Potentiation by naltrexone of d-amphetamine-induced behavioral suppression and its reversal by clonidine

Rats were trained to perform a fixed ratio-15 operant for food reinforcement during a 30 minute daily session. Naltrexone, in doses up to 45 mg/kg administered 15 min before the behavioral session, failed to disrupt responding. However, 0.3 and 1.0 mg naltrexone/kg produced a dose related potentiation of the operant behavioral suppression induced by 1.0 mg d-amphetamine/kg injected immediately before the session. The naltrexone/d-amphetamine combination also produced excessive salivation and postural abnormalities not seen when either drug was administered alone. [A subsequent study indicated that the salivation induced by naltrexone in combination with d-amphetamine may require previous exposure to naltrexone and/or d-amphetamine.] Blockade of dopamine receptors with pimozide did not modify the interaction. Functional noradrenergic blockade with a low dose of clonidine significantly reversed the potentiated suppression, of operant behavior, as well as the excessive salivation and abnormal posture. These data suggest that there is an important noradrenergic component to the interaction of naltrexone with d-amphetamine. The impressive interaction of behaviorally inactive doses of naltrexone with a moderate dose of d-amphetamine reported here for rats may have clinical implications for detoxified opiate addicts maintained on naltrexone in antagonist therapy programs.     

Operant performance following tail-pinch in the rat: effects of d-amphetamine

To extend the investigation of tail-pinch induced behavioral changes, rats performing on a differential reinforcement of low rates of 10 sec (DRL10), a fixed-interval of 60 sec (F160), and a fixed-ratio of 20 (FR20) schedules were exposed to a paper clip applied to the tail. While a 10 min tail-pinch conducted 1 hr before operant sessions significantly altered the DRL10 behavior, this stressor had little effect on either F160 or FR20 responding. Marked DRL10 behavior performance changes following tail-pinch included increases in the number of lever presses, decreases in the number of the reinforcers, and disruption in the frequency distribution of inter-response times (IRT). These DRL10 operant deficits were diminished when the subject received a tail-pinch pretreatment followed by d-amphetamine treatment (0.2 and 2.0 mg/kg). In combination with biochemical data from others, the present results suggest that catecholamine systems are involved in modulation of DRL10 behavior following tail-pinch.     

Response of hepatic carbohydrate and cyclic AMP metabolism to cadmium treatment in rats.

Daily intraperitoneal injection of cadmium chloride (0.25 or 1 mg/kg) for 21 or 45 days into rats significantly stimulated the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-diphosphatase, and glucose-6-phosphatase, increased the concentrations of glucose and urea in the blood, and decreased the levels of glycogen in the liver. Whereas chronic cadmium treatment failed to alter adenosine-3',5'-monophosphate phosphodiesterase (phosphodiesterase) activity, the endogenous levels of cyclic AMP (cAMP) and the activity of basal- and fluoride-stimulated forms of hepatic adenylate cyclase (AC) were markedly increased in cadmium-injected animals. Treatment with the higher dose (1.0 mg/kg) of cadmium chloride for 45 days produced greater metabolic alterations in hepatic tissue than those seen with the lower dose (0.25 mg/kg) given for a shorter period of time (21 days). Discontinuation of cadmium administration for 14 days in rats previously injected with cadmium chloride (1 mg/kg per day) for 21 days, failed to reverse the observed changes in hepatic cAMP or carbohydrate metabolism. A similar persistence of metabolic alterations was noted in rats treated with cadmium (1 mg/kg per day) for 45 days and subsequently maintained without additional treatment for 28 days. Administration of an acute dose of cadmium chloride (60 mg/kg) decreased hepatic phosphodiesterase activity and glycogen content 1 h after the injection. In addition, acute cadmium exposure increased blood glucose, serum urea, and hepatic cAMP levels, and produced an augmentation of basal- and fluoride-activated AC. However, the activities of various hepatic gluconeogenic enzymes remained unaffected in animals given an acute dose of cadmium chloride (60 mg/kg). Data provide evidence that suggests that the gluconeogenic potential of liver is markedly enhanced following chronic exposure to cadmium and that the cadmium-induced changes in carbohydrate metabolism may be associated with an enhanced synthesis of cAMP. In addition, the present study shows that the cadmium-induced metabolic alterations persist even after the cessation of cadmium treatment for a period of 28 days.     

D-amphetamine-induced hypothermia and hypermotility in rats: Changes after systemic administration of beta-endorphin

Systemically administered beta-endorphin was tested in rats for its ability to modify the hypothermia and hypermotility induced by d-amphetamine. Colonic temperature and motor activity were measured in a cold (4°C) ambient temperature in animals given IP injections of beta-endorphin (0.1, 1.0, or 3.0 mg/kg), naloxone (10 mg/kg), or morphine (30 mg/kg). The same measurements were taken in animals given beta-endorphin (1.0 mg/kg) in combination with naloxone or saline pretreatment and d-amphetamine (15 mg/kg) or saline post-treatment. Morphine alone had a biphasic effect on thermoregulation, but did not affect d-amphetamine-induced hypothermia. Activity scores were decreased by morphine, in both d-amphetamine and saline treated animals. The thermal response of rats to beta-endorphin alone was variable, depending on dosage, but all 3 dosages partially blocked the hypothermic effect of d-amphetamine. Naloxone blocked the thermal effects of both beta-endorphin and d-amphetamine. Motor activity tended to be decreased by naloxone, regardless of amphetamine treatment, but beta-endorphin tended to increase activity in amphetamine-treated animals and reduce it in saline-treated controls. In their actions on both thermoregulation and activity, naloxone and beta-endorphin appeared to interact independently with d-amphetamine, often producing effects in the same direction, but in combination, they tended to be mutually inhibitory.     

A comparison of dressed crab and a cadmium salt (CdCl2) as cadmium sources in rat diets

1. A long term low level exposure experiment was conducted on rats in order to determine the metabolic patterns of realistic environmental dietary levels of cadmium from different sources. 2. Male and female rats were fed a diet for 6 months with a high crab content containing 4 mg Cd/kg as organic bound cadmium from dressed crab, a diet with low crab content containing 0.2 mg Cd/kg as organic bound cadmium, a casein based diet containing 4 mg Cd/kg as cadmium chloride and a low cadmium level control diet. 3. Analysis of the cadmium levels in the kidney, liver and spleen showed that uptake from the dressed crab was only half of that from the diet fortified with cadmium chloride.     

Acute effects of d-amphetamine on the differential reinforcement of low-rate (DRL) schedule behavior in the rat: comparison with selective dopamine receptor antagonists

Amphetamine and it analogs have been shown to affect operant behavior maintained on the differential reinforcement of a low-rate (DRL) schedule. The aim of the present study was to investigate what specific component of the DRL response is affected by d-amphetamine. The acute effects of d-amphetamine on a DRL task were compared with those of the selective dopamine D1 and D2 receptor antagonists, SCH23390 and raclopride, respectively. Pentylenetetrazole and ketamine were also used as two reference drugs for comparison with d-amphetamine as a psychostimulant. Rats were trained to press a lever for water reinforcement on a DRL 10-s schedule. Acute treatment of d-amphetamine (0, 0.5, and 1.0 mg/kg) significantly increased the response rate and decreased the reinforcement in a dose-related fashion. It also caused a horizontal leftward shift in the inter-response time (IRT) distribution at the doses tested. Such a shifting effect was confirmed by a significant decrease in the peak time, while the mean peak rate and burse response remained unaffected. In contrast, both SCH23390 (0, 0.05, and 0.10 mg/kg) and raclopride (0, 0.2, and 0.4 mg/kg) significantly decreased the total, non-reinforced, and burst responses. The de-burst IRT distributions were flattened out as shown by the dose-related decreases in the mean peak rate for both dopamine antagonists, but no dramatic shift in peak time was detected. Interestingly, neither pentylenetetrazole (0, 5, and 10 mg/kg) nor ketamine (0, 1, and 10 mg/kg) disrupted the DRL behavioral performance. It is then conceivable that d-amphetamine at the doses tested affects the temporal regulation of DRL behavior. The effectiveness of d-amphetamine is derived from its drug action as a psychostimulant. Taken together, these data suggest that different behavioral components of DRL task are differentially sensitive to pharmacological manipulation.     

Morphine self-administration added to food conditioning: methodological variant in rats]

Rats with permanent intra-jugular cannula are submitted to an alimentary operant reinforcement schedule with fixed ratio type FR 1, FR5, then FR 20. As a result, the animals are self administering (together with the alimentary inducer) a slow (about 5 sec) intravenous infusion of morphine (0.05 mg/kg). 20 per cent only of the experimental population exhibit a psychogenic dependance afterward. On the other hand, the animals for which morphine self-administration has been substituted to the alimentary reinforcement without respecting a transitory period combining both types of reinforcement have never shown any tendancy toward morphine self-administration. The lack of positive results could be related to the marked duration of the self-injection.     

Estimation of absorbed cadmium in tissues of male and female albino rats through different routes of administration

The resultant effects of cadmium exposure are seen in almost all the systems of the body, however, this study is designed to quantify its accumulation in tissues of animals exposed to cadmium. The rats were divided into two distinct groups of males and females, which were then divided into three groups, each for the monitoring of exposure. Group 1 served as control male and female and received normal rat chow and tap water. Group 2 males and females were treated with 5 mg/kg body weight of cadmium chloride (Cd) intraperitoneally for eight days while Group 3 males and females rats received 100 ppm of Cd in drinking water for 18 days. The concentrations of cadmium were analyzed in tissues (lung, stomach, kidney, heart, spleen, blood) by AAS. There were significant (P.     

Capsaicin does not attenuate bombesin-induced suppression of operant responding for food reward.

Systemic treatment with capsaicin, a neurotoxin which damages unmyelinated peptide-containing sensory neurons, has been shown to attenuate bombesin (BBS)-induced suppression of food intake. To determine whether capsaicin-sensitive fibers mediate the effect of BBS on appetitive motivation, we examined BBS-induced suppression of operant responding in rats pretreated neonatally with capsaicin (50 mg/kg; SC) or control vehicle. At 8-10 weeks of age, rats were trained to bar press for food. After achieving a stable level of performance, the animals were injected with BBS (10 micrograms/kg), normal saline, or prefed with 20 Noyes 45-mg pellets. Animals were then tested in an operant chamber on an FR 5 schedule of reinforcement for one hour. The results indicated that BBS suppressed bar pressing, regardless of whether animals were pretreated with capsaicin or control vehicle. These findings are inconsistent with the hypothesis that BBS induces satiety via capsaicin-sensitive neurons. The results suggest the possibility that more than one mechanism may mediate the effects of BBS: a neural mechanism involved in consummatory responses and a humoral mechanism involved in the operant response.     

Alterations in plasma sodium and potassium levels following chronic oral ingestion of lead, mercury and cadmium in male albino rats.

Adult male albino rats were orally administered 0, 25, 50 and 100 ppm of lead nitrate, mercuric chloride and cadmium chloride for 60, 120 and 180 days. The plasma sodium levels were decreased in rats exposed to varying doses of lead and mercury up to 180 days, while animals which consumed cadmium chloride showed an increase in sodium levels. In lead and mercury treated animals, plasma potassium levels were increased up to 180 days. The levels were decreased in cadmium exposed rats. These observations suggest that chronic exposure to these heavy metals considerably influences plasma sodium and potassium levels depending on the dose and duration of exposure.     

Prolonged microwave irradiation of rats: Effects on concurrent operant behavior

Two measures of performance were used to study the effects of pulse-modulated microwave radiation (PM MWR) on schedule-controlled operant behavior of rats: 1) cued (S^D), fixed-ratio (FR) bar pressing for food reinforcement; and 2) noncued (S^d) bar pressing in the absence of food reinforcement. The animals were irradiated and the behavioral data were obtained concurrently, during daily three-hour sessions, five days per week for six to nine weeks. Each experiment began with a two to three-week baseline interval of sham irradiation; a two to three-week interval of sham irradiation followed the irradiation phase. The irradiated animals were exposed to 1.3-Ghz PM MWR (pulse width of 1 microsecond at 600 pulses per second) at whole-body, average specific absorbed-dose rates of from 1.5–6.7 mW/g. Control and irradiated animals were tested in identical, cylindrical waveguide exposure/behavioral assemblies; different groups of irradiated and sham-irradiated animals were used for each dose rate. At 1.5 mW/g, the levels of S^D operant responding by control and irradiated animals were comparable, and showed similar progressive diminutions over the course of each daily session. S^d operant responding was more variable, but again comparable, with both groups showing similar, progressive declines in rate of responding during each session. At 3.6 mW/g, no specific effects on S^D operant response rates were observed. However, there was an initial and transient increase in the rate of extinction of S^d responding. At 6.7 mW/g, S^D response rates were slightly reduced, whereas there was a major reduction in noncued (S^d) operant responding followed by a sharp rebound during the first post-MWR week. This marked reduction in S^d operant responding at MWR onset was in contrast to the relative stability and persistence of FR responding for food reinforcement.     

Evidence of possible opiate dependence during the behavioral depressant action of a single dose of morphine

Rats were trained to lever press for food pellets under a 20 response fixed ratio (FR 20) schedule of reinforcement. A single injection of 15 mg morphine SO₄/kg suppressed operant behavior for $\text{1}\text{1}\text{2}\text{–3}\text{1}\text{2}\text{hrs}$, after which time responding resumed at a reduced rate. When 0.25 mg naloxone HCl/kg was given during the recovery phase, the behavioral depressant effect of the narcotic was immediately reversed and operant performance returned to predrug rates. In contrast, when 0.5 mg naloxone/kg was given at this time, operant behavior was abolished for at least 1 hr. Naloxone, at these doses, did not affect responding in drug-naive subjects. These results suggest that a single, relatively low dose of morphine can induce transient dependence which is detectable for several hrs after drug administration, at a time when the acute pharmacological actions of morphine are still apparent.     

The role of undernutrition in animal models of hyperactivity

The influence of neonatal growth retardation on subsequent spontaneous activity and activity following d-amphetamine (10 mg/kg, i.p.) was studied in CD-1 mice. Different growth rates were obtained by raising mice in litters of either 8 or 16 sucklings per lactating dam. The testing protocol was specifically designed to duplicate a procedure used to assess the influence of neonatal lead exposure on locomotor activity. At 35 to 37 days of age mice were individually tested for general locomotor activity and drug response. Developmental growth retardation influenced their pattern of habituation to the test apparatus and their locomotor response to emphetamine. It was concluded that growth retardation may partially account for behavioral effects previously attributed to the neurotoxic effects of viruses, 6-hydroxydopamine or inorganic lead.     

Iron deficiency induces reversal of dopamine dependent circadian cycles: differential response to d-amphetamine and TRH

Rats made nutritionally iron-deficient (ID) have significantly diminished haemoglobin, serum iron and hypothermic response to d-amphetamine (15 mg/kg). The reduction of d-amphetamine induced hypothermia is comparatively greater in the dark than in the light period. Neither TRH (1 mg/kg) nor CG 3703, a peptidase resistant TRH analogue (1 mg/kg), induced hypothermia in control of ID animals. However, in combination with d-amphetamine, TRH and CG 3703 did not alter the hypothermic effect observed initially with d-amphetamine. In contrast to control animals, ID rats treated with saline or d-amphetamine (15 mg/kg) exhibited a greater degree of motor activity in the light as compared to the dark period. However, the overall activity (light plus dark) was unchanged in the ID group. The motor activity in response to TRH or CG 3703 was not changed as a result of iron-deficiency. These differential responses may be due to a more pronounced action of d-amphetamine on dopaminergic system, which is known to be changed in iron-deficiency, and of TRH and CG 3703 on the noradrenergic neurones.     

Ascorbic acid blockade of muscle contractions by neurotransmitters and 2-aminoethanol.

Rats given intracisternal administration of 5–6 dihydroxytryptamine (5,6 DHT) 5 days after birth were tested at two subsequent periods for alterations in locomotor activity and responsiveness to dl-amphetamine and scopolamine. Later in life they were given amphetamine while performing on an FR-6 operant schedule for food reward. Biochemical analyses revealed that the 5,6 DHT treatment produced reductions in forebrain serotonin content. There was no alteration in the treated animals in locomotor activity or in responsiveness to amphetamine in the open field. However, animals given the highest dose (75 μg) of 5,6 DHT neonatally showed open field activity increases at high doses of scopolamine significantly more frequently than the other groups of animals. Although treatment with 5,6 DHT did not affect response rates on the FR task under no-drug conditions, the rate-suppressive effects of amphetamine on the FR task were greatly enhanced in the treated animals.     

Potentiation of apomorphine and d-amphetamine effects by naloxone

The effects of naloxone, an opiate antagonist, on the stereotypic behavior and locomotor activity induced by apomorphine and d-amphetamine were studied. Groups of adult male Sprague-Dawley rats were first tested for stereotypy and locomotor activity after apomorphine (0.0 – 2.0 mg/kg) or d-amphetamine (0.0 – 10.0 mg/kg). Groups were subsequently tested with saline or naloxone (1.0 – 4.0 mg/kg) plus the previously used dosage of apomorphine or d-amphetamine. Naloxone alone did not produce stereotypy, but did significantly reduce locomotor activity. Naloxone potentiated apomorphine and d-amphetamine induced stereotypy. Apomorphine-induced activity was increased by naloxone, but d-amphetamine-induced activity at 2.5 mg/kg was reduced. The results are compatible with the suggestion that naloxone may potentiate both apomorphine and d-amphetamine by inhibiting an opiate receptor mechanism which normally interacts with catecholamine neuronal action.     

Tolerance to d-amphetamine: behavioral specificity.

In a Y-maze exploratory task mice tend to enter that compartment which was least recently visited (spontaneous alternation). Low doses of d-amphetamine (1.0 mg/kg) reduce alternation to chance levels, while high doses (10.0 mg/kg) result in animals successively visiting only two compartments of the Y-maze (perseveration). Following daily d-amphetamine injection (1.0 or 10.0 mg/kg) over a 30 day period tolerance to the d-amphetamine induced perseveration was observed; however, chronic amphetamine treatment did not modify the locomotor stimulating effects of d-amphetamine or the reduction of alternation to chance levels produced by low doses of the drug. It was hypothesized that tolerance to d-amphetamine occurs exclusively to behaviors mediated by norepinephrine.     

Viscum album prevents haematological changes,electrolyte imbalance,changes in liver function enzymes and histological alterations in some selected tissues in cadmium chloride-intoxicated rats

BackgroundThe use of Viscum album to treat different diseases is popular in the practise of alternative medicine. We investigated the ability of the aqueous extract of V. album to protect against the toxic effects of cadmium.MethodsThirty rats used for the experiment were treated as follows; Group 1 – no cadmium or extract. Group 2–10 mg/kg body weight of cadmium chloride. Group 3–10 mg/kg body weight of cadmium chloride and 200 mg/kg body weight of aqueous extract of V. album. Group 4–10 mg/kg body weight of cadmium chloride and 400 mg/kg body weight of aqueous extract of V. album. Group 5–10 mg/kg body weight of cadmium chloride with 800 mg/kg body weight of aqueous extract of V. album. Group 6–10 mg/kg body weight of cadmium chloride and atorvastatin (100 mg/kg body weight).ResultsApart from WBC and platelets, other haematological parameters and electrolytes, urea and creatinine levels were not significantly affected by the administration of cadmium chloride along with the aqueous extract of V. album. Treatment with the extract caused significant decreases in the hepatosomatic index, cardiosomatic index, and increase in renosomatic index of the test rats. It also resulted in significant (P < 0.05) decrease in AST level. Histological report also shows that treatment with the extract restored the normal myocardium and vascular architecture of the heart, normal portal and vascular architecture of the liver and normal glomerular and tubular architecture of the kidney, in the cadmium-intoxicated experimental rats.ConclusionV. album protects against the toxic effects of cadmium chloride.     

Cadmium chronotoxicity at pituitary level: effects on plasma ACTH,GH, and TSH daily pattern

Cadmium is an endocrine disruptor that has been shown to induce chronotoxic effects. The present study was designed to evaluate the possible cadmium effects on the daily secretory pattern of adrenocorticotropin hormone (ACTH), growth hormone (GH), and thyroid-stimulating hormone (TSH) in adult male Sprague-Dawley rats. For this purpose, animals were treated with cadmium at two different doses [25 and 50 mg/l cadmium chloride (CdCl₂)] in the drinking water for 30 days. Control age-matched rats received cadmium-free water. After the treatment, rats were killed at six different time intervals throughout a 24-h cycle. Cadmium exposure modified the 24-h pattern of plasma ACTH and GH levels, as the peak of ACTH content between 12:00 and 16:00 h in controls appeared at 12:00 h in the group treated with the lowest dose used, while it appeared between 16:00 and 20:00 h in rats exposed to 50 mg/l CdCl₂. In addition, the peak of GH content found at 04:00 h in controls moved to 16:00 h in rats exposed to 25 mg/l CdCl₂, and the highest dose used abolished 24-h changes of GH secretion. The metal treatment did not modify ACTH secretory pattern. Exposure to cadmium also increased ACTH and TSH medium levels around the clock with both doses used. These results suggest that cadmium modifies ACTH and TSH medium levels around the clock, as well as disrupted ACTH and GH secretory pattern, thus confirming the metal chronotoxicity at pituitary level.     

Role of adenosine in hypoxic ventilatory depression

The role of adenosine in the ventilatory depression induced by hypoxia was studied in 82 spontaneously breathing urethan-anesthetized 4-day-old rabbit pups. Respiration was monitored with a pneumotachograph. The animals were exposed to hypoxia (6% O2 in N2) for 30 min or until the occurrence of terminal apnea. In all animals hypoxia produced an initial increase in ventilation followed by a decrease. In the control group 52% of the animals became apneic after 7 min of hypoxic exposure. By contrast, pretreatment with dipyridamole (10 or 20 mg/kg), an adenosine uptake blocker, significantly shortened the time needed to reach apnea. Thus at 7 min of hypoxia 93% of the animals that received dipyridamole became apneic. On the other hand, administration of adenosine antagonists 8-p-sulfophenyltheophylline (5 or 8 mg/kg) and aminophylline (10 or 25 mg/kg) significantly prolonged the time required to produce apnea. Only 20% of the animals that received these antagonists became apneic at 7 min of hypoxia. These results suggest that adenosine is potentially involved in the ventilatory depression produced by hypoxia in neonatal rabbit pups.