: The present results are consistent with the notion that accumbens dopamine sets constraints upon which food-related response is selected in a particular situation, and that these depletions alter the relative allocation of food- related responses.
Abstract: Rats were tested on days 1, 3, and 5 of a 5-day test week in an operant chamber in which they could either lever press on a fixed-ratio 5 (FR5) schedule to obtain food pellets (Bioserve) or approach and consume lab chow that was also available in the chamber (Teklad Premier). Rats typically pressed at high rates to obtain the food pellets and ate little of the lab chow. On days 2 and 4 of each week lab chow was not concurrently available, and rats could only lever press on the FR5 schedule for pellets to obtain food. Dopamine depletions produced by intraaccumbens injections of the neurotoxic agent 6-hydroxydopamine produced a dramatic decrease in lever pressing and increase in chow consumption on days when lab chow was available. Lever pressing was not significantly reduced in dopamine-depleted rats on days when chow was not available, although there was a significant correlation between lever pressing and accumbens dopamine levels. These results suggest that nucleus accumbens dopamine depletions do not produce a general deficit in food motivation. Moreover, accumbens dopamine depletions do not appear to produce severe deficits in fine motor control that impair the execution of individual motor acts involved in lever pressing. Rather, the present results are consistent with the notion that accumbens dopamine sets constraints upon which food-related response is selected in a particular situation, and that these depletions alter the relative allocation of food-related responses.
180 citations
TL;DR: Whether cannabinoid receptors exhibit downregulation as a consequence of the chronic exposure to delta 9-tetrahydrocannabinol (THC), which might explain certain tolerance phenomena observed in relation to motor and limbic effects of marijuana, is examined.
Abstract: Specific cannabinoid receptors have been recently described in extrapyramidal and limbic areas and presumably might mediate the effects of marijuana exposure on behavioral processes related to those areas. In this work, we examined whether cannabinoid receptors exhibit downregulation as a consequence of the chronic exposure to Δ 9 -tetrahydrocannabinol (THC), which might explain certain tolerance phenomena observed in relation to motor and limbic effects of marijuana. To this end, we first characterized the binding of cannabinoid receptors, by using [ 3 H]CP-55,940 binding assays, in the striatum, limbic forebrain, and ventral mesencephalon of male rats, and, second, we measured the density and affinity of those receptors in these brain areas after 7 days of a daily treatment with THC. Development of a tolerance phenomenon was behaviorally tested by using an open-field technique. Results were as follows. The three areas studies presented specific and saturable binding for the cannabinoid ligand, as revealed by their corresponding association and dissociation curves, displacement by THC, saturation curves, and Scatchard plots. A chronic treatment with THC produced the expected tolerance phenomenon: The decrease caused by an dose in spontaneous locomotor (49.4%) and exploratory (59.7%) activities and, mainly, the increase in the time spent by the rat in inactivity (181.7%) were diminished after 7 days of daily treatment (39.4, 40.4, and 31.7%, respectively). This tolerance was accompanied by significant decreases in the density of cannabinoid receptors in the striatum and limbic forebrain, the areas where nerve terminals for nigrostriatal and mesolimbic dopaminergic systems, respectively, which play an important role in those processes, are located. This downregulation phenomenon was also observed in the ventral mesencephalon, the area where cell bodies for both dopaminergic neuronal systems are clustered, but the decrease was smaller and nonsignificant. No modifications were seen in the affinity of these receptors by chronic exposure to THC. In summary, a chronic treatment with THC produced downregulation of cannabinoid receptors in the striatum and limbic forebrain and a nonsignificant trend in the ventral mesencephalon. This observation might explain the tolerance phenomena observed in the effects of THC on motor and limbic behaviors after chronic exposures.
170 citations
TL;DR: In this article, the effects of age, gender, satiety status, route of drug administration, and dose on intake of light marijuana users were investigated. But, the effects were not significantly associated with drug effects on food intake.
Abstract: Appetite stimulation by cannabinoids is highly variable. Four within-subject design studies explored the effects of age, gender, satiety status, route of drug administration, and dose on intake. One study involved a single oral administration of active drug (15 mg males, 10 mg females) or placebo to an age and gender stratified sample of 57 healthy, adult light marijuana users. Eleven subjects received single doses by oral, sublingual, and inhaled routes in a second study. In the third study, 10 subjects ingested a single oral dose in fasted and fed states. A 2.5 mg dose was administered b.i.d. for 3 days by oral and rectal suppository routes in the fourth study. Mean daily energy intake was significantly elevated following chronic dosing by rectal suppository, but not oral capsule, relative to all acute dosing regimens except inhalation. Total daily energy intake was comparable on fed and fasted days, suggesting satiety mechanisms were not impaired by the drug. Subject age, gender, reported "high," and plasma drug level were not significantly associated with drug effects on food intake.
TL;DR: Results from saline-injected control animals indicated that EC animals exhibited less vertical activity than IC animals when exposed to the CPP apparatus, andEC animals exhibited a greater magnitude of amphetamine-induced CPP than both the SC and IC animals.
Abstract: This study examined the influence of environmental enrichment on the behavioral response to amphetamine. Beginning at 21 days of age, rats were raised in one of three different environmental conditions: a) an enriched condition (EC), in which animals were caged in groups and provided with novel objects daily; b) a social condition (SC), in which animals were caged in groups without any novel objects; and c) an isolated condition (IC), in which animals were caged individually without any novel objects. At 53 days of age, animals from each environmental condition were assessed for amphetamine-induced changes in locomotor activity and reward using the conditioned place preference (CPP) paradigm. Results from saline-injected control animals indicated that EC animals exhibited less vertical activity than IC animals when exposed to the CPP apparatus. When challenged with amphetamine (0.5 or 2.0 mg/kg), there were no significant differences between SC and IC animals in either locomotor behavior or CPP. However, EC animals exhibited more horizontal and vertical activity following amphetamine than both the SC and IC animals. Similarly, EC animals exhibited a greater magnitude of amphetamine-induced CPP than both the SC and IC animals.
TL;DR: Administration of tyrosine significantly improved matching accuracy at the longest delay interval most affected by cold exposure, such that matching accuracy in the cold following tyrosines was at the same level as matching accuracy following placebo or tyrosINE administration at 22 degrees C.
Abstract: Acute exposure to cold stress has been shown to impair short-term, or working, memory, which may be related to reduction in, or disruption of, sustained release of brain catecholamines. Administering a supplemental dose of the catecholamine precursor tyrosine may alleviate cold stress-induced memory impairments by preventing cold-induced deficits in brain catecholamine levels. The present experiment determined whether administration of tyrosine would prevent a cold-induced working memory deficit, using a computer-based delayed matching-to-sample (DMTS) memory task. Eight male volunteers performed the DMTS task for 30 min at an ambient temperature of either 4 degrees C (cold) or 22 degrees C following a 30-min preexposure period and 2 h after ingesting 150 mg/kg of L-tyrosine or placebo. Subjects demonstrated a decline in matching accuracy on the DMTS task as delay interval increased, such that matching accuracy following a 16-s delay between sample and comparison stimuli was lower than that following a delay of 2 or 8 s. Consistent with previous research, and relative to 22 degrees C exposure sessions, matching accuracy during 4 degrees C exposure sessions was reduced significantly following placebo administration, which is attributed to the effect of cold exposure on short-term, or working, memory. Administration of tyrosine significantly improved matching accuracy at the longest delay interval most affected by cold exposure, such that matching accuracy in the cold following tyrosine was at the same level as matching accuracy following placebo or tyrosine administration at 22 degrees C. Tyrosine administered prior to 22 degrees C exposure had no effect on DMTS performance.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The hypothesis that neurosteroids could be involved in the termination of a stress response is supported by the effects of these compounds in mice on motor activity and behavior in the elevated plus maze.
Abstract: Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are neurosteroids that have been shown to interact with the GABA system. The present study examined the effects of these compounds in mice on motor activity and behavior in the elevated plus maze. Doses of 0.5 mg/kg and above of DHEA reduced motor activity. This effect was blocked by diazepam, RO15-1788, pentylenetetrazole (PTZ), and ethanol. Both DHEA and DHEAS showed anxiolytic activity in the plus maze test, with DHEA being effective over a very wide range doses (5 μg/kg to 1.0 mg/kg). Both Ro15-1788 and PTZ blocked the anxiolytic effect of DHEA, there was no interaction with diazepam, and ethanol enhanced the anxiolytic effect of DHEA. At 1.0 mg/kg, DHEAS blocked the anxiolytic effect of ethanol. These results support the hypothesis that neurosteroids could be involved in the termination of a stress response.
TL;DR: The present findings suggest an additional defect in monoamine uptake and catabolism in iron-deficient rats, and diminished numbers of D2 receptors are suggested.
Abstract: The effect of iron deficiency on brain monoamine metabolism using in vivo microdialysis techniques has not been previously reported. We, therefore, examined the monoamines, dopamine and norepinephrine, and their metabolites at steady state by in vivo microdialysis in rat brain caudate-putamen in 11-week-old iron-deficient anemic (hemoglobin 14 g/dl). Caudate-putamen dopamine (DA), dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA) concentrations were increased by 53%, 57%, and 30% (p < 0.001), respectively, in iron-deficient rats in samples collected over a 4-h period. While diminished numbers of D2 receptors have been previously reported, the present findings suggest an additional defect in monoamine uptake and catabolism.
TL;DR: The findings indicate that the reinforcing value of smoking is increased by overnight abstinence, the presence of a lit cigarette under lean reinforcement conditions, and the order in which reinforcement schedules are presented.
Abstract: One definition of the reinforcing value of a drug is the degree to which an organism will work to obtain it. Male and female smokers (n = 8 each) engaged in a task involving concurrent schedules of reinforcement for responding to receive cigarette puffs versus money on four occasions, following overnight abstinence versus no abstinence and in the presence of a lit cigarette (smoking "cue") or with no cigarette (2 x 2 design). Reinforcement schedule for puffs ranged from variable ratio 4 (VR4) to VR32, with schedule order during the first five trials (VR4 first, VR32 first) counterbalanced and repeated in reverse sequence during the second five trials. Schedule for money remained at VR4 during all trials. Results indicated significantly greater responding for puffs after overnight abstinence and in the presence of the smoking cue, although effect of the cue was specific to the "leaner" VR schedules (VR16, VR32). Unexpectedly, not only was reinforcement schedule for puffs a significant determinant of responding, but the order of these schedules (i.e., VR4 first vs. VR32 first) produced a significant overall difference in responding for puffs, especially in the presence of the cue. There was no difference in responding between males and females. These findings indicate that the reinforcing value of smoking is increased by overnight abstinence, the presence of a lit cigarette under lean reinforcement conditions, and the order in which reinforcement schedules are presented.
TL;DR: In this article, the effects of four dopamine receptor ligands were examined in an ethological version of the murine elevated plus-maze test, and the relative importance of D1 and D2 receptor mechanisms in plusmaze anxiety was discussed.
Abstract: To further our understanding of the potential role of dopamine in mechanisms of anxiety, the effects of four dopamine receptor ligands were examined in an ethological version of the murine elevated plus-maze test. The D1 receptor partial agonist, SKF 38393 (2.5-20.0 mg/kg), had minimal behavioural activity in this test, whereas the selective D1 receptor antagonist, SCH 23390 (0.025-0.2 mg/kg), had dose-dependent but behaviourally nonspecific effects. Quinpirole (0.0625-0.5 mg/kg), a D2 receptor agonist, had no effects at low doses but severely disrupted locomotion and exploration at the highest doses tested. In marked contrast to the lack of effect or nonspecific effects seen with the other ligands tested, the D2 receptor antagonist, sulpiride (2.5-20.0 mg/kg), produced an unambiguous anxiolytic-like profile under present test conditions. Although none of the doses tested adversely affected general activity, clear antianxiety effects were observed on both traditional and novel (i.e., risk assessment) behavioural measures. Data are discussed in relation to the relative importance of D1 and D2 receptor mechanisms in plus-maze anxiety, and the need to further assess D2 involvement through the use of more selective compounds.
TL;DR: The results suggest that the locomotor stimulant effect of caffeine, like that of d-amphetamine, is mediated through dopaminergic systems; both D1 and D2 receptors appear to be involved.
Abstract: The mechanism of action for the behavioral stimulant effects of caffeine has been extensively studied, but results have been ambiguous and inconsistent. The present study examined the role of dopamine in caffeine-induced stimulation of locomotor activity in rats. d-Amphetamine was also tested for comparison. Locomotor activity of male Sprague-Dawley rats (300–350 g) was measured using two-channel electronic activity monitors. Activity counts were recorded for 30 min following a 30-min pretreatment with either caffeine (3.0–100 mg/kg, IP) or d-amphetamine (0.1–3.0 mg/kg, IP) alone and in combination with the D1 dopamine antagonist SCH23390 (0.01 and 0.003 mg/kg, SC) or the D2 dopamine antagonists sulpiride (30 mg/kg, SC) or eticlopride (0.03 mg/kg, SC). Caffeine and d-amphetamine dose dependently increased locomotor activity. This effect of both caffeine and d-amphetamine was blocked by SCH23390 as well as by eticlopride. Sulpiride blocked the stimulatory effects of caffeine but not d-amphetamine. These results suggest that the locomotor stimulant effect of caffeine, like that of d-amphetamine, is mediated through dopaminergic systems; both D1 and D2 receptors appear to be involved.
TL;DR: Results show that σ sites mediate a modulation of the NMDA receptor complex-dependent learning processes and may similarly affect the cholinergic nicotinic memory processes and the PCP derivative PRE-084 reverses the amnesia induced by a drug acting at thePCP site.
Abstract: We investigated the effect of the sigma selective PCP derivative PRE-084 on the impairment of learning induced in mice by the noncompetitive NMDA antagonist MK-801. Learning capacities were evaluated using the spontaneous alternation in a Y-maze test for spatial working memory, the step-down passive avoidance and the elevated plus-maze test for long-term memory. At doses about 1 mg/kg IP, PRE-084 significantly attenuated MK-801 (0.2 mg/kg IP) induced impairment of learning. The dose-response curve was bell-shaped which is typical for cognition enhancers. The effect of PRE-084 was antagonized by BMY-14802 (10 mg/kg IP) and suppressed by a chronic treatment with haloperidol (4 mg/kg/day SC for 7 days). Furthermore, PRE-084 did not affect scopolamine (1 mg/kg SC) induced amnesia but significantly attenuated mecamylamine (10 mg/kg IP) induced amnesia. These results show that sigma sites mediate a modulation of the NMDA receptor complex-dependent learning processes and may similarly affect the cholinergic nicotinic memory processes. Moreover, the PCP derivative PRE-084, acting selectively at sigma sites, reverses the amnesia induced by a drug acting at the PCP site.
TL;DR: The effects of amphetamine exposure persist for 45 days following treatment, which suggest a long-lasting phenomenon, and shorter latencies to acquisition also occurred when the training dose of cocaine was increased, suggesting that the treatment had sensitized rats to cocaine's reinforcing properties.
Abstract: This study assessed the enduring effects of amphetamine preexposure on the subsequent reinforcing effects of cocaine. Rats received nine daily injections of either d-amphetamine SO4 (2.0 mg/kg, IP) or vehicle 45 days prior to testing of the acquisition of cocaine (0.25 mg/kg/infusion) self-administration. The latency to acquire reliable cocaine self-administration was shorter (day 3) in the amphetamine-preexposed rats than in the vehicle-preexposed rats (day 6). These data are comparable to those observed when testing was carried out 1 day following the treatment. In previous studies, shorter latencies to acquisition also occurred when the training dose of cocaine was increased, suggesting that the treatment had sensitized rats to cocaine's reinforcing properties. These effects of amphetamine exposure persist for 45 days following treatment, which suggest a long-lasting phenomenon.
TL;DR: The results suggest that the adrenal secretion of corticosterone directly or indirectly modulates the intake of alcohol in high-preferring rats.
Abstract: The fluid intake of male Wistar rats with simultaneous access to water and 6% ethanol was determined between 0900 and 1500 h. In high-preferring males (normally covering > 60% of their daily fluid consumption in the form of ethanol), two injections with the corticosterone synthesis inhibitor metyrapone (50 mg/kg) at 0900 h and 1200 h for 4 consecutive days significantly reduced ethanol preference such that they preferred water over alcohol. Treatment with corticosterone (0.6 mg/kg) 2 h before each metyrapone injection partially cancelled this effect of the synthesis inhibitor. By contrast, there was no significant effect of metyrapone treatment on the drinking of ethanol in low-preferring rats (normally covering < 30% of their daily fluid consumption in the form of ethanol). These results suggest that the adrenal secretion of corticosterone directly or indirectly modulates the intake of alcohol in high-preferring rats.
TL;DR: Results show selective activation of the mesolimbic dopaminergic projection system as a consequence of a conditioned taste stimulus paired with a nutritive gastric load, suggesting that conditioned DA release may play a role in learned ingestive behavior based on the postingestive effects of food.
Abstract: Rats were prepared with intragastric (IG) cannulae for infusing a nutrient into the stomach and microdialysis guide shafts in the nucleus accumbens (NAC) and striatum (STR) for measuring changes in extracellular dopamine. Prior to dialysis, subjects were trained to prefer the mildly bitter taste of sucrose octaacetate (SOA; CS+) by pairing voluntary intake with automatic IG infusions of nutritive polycose. The mildly sour taste of citric acid (CS−) was paired with IG water infusions as a control. Unconditioned animals received four exposures to SOA and citric acid on counterbalanced, alternating days. After training, dialysis samples were collected every 30 min before, during, and after intake of the CS+ or CS− in response to 14 h water deprivation on counterbalanced, consecutive days. Voluntary intake of the CS+ for 30 min significantly increased extracellular DA in the NAC but not in the STR of conditioned subjects. Intake of the CS− did not alter DA efflux at either site. Unconditioned, control rats also showed no DA response to either taste. These results show selective activation of the mesolimbic dopaminergic projection system as a consequence of a conditioned taste stimulus paired with a nutritive gastric load. This suggests that conditioned DA release may play a role in learned ingestive behavior based on the postingestive effects of food.
TL;DR: It is suggested that both competitive and noncompetitive NMDA antagonists block sensitization to MA and that repeated administration withNMDA antagonists results in behavioral tolerance.
Abstract: The present study examined the effects of both competitive (D-CPP-ene) and noncompetitive (MK-801) NMDA antagonists on behavioral sensitization to methamphetamine (MA). Behavioral effects of repeated administration of NMDA antagonists were also examined. Rats treated with MA according to an escalating dose schedule (2.5, 5, 7.5, and 10.0 mg/kg, SC, twice a day on days 1, 3, 5, and 7, respectively) indicated behavioral supersensitivity. Pretreatment with either MK-801 (0.5 mg/kg, IP) or D-CPP-ene (20 mg/kg, IP) prior to MA administration prevented the development of the supersensitivity. Rats treated with MK-801 showed a decrease in the motor activity when subsequently challenged with MK-801 compared with saline-treated rats. Likewise, rats administered with D-CPP-ene showed decreased motor activity when challenged with D-CPP-ene. There was no cross-sensitization nor tolerance between MA and MK-801 or D-CPP-ene. These results suggest that both competitive and noncompetitive NMDA antagonists block sensitization to MA and that repeated administration with NMDA antagonists results in behavioral tolerance.
TL;DR: The data show clear pharmacological differences between DEX- and PCP-induced stimulation, and most drugs tested depressed spontaneous motor activity.
Abstract: d-Amphetamine (DEX) and phencyclidine (PCP) increased motor activity in rats as measured in automated activity cages. Analysis of the stimulation indicated that both drugs increased horizontal activity (total activity), locomotion, and peripheral activity. However, DEX increased while PCP decreased the incidence of rearing. The ability of different drugs to antagonise DEX- and PCP-induced increases in total activity (called stimulation) was measured. Dopamine (DA) D1 receptor antagonists (SCH23390, NNC-01-0112) were 7-8 times more potent in blocking DEX than PCP. DA D2 receptor antagonists (raclopride, remoxipride, haloperidol) were only 1-2 times more potent against DEX-induced stimulation. Nonselective DA receptor antagonists were also tested. Chlorpromazine was more potent against DEX than against PCP. Buspirone and sertindole were slightly more potent in blocking PCP than DEX. Ritanserin (5-HT2 receptor antagonist) was inactive against both stimulants. 8-OH-DPAT (5-HT1A receptor agonist) potentiated the stimulant effects of DEX and PCP. Prazosin (alpha 1-adrenergic receptor antagonist) partially blocked both DEX and PCP. Most drugs tested depressed spontaneous motor activity. Remoxipride and sertindole, however, caused very little depression even at doses several times higher than those needed to block DEX or PCP. The data show clear pharmacological differences between DEX- and PCP-induced stimulation.
TL;DR: Serotonergic systems may play an important role in the control of anabolic steroid-induced aggressive dominance as well as the antidominant effect of morphine, according to the data.
Abstract: The present study investigates the role of serotonergic systems in anabolic steroid-induced aggression. An animal model of aggressive dominance was used to assess the chronic effects of testosterone propionate. When rats that had become dominant following administration of testosterone propionate received serotonergic agonists with selectivity for the 5-HT1A receptor (8-OH-DPAT, buspirone, gepirone), the 5-H1B receptor (eltoprazine, TFMPP), or the 5-HT2A/2C receptor (DOM), a dose-dependent decrease in dominance was demonstrated. Pretreatment with three serotonergic antagonists (pizotyline, pirenpirone, and pindolol) blocked agonist-induced reductions in dominance in varying degrees. Nonserotonergic agonists with CNS depressant effects were also tested in dominant animals. The benzodiazepine, chlordiazepoxide, did not reduce dominance except at doses that interfered with motor behavior. The opioid agonist, morphine, dose dependently decreased dominance, but this effect was reversible with administration of the serotonergic antagonist, pirenpirone, suggesting the antidominant effect of morphine had a serotonergic component. Biochemical experiments demonstrated that following chronic testosterone propionate, there was a decrease in levels of 5-HT and 5-HIAA in the hippocampus but not in the striatum or the frontal cortex. Chronic testosterone propionate also caused an increase in the affinity of [3H]8-OH-DPAT for the 5-HT1A receptor but no corresponding change in the density of 5-HT1A binding sites in the hippocampus. There was also no change in the properties of the 5-HT2 receptor in the frontal cortex following chronic testosterone propionate. These data suggest that serotonergic systems may play an important role in the control of anabolic steroid-induced aggressive dominance.
TL;DR: Since upregulated [3H]nicotine binding returns to control levels in adult animals within seven days following termination of chronic nicotine infusion, it is unlikely that simple upregulation is responsible for the changes observed in 20-30-day-old mouse brains.
Abstract: Maternal smoking during pregnancy may affect development of the child, but little is known about potential mechanisms of these effects. Since chronic nicotine treatment alters brain nicotinic receptors in adults and also evokes tolerance which is regulated by genetic factors, pregnant mice of two inbred strains underwent chronic nicotine infusion to determine whether the developmental pattern of mouse brain nicotinic receptors would be altered. C3H/2ibg and C57BL/6ibg mice were infused SC with saline or 2.0 mg/kg/h nicotine during the last half of pregnancy. The developmental profiles of [ 3 H]nicotine and α-[ 125 I]bungarotoxin binding in seven brain regions obtained from the offspring were measured. Prenatal nicotine treatment increased levels of [ 3 H]nicotine binding at birth in the C3H hypothalamus, hippocampus, and possibly the cortex, and in the C57BL cortex. At later ages (20–30 days), [ 3 H]nicotine binding was elevated in the C3H hindbrain, hippocampus, striatum, midbrain, and possibly the cortex. The C57BL hindbrain, hippocampus, midbrain, and cortex also showed increased binding at 20–30 days. Little, if any, effect of prenatal nicotine treatment was observed on the development of the α-[ 125 I]bungarotoxin binding site. Since upregulated [ 3 H]nicotine binding returns to control levels in adult animals within seven days following termination of chronic nicotine infusion, it is unlikely that simple upregulation is responsible for the changes observed in 20–30-day-old mouse brains.
TL;DR: Dopamine concentration was decreased in the VTA and STR but was increased in the SN of the hyperactive offspring of nicotine-treated dams, and the reduction in striatal DA level was associated with a reduction in the number of D2 receptors in that area.
Abstract: To evaluate the involvement of the mesolimbic and nigrostriatal dopaminergic systems in hyperactivity in offspring of nicotine-treated dams, timed-pregnant Sprague-Dawley rats were implanted SC on gestational day 4 with osmotic minipumps to receive saline or nicotine (3 or 6 mg/kg/day) for 16 days. Hyperactive and nonhyperactive male offspring of nicotine-treated dams as well as nonhyperactive offspring of saline-treated dams were selected and sacrificed at day 22 postnatally. Discrete brain areas (the nucleus accumbens [NAcc], striatum [STR], frontal cortex [FC], ventral tegmental area [VTA], and substantia nigra [SN]) were microdissected for the evaluation of dopamine (DA) concentration and/or the D2 receptor subtype. Dopamine concentration was decreased in the VTA and STR but was increased in the SN of the hyperactive offspring. The reduction in striatal DA level was associated with a reduction in the number of D2 receptors in that area. The data suggest a role for the VTA and striatal dopaminergic system in offspring hyperactivity.
TL;DR: The results suggest the GABAA receptor binding site for neuroactive steroids is behaviorally active in neonates as well as in adults, and that the anxiolytic effects of the neuro active steroids at this site may be dissociable from their sedative effects at low doses.
Abstract: Several of the recently characterized neuroactive steroids have been proposed to have anxiolytic effects in behavioral models when subjects were tested as adults. In this experiment, the effects of infant subjects were examined using the isolation distress model of anxiety. The production of ultrasonic vocalizations in week-old rat pups after maternal separation was assessed after ICV injections of vehicle or allopregnanolone (1.25–5 μg), or sham injections. Subjects were also observed for activity and behavioral responses and tested on three measures of sedation. Allopregnanolone caused a dose-dependent decrease in ultrasonic vocalizations, with increasing motor incoordination, ataxia, and turning at the higher doses. Sex differences were not observed for any measure. These results suggest the GABAA receptor binding site for neuroactive steroids is behaviorally active in neonates as well as in adults, and that the anxiolytic effects of the neuroactive steroids at this site may be dissociable from their sedative effects at low doses.
TL;DR: The results indicate that in the long term paroxetine has an anxiolytic action, and support the clinical evidence for its therapeutic use in the treatment of anxiety disorders in addition to its established role as an antidepressant.
Abstract: The effects of short- and long-term administration of the selective serotonin reuptake inhibitor paroxetine were investigated in a rat social interaction test. A single administration of paroxetine at oral doses of 0.3, 1, 3 and 10 mg/kg had no effect on social interaction between pairs of male rats under bright light (high anxiety) conditions. After 21 days of daily administration, paroxetine given orally at 3 mg/kg significantly (p < 0.01) increased the time spent in social interaction by pairs of rats tested under the same conditions, with no effect on locomotor activity, indicating an anxiolytic-like effect. The magnitude of increase (+97%) was comparable to that seen after a single dose of chlordiazepoxide (4 mg/kg orally). Although there was also an increase in time spent in social interaction after 21 days of repeated oral administration of paroxetine at 0.3, 1, and 10 mg/kg (+44, +56, and +54% increases, respectively), statistical significance was not achieved. These results indicate that in the long term paroxetine has an anxiolytic action, and thus support the clinical evidence for its therapeutic use in the treatment of anxiety disorders in addition to its established role as an antidepressant.
TL;DR: Male C57BL/6By mice developed a preference for cocaine when given a choice of drinking either water or a solution containing cocaine (200 mg/l), and an acute challenge injection of cocaine produced a significant increase in cocaine-induced locomotor activity and stereotypy in mice previously exposed to cocaine in their drinking water (cocaine choice group.
Abstract: After a period of forced exposure to 300 mg/l cocaine HCl in drinking water for a period of one week, followed by forced exposure to 200 mg/l cocaine for an additional week, male C57BL/6By mice developed a preference for cocaine when given a choice of drinking either water or a solution containing cocaine (200 mg/l). The mean daily intake of cocaine during the choice period was 26 ± 1 mg/kg or, when expressed as the ratio of cocaine over total fluid intake, represented a cocaine preference of 71 ± 2%. Administration of ibogaine HCl (40 mg/kg, two injections 6 h apart) two weeks after the beginning of the choice period reduced the cocaine preference for at least five days; the mean daily intake of cocaine was reduced by 38% (to 16 ± 1 mg/kg per day; p μ g/g wet wt for water vs. mice treated with water plus ibogaine and 9.3 ± 0.2 and 11.8 ± 0.7 μ g/g wet wt for cocaine drinking vs. cocaine drinking plus ibogaine treatment). Neither the reduction in cocaine preference nor attenuation in cocaine-induced ambulatory and stereotypy activity by ibogaine was accounted for by changes in brain levels of cocaine.