Sensitization to the hyperthermic and catecholamine-releasing effects of morphine

Rats were given alternating injections (one per day) of morphine (5 mg/kg) and saline, each substance paired with a distinct set of environmental cues. Over the course of nine injections of the drug, the hyperthermic response to morphine gradually increased. On the tenth such exposure to morphine, half of the rats were injected in the presence of cues previously paired with the drug, and half were injected in the presence of saline cues. In the former (drug-cue) group, hyperthermia, and plasma norepinephrine and epinephrine levels were significantly greater than in rats receiving morphine for the first time. The latter (saline-cue) group showed an intermediate thermic and catecholamine response, not statistically different from drug-cue or control animals. Under these conditions, the enhanced hyperthermic response to morphine (which has been variously described as sensitization or tolerance), was found to be accompanied by a similar increase in elevation of plasma catecholamines.     

Centrally administered vasopressin cross-sensitizes rats to amphetamine and drinking hypertonic NaCl

Prior sodium restriction cross-sensitizes rats to the psychomotor effects of amphetamines and vice versa. Repeated central injections of vasopressin (VP) induce a psychomotor sensitization similar to amphetamine sensitization and repeated sodium deficiency. Thus brain VP signaling may be a common mechanism involved in mediating these two motivational systems. In experiment 1, we tested the hypothesis that rats previously sensitized to central VP would show enhanced psychomotor responses to amphetamine. Rats were administered saline, VP (50 ng), or amphetamine (1 mg/kg or 3 mg/kg) on days 1 and 2, and given saline or amphetamine on day 3. Amphetamine produced psychomotor arousal in all groups. However, amphetamine on day 3 elicited a significantly greater psychomotor response in rats that had prior injections of amphetamine or VP than in rats previously treated with saline. In experiment 2, the hypothesis that prior experience with central VP would cross-sensitize rats to drinking hypertonic sodium (NaCl) solutions was tested. Rats were administered VP (50 ng) or saline for 3 days. On the fourth day, nondeprived rats were given access to 0.3 M NaCl and water for 1 h. Control and saline-treated rats only drank 1 ml of 0.3 M NaCl, but rats previously exposed to central VP drank significantly more hypertonic saline (4 ml). These results show that prior experience with central VP cross-sensitizes rats to the psychomotor stimulant effects of amphetamine and the ingestion of concentrated NaCl solutions. This pattern of cross-sensitization links central VP signaling, amphetamine, and sodium deficiency, and therefore it may play a role in the cross-sensitization between sodium appetite and amphetamines.     

Conditioned place preference from intra-accumbens but not intra-caudate amphetamine injections

Rats received injections of d-amphetamine sulphate (10 micrograms in 0.5 ul) in nucleus accumbens and were placed into one of two (randomly assigned) distinctive environments. The next day the rats were placed into the other environment and received either a saline injection or no treatment. This procedure was repeated six times. When the rats were allowed a free choice between the two environments they showed a significant preference for the one that had been paired with amphetamine. This finding suggests that amphetamine-stimulated release of dopamine in nucleus accumbens can increase the incentive value of neutral stimuli with which it is paired. When the same procedure was carried out with a group of rats that received amphetamine injections in the dorsolateral caudate nucleus, no preference for the side paired with the drug was evident. This suggests that there is functional differentiation between different parts of the dopaminergic terminal system.     

Adaptation to cold swim stress-induced hypothermia: Absence of Pavlovian conditional tolerance

Mice subjected to cold swim stress developed pronounced hypothermia. Exposure to warm water swim, however, had little or no effect on body temperature. After repeated exposure to cold swim, the stress-induced hypothermia was attenuated. The finding that cold swim resulted in hypothermia, whereas warm swim had no effect in this respect, provided a useful experimental design by which to assess the role of conditioning factors in the adaptation to the thermic effects of cold swim. In two subsequent experiments, mice received cold swim either in a familiar environment or in a novel environment. Adaptation to the thermic effects of cold swim was observed when mice were tested in the distinctive environment, regardless of the environmental cues previously paired with repeated exposure to the cold swim stress. These findings suggest that contextual cues were not of primary importance in the development of tolerance to the thermic effects of cold swim stress.     

RGS mRNA expression in rat striatum: modulation by dopamine receptors and effects of repeated amphetamine administration

Single injections of cocaine, amphetamine, or methamphetamine increased RGS2 mRNA levels in rat striatum by two- to fourfold. The D1 dopamine receptor-selective antagonist SCH-23390 had no effect by itself but strongly attenuated RGS2 mRNA induction by amphetamine. In contrast, the D2 receptor-selective antagonist raclopride induced RGS2 mRNA when administered alone and greatly enhanced stimulation by amphetamine. To examine the effects of repeated amphetamine on RGS2 expression, rats were treated with escalating doses of amphetamine (1.0-7.5 mg/kg) for 4 days, followed by 8 days of multiple daily injections (7.5 mg/kg/2 h x four injections). Twenty hours after the last injection the animals were challenged with amphetamine (7.5 mg/kg) or vehicle and killed 1 h later. In drug-naive animals, acute amphetamine induced the expression of RGS2, 3, and 5 and the immediate early genes c-fos and zif/268. RGS4 mRNA levels were not affected. Prior repeated treatment with amphetamine strongly suppressed induction of immediate early genes and RGS5 to a challenge dose of amphetamine. In sharp contrast, prior exposure to amphetamine did not reduce the induction of RGS2 and RGS3 mRNAs to a challenge dose of amphetamine, indicating that control of these genes is resistant to amphetamine-induced tolerance. These data establish a role for dopamine receptors in the regulation of RGS2 expression and suggest that RGS2 and 3 might mediate some aspects of amphetamine-induced tolerance.     

The effect of pentobarbital on the antinociceptive action of morphine in morphine-tolerant and non-tolerant rats

The interaction of sodium pentobarbital with morphine sulfate in both morphine-tolerant and non-tolerant rats was investigated using the tail-compression test for analgesia. Male Sprague-Dawley rats (300–350 g) were given pentobarbital (4, 8, or 16 mg/kg) 5 min before morphine (2, 4, 6, or 8 mg/kg). Control animals received two saline injections, or pentobarbital plus saline, or saline plus morphine. All injections were subcutaneous. Prior to the first injection, a baseline nociceptive threshold was determined for each rat by applying a modified micrometer to its tail and increasing the pressure until a squeak was elicited. Test readings were taken every half-hour for 2 hr beginning 30 min after the second injection. For the chronic studies, animals were first made tolerant to morphine by the administration of the narcotic twice a day for 3 days, increasing the dose from 10 to 50 mg/kg/injection. Identical testing procedures were then followed with these rats except that the test dose of morphine given on day 4 was in the range 8–128 mg/kg. It was found that Na pentobarbital, in the subanesthetic doses used, had neither antinociceptive nor hyperalgesic properties. Furthermore, the barbiturate had no effect on the antinociceptive action of morphine in either morphine-tolerant or non-tolerant rats.     

Effect of repeated nicotine exposure on core temperature and motor activity in male and female rats

Comparatively little is known about the thermoregulatory effects of single and repeated administration of nicotine. Nicotine is a relatively fast acting drug that induces transient changes in core temperature (T_c) of rodents. The development of radio telemetry allows one to detect subtle and rapid changes in T_c that otherwise are difficult to measure with conventional colonic probe techniques. To this end, T_c and motor activity (MA) were monitored by radio telemetry in male and female Sprague-Dawley rats following five daily injections of saline or nicotine tartrate (0.5 mg/kg; sc). The first injection of saline led to a transient increase in T_c that was attributed to the handling and injection procedures. Rats dosed with nicotine for the first time were hypothermic for approximately 2 h after injection. The hypothermia was attributed to an impaired increase in T_c from handling and injection. A transient hyperthermic response began to develop with each successive injection of nicotine. After the fourth injection of nicotine, T_c of male rats increased by 0.5°C above controls; T_c of females increased by 0.25°C above controls after the fifth injection. MA also increased transiently with each injection of saline and nicotine. The MA response of females was significantly greater than the males for the second through fifth injections of nicotine. Overall, the thermoregulatory system develops sensitization with 4–5 repeated injections of nicotine. The mediation of a hyperthermic response to a systemically administered cholinergic agonist is a novel effect. It may aid in understanding the delayed hyperthermic response to organophosphate pesticides. The sensitization of the thermoregulatory system to nicotine may shed light on the neuropharmacological mechanisms of this drug.     

Reserpine-induced hypothermia and its reversal by dopamine agonists

Prior treatments with reserpine altered the thermic response of mice to subsequently administered apomorphine and amphetamine. Thus, normal mice exhibited hypo- and hyper-thermic responses to apomorphine and (+)-amphetamine, respectively but did not respond to (-)-amphetamine. These responses were each readily attenuated by haloperidol. Reserpinized mice, on the other hand, exhibited hyperthermic responses to all three agonists and these responses were not attenuated by haloperidol. In addition to its hypothermic action, reserpine also produced hypoactivity which was reversed by (+)-amphetamine. This reversal of hypoactivity was attenuated by haloperidol. These data suggest that reversal of reserpine-induced hypothermia by dopamine agonists results through activation of mechanisms which are separate from those normally associated with agonist-induced thermic responses. Reversal of hypoactivity, on the other hand, appears to be due to reactivation of those systems which normally regulate locomotor activity.     

Short-term tolerance to morphine: effects of diazepam, phenobarbital, and amphetamine

Short-term tolerance to morphine, which can be demonstrated in as little as 3 hours after a single administration of the opiate, was examined in animals chronically pretreated with diazepam, phenobarbital, or amphetamine. Tail-flick latency in mice and changes in plasma corticosterone in rats were the parameters tested in these experiments. Rats primed with either saline or morphine, 10 mg/kg, were injected 3 hours subsequently with morphine, 5 mg/kg. Those primed with saline showed the characteristic plasma corticosterone elevation following morphine, when serial blood samples were examined, whereas those previously treated with morphine did not. Mice were primed with saline or either of two doses of morphine, 30 or 100 mg/kg, 3.5 hours prior to estimation of tail-flick latency and ED50 determinations. Mice primed with either dose of morphine had significantly higher ED50's than those primed with saline. Chronic treatment with diazepam or amphetamine in either species did not significantly alter short-term tolerance development by either parameter. However, with phenobarbital pretreatment, the plasma corticosterone response was attenuated and short-term tolerance to morphine's analgesic effects did not occur. Further studies in morphine-pelleted mice showed that analgesic tolerance occurred similarly in all groups. This suggests that barbiturates may delay the process.     

Variability in development of tolerance to repeated injections of low doses of dl-amphetamine in rats

Male albino rats received injections of saline for 5 days before and 5 days after a series of 10 daily injections of dl-amphetamine, 1 or 5 mg/kg, sc. Core temperatures were measured every 30 min for 4 h after each injection and feeding activity (on a CRF operant schedule) every 30 min throughout. After amphetamine at either 0800 or 2000 h, a dose-related hyperthermia, stereotypic behavior, and an initial inhibition of feeding occurred. This anorexia decreased over the 4-h post injection period only in the evening-injected rats receiving 5 mg/kg. Mean body weights of all groups continued to increase during amphetamine administration. Mean 24-h food intake tended to remain below that in the control period and the hyperthermic response did not change significantly in any group. Initially on withdrawal from amphetamine all groups showed 'rebound' feeding. Taken with earlier reports, these results suggest that tolerance development to amphetamine-induced anorexia, hyperthermia, and stereotypic behavior occurs at different rates and is dependent upon frequency, route, dose, time, the amphetamine used, and whether the diet was restricted.     

Nicotine increases sucrose self-administration and seeking in rats

Associations between nicotine in cigarettes and food consumption may alter the incentive value of food such that food cue-reactivity is exaggerated during abstinence from smoking. This effect may contribute to the weight gain associated with cessation of smoking. We examined the effects of nicotine (0.4 mg/kg base subcutaneous) paired (NPD) or unpaired (NUP) with 10% sucrose self-administration (SA; 0.2 ml/delivery, 1 h/day for 10 days) on SA response rate and intake as well as sucrose cue-reactivity following either 1 or 30 days of forced abstinence. Rats were administered the training dose of nicotine prior to a second, consecutive cue-reactivity session. NPD rats responded at over three times the rate for sucrose and earned nearly twice the number of sucrose deliveries as NUP rats or saline controls. Sucrose cue-reactivity was greater after 30 days versus 1 day of forced abstinence for all groups. History of nicotine exposure had no effect on sucrose cue-reactivity. However, the subsequent injection of nicotine increased sucrose cue-reactivity only in the NPD groups. There were no abstinent-dependent effects of nicotine challenge on sucrose cue-reactivity. A study conducted in parallel with water as the reinforcer revealed a less dramatic effect of nicotine on intake. There was no history or abstinence-dependent effects of nicotine on water cue-reactivity. Nicotine increases the reinforcing effects of sucrose and sucrose-paired cues when nicotine is present. An implication of these findings is that relapse to nicotine (cigarettes) could substantially elevate food cue-reactivity.     

Reduced tolerance to morphine thermoregulatory effects in senescent rats

Age-related differences in the thermoregulatory response to morphine have been shown in rats. To determine if these age-related differences would be reflected in the acquisition of tolerance, we studied morphine tolerance induced by either a single morphine dose or implantation of a morphine pellet. precipitated withdrawal was also analyzed by inducing withdrawal with naloxone in morphine-pelleted rats. Senescent (26 or 27 month old), mature (10 or 11 month old) and young (3 or 4 month old) male Fischer 344 rats were restrained and changes in rectal temperature were monitored for six hours after morphine administration. Only mature and young rats exhibited increased hyperthermic responses to a second low dose of morphine (5 mg/kg s.c.). Only young rats became tolerant after a single higher morphine dose (25 mg/kg s.c.). All age groups showed tolerance three days after morphine pellet implantation. Hypothermia was equivalent in all age groups when withdrawal was induced by naloxone in morphine-pelleted rats. These results indicate that older rats were more resistant to the acquisition of tolerance to the thermic effects of morphine; however; with continued morphine treatment, rats became tolerant regardless of age.     

Intravenous morphine infusion (IMF) to drug-naive, conscious rats evokes bradycardic, hypotensive effects, but pressor actions are elicited after IMF to rats previously given morphine

Hemodynamic (blood pressure and heart rate) responses of conscious drug-naive rats were studied following intravenous (i.v.) infusion of sterile saline, morphine sulphate, and then naloxone hydrochloride, as well as of other groups previously injected with morphine sulphate. Those groups chronically given morphine sulphate received twice daily injections of morphine sulphate (5 mg/kg, s.c. per injection) for 3 or 6 days before testing with the i.v. infusion of morphine sulphate. Drugs were infused (135 microL/min) through an indwelling femoral venous catheter via a Harvard infusion pump, and blood pressure was recorded from the abdominal aorta via a femoral arterial catheter. Other pretreatment studies were done to determine the receptor mechanisms mediating the blood pressure responses of drug-naive and chronic morphine-treated rats, whereby equimolar doses (0.32 mumol) of specific receptor antagonists were given as a bolus i.v. injection 5 min after saline but before subsequent infusion with morphine sulphate. Intravenous infusion of morphine sulphate (7.5 mg/kg total over 15 min) to drug-native rats caused a transient but precipitous fall in mean arterial pressure and mean heart rate with an associated rise in mean pulse pressure; these effects were blocked in other groups pretreated with atropine. Interestingly, however, rats chronically injected with morphine sulphate for 3 days previously evoked a transient pressor response when subsequently infused i.v. with morphine sulphate, actions that were blocked in other groups when pretreated i.v. with 0.32 mumol of phentolamine, yohimbine, prazosin, or guanethidine. A greater and persistent pressor response occurred following morphine infusion to groups of rats previously injected over 6 days with morphine sulphate, which was associated with tachycardia during the later stages of the 15-min morphine sulphate infusion period. The prolonged pressor and tachycardic responses of this 6-day chronically injected group were completely blocked in another group pretreated i.v. with both phentolamine and propranolol (0.32 mumol). The results suggest that morphine sulphate infusion to conscious, drug-naive rats evokes classical hypotensive effects due to decreases in mean heart rate caused by activation of parasympathetic vagal activity. With 3 or 6 days of chronic morphine sulphate administration beforehand, subsequent i.v. infusion of morphine sulphate evoked pressor actions felt to be caused by a progressive activation of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 400 WORDS)     

Fluoxetine-induced attenuation of amphetamine self-administration in rats

Daily injections of fluoxetine (5.0 mg/kg i.p.) to rats trained to self-administer intravenous d-amphetamine produced marked decreases in drug intake on three successive days of treatment. After fluoxetine injections were stopped, the number of daily amphetamine self-injections was still significantly reduced for an additional 2 days. When trained amphetamine self-administration animals were placed in an apparatus which delivered i.v. saline with each lever press, increased self-injection is observed. Acute fluoxetine injection did not alter this response. However, if fluoxetine is given prior to amphetamine exposure for 1 day and animals are then tested for the saline response, lever pressing activity is significantly reduced. These data might suggest that 5-hydroxytryptaminergic neurons mediate some aversive or negative reinforcing property of amphetamine. If true, this finding could be exploited clinically in cases of human psychomotor stimulant addiction.     

Ro 15-1788 antagonizes the discriminative stimulus effects of diazepam in rats but not similar effects of pentobarbital

The benzodiazepine antagonist properties of Ro 15-1788 were evaluated in rats trained to discriminate between saline and either 1.0 mg/kg of diazepam or 10 mg/kg of pentobarbital in a two-choice discrete-trial shock avoidance procedure. When administered alone, 1.0 mg/kg of diazepam and 10 mg/kg of pentobarbital produced comparable amounts of drug-appropriate responding (> 84%), whether rats were trained to discriminate between diazepam or pentobarbital and saline. Ro 15-1788 (3–32 mg/kg, p.o.), administered 10 min before diazepam or pentobarbital, produced a dose-related blockade of the discriminative effects of diazepam in both groups of rats, but was completely ineffective in blocking the discriminative effects of pentobarbital. The dose-effect curve for the discriminative effects of diazepam was shifted to the right in a parallel fashion 3- and 13-fold by 10 and 32 mg/kg of Ro 15-1788, respectively, indicating that Ro 15-1788 acts as a surmountable, competitive antagonist of diazepam. When administered alone, Ro 15-1788 (32–100 mg/kg, p.o.) produced primarily saline-appropriate responding, although 100 mg/kg of Ro 15-1788 produced drug-appropriate responding in one out of eight rats. When administered orally 30 min after diazepam, Ro 15-1788 (32 mg/kg) completely reversed within 10 min the discriminative effects of diazepam. The blockade of diazepam's discriminative effects by 32 mg/kg of Ro 15-1788 appeared to last at least as long (approximately 2 hr) as the effects of diazepam alone.     

甲基苯丙胺中毒mG1uR5 的表达

目的:研究代谢性谷氨酸受体5(mG1uR5)在甲基苯丙胺中毒的损伤机制中的作用。方法:设立实验组,对照组。实验组分别给予20 mg/kg,10 mg/kg腹腔注射MA;对照组分别给予同剂量的生理盐水。末次注射后24 h内腹腔注射戊巴比妥钠麻醉大鼠后用4%多聚甲醛灌注、取脑后行代谢性谷氨酸受体5的免疫组织化学染色,观察并计数mG1uR5在不同脑区的表达。结果:实验组mG1uR5在大脑纹状体、海马的表达较对照组显著增强,差异有显著性(P<0.05),并呈剂量依赖性。结论:mG1uR5参与了甲基苯丙胺中毒的损伤机制。     

Cues paired with either rapid or slower self-administered cocaine injections acquire similar conditioned rewarding properties

The faster drugs of abuse reach the brain, the more addictive they can be. It is not known why this is. Environmental stimuli associated with drugs can promote the development and persistence of addiction by invigorating and precipitating drug-seeking behaviour. We determined, therefore, whether cues associated with the self-administration of rapidly delivered cocaine (injected intravenously over 5 versus 90 seconds) would acquire greater conditioned rewarding properties, as assessed by the performance of an operant response reinforced solely by the cues. Rats nose-poked for intravenous cocaine infusions delivered either over 5 or 90 seconds. Discrete visual cues accompanied each infusion. The rats could then press a lever to obtain the cues--now a conditioned reward--or an inactive lever. Rats in both the 5- and 90-second groups pressed more on the active versus inactive lever following extensive (24 sessions) but not following limited (3 sessions) self-administration training. There were no group differences in this behaviour. Following withdrawal from cocaine self-administration, lever discrimination progressively abated in both groups and was lost by withdrawal day 30. However, the rewarding properties of the cues were not "forgotten" because on withdrawal days 32-33, amphetamine selectively enhanced active-lever pressing, and did so to a similar extent in both groups. Thus, cues paired with rapid or slower cocaine delivery acquire similar conditioned rewarding properties. We conclude, therefore, that the rapid delivery of cocaine to the brain promotes addiction by mechanisms that might not involve a greater ability of drug cues to control behaviour.     

Recovery of Pavlovian sign-tracking (autoshaping) following the discontinuation of inter-trial interval food in rats

In pigeons, Pavlovian autoshaped keypecking produced by keylight-food pairings has been eliminated by introducing food during periods between CS presentations (i.e., during the inter-trial intervals). Keypecking eliminated in this manner reappears when the inter-trial USs are discontinued even though the CS is no longer paired with US. The present experiment investigated whether this recovery of responding produced by discontinuing unpaired inter-trial US presentations could be extended to another species, rats, within a Pavlovian sign-tracking paradigm. Rats were initially trained on a procedure where insertion of one retractable lever (CS(+)) was followed, response independently, with food, while insertion of another lever (CS(-)) was not paired with food. Rats quickly came to contact the CS(+) lever at high rates, but contacted the CS(-) lever infrequently. In the next phase, CS(+) was no longer followed by food. Explicitly unpaired food was presented only during the inter-trial intervals when both levers were absent. This treatment essentially eliminated the sign-tracking response. In the final phase, the unpaired inter-trial food presentations were discontinued while both CSs continued to be presented without food. This produced a significant recovery of the sign-tracking elicited by the CS(+) lever, extending the species generality of the Pavlovian resurgence phenomenon that has previously only been reported in pigeons, to rats.     

Neuropeptide Y prepares rats for scheduled feeding

When neuropeptide Y (NPY) is administered centrally, meal-anticipatory responses are elicited. If an increase of endogenous NPY is a signal that heralds an imminent large caloric load, timed daily NPY injections may be expected to condition meal-anticipatory responses that facilitate ingestion. Rats received 4-h access to food beginning in the morning and then timed (1600 h), daily third-ventricular injections of NPY or saline for 7 days. On test day (day 8), animals received the conditioning drug (NPY or saline) or the opposite drug. Food was available immediately after injection on test day, and intake was measured. Rats conditioned with NPY and then given saline ate significantly more than rats conditioned with saline and then given saline; they ate the same amount as rats given NPY. Although they ate more, rats trained with NPY did not have changed plasma glucose, insulin, or ghrelin. These data suggest that NPY plays a role in mediating conditionable food-anticipatory responses that help to cope with the effects of large caloric loads.     

MDA: a psychoactive agent with dual stimulus effects

Rats were trained to discriminate injections of either (+)-amphetamine (1.0 mg/kg) or racemic MDA (1.5 mg/kg) from saline in a two-lever drug discrimination task. After stable discrimination performances (greater than 85%) were attained in each group, stimulus generalization studies were conducted. The amphetamine-stimulus generalized to MDA, but not to the hallucinogenic agent DOM; the MDA-stimulus generalized to both amphetamine and DOM. Taken together with our previous finding that DOM-stimulus generalization occurs to MDA but not to amphetamine, the present study suggests that MDA is capable of producing dual stimulus effects in animals. In addition to these salient features, the results of this study also have an impact on stimulus specificity, and further emphasize the importance of thorough dose-response relationships as related to tests of stimulus generalization.