Discriminative stimulus,antagonist, and rate-decreasing effects of cyclorphan: Multiple modes of action

The discriminative effects of cyclorphan were studied in pigeons trained to discriminate 0.32 mg/kg ethylketazocine, 1.8 mg/kg cyclazocine, or 32 mg/kg naltrexone from saline. A fourth group of pigeons was administered 100 mg/kg/day morphine and trained to discriminate 0.1 mg/kg naltrexone from saline. Cyclorphan produced dose-related ethylketazocine-appropriate responding that reached a maximum of 83% of the total session responses at 0.3 mg/kg. Higher cyclorphan doses produced less ethylketazocine-appropriate responding. In pigeons trained to discriminate cyclazocine from saline, maximum drug-appropriate responding of greater than 90% occured at 5.6–10.0 mg/kg cyclorphan. In narcotic-naive pigeons trained to discriminate 32 mg/kg naltrexone from saline, cyclorphan produced a maximum of less than 50% drug-appropriate responding. In contrast, in pigeons chronically administered morphine and trained to discriminate 0.1 mg/kg naltrexone from saline, 1.0 mg/kg cyclorphan resulted in 100% drug-appropriate responding. In pigeons responding under a multiple fixed-interval, fixed-ratio schedule of food delivery, cyclorphan produced a complete dose-related reversal of the rate-decreasing effects of 10 mg/kg morphine, the maximally effective antagonist doses being 1.0–3.2 mg/kg. Higher cyclorphan doses (10 mg/kg) resulted in response rate decreases that were not reversed by naloxone (1 mg/kg). Thus, cyclorphan has discriminative effects that are similar to those of both ethylketazocine and, at 20-fold higher doses, cyclazocine. In addition, in morphine-treated pigeons, cyclorphan, across the same range of doses that produce ethylketazocine-appropriate responding, has discriminative effects that are similar to those of naltrexone, an effect that is probably related to the antagonist action of the drug.     

The effects of phencyclidine on operant behavior in the rat: biphasic effect and tolerance development

Rats were trained to respond on a variable interval 60 sec (VI-60) schedule of water reinforcement. Phencyclidine (PCD) in doses of 0.25, 0.5, and 1.0 mg/kg i.p. increased response rates, respectively, to 118%, 140%, and 143% of the control rates. In contrast, doses of 2.0 and 4.0 mg/kg decreased response rates to 73% and 6% of the control rates. In the tolerance study, one group of rats received daily treatments of 4.0 mg/kg PCD immediately prior to the operant session, while a second group received the same daily dose of PCD after the operant session. When both groups of animals were treated prior to the operant session on a test day, they both displayed complete tolerance to the rate depressant effect of PCD. These results indicate that the observed tolerance to PCD was not dependent on behavioral compensatory mechanisms.     

Behavioral effects of phencyclidine (PCP) in the dog: A possible animal model of PCP toxicity in humans

The acute behavioral effects of PCP, given intravenously in doses of .25, .50, 1.00, 2.50 and 5.00 mg/kg, were examined in 8 male mongrel dogs tested in an open field arena. All doses produced an initial “eyes open” coma accompanied by tremors, rigidity, jerky limb movements, nystagmus, excessive salivation, head weaving, stiff tail, and stereotyped sniffing. In addition, doses of 1.0 mg/kg and above produced jaw snapping, opisthothonus and clonic/tonic seizures. Following recovery from coma, animals evinced pronounced hyperactivity and stereotyped circling. In contrast to other laboratory animal species, the behavioral effects produced by PCP in the dog are strikingly similar to those reported to occur in humans after PCP administration, suggesting that this species may provide an excellent laboratory animal model for studying PCP toxicity.     

Comparison of anorectic drugs in rats trained to discriminate between satiation and deprivation

Eight male rats were trained to discriminate between the internal states produced by food deprivation of 3 hours (satiation) and that produced by food deprivation of 27 hours duration (deprivation). One lever, in a two-lever operant chamber, had to be pressed to receive reinforcement in the satiation state, whereas pressing the other lever was required when the rat was in the deprivation state. Once the rats were trained, increasing the number of hours of food deprivation, from 1 to 48 hours, resulted in more deprivation-appropriate lever responses in the two-lever operant task. Administration of doses of fenfluramine (0.5-1.5 mg.kg), its active metabolite norfenfluramine (0.25-1.0 mg/kg) or d-amphetamine (0.5-1.5 mg/kg) produced a dose-responsive decrease in deprivation-appropriate responses when each drug/dose was injected (i.p.) 15 min prior to deprivation (27 hours) testing. Norfenfluramine was 1.5 times more potent than fenfluramine which was 1.5 times more potent than amphetamine.     

Enhanced sensitivity to naltrexone is associated with an up-regulation in GABA receptor function.

Rats were made sensitive to the effects of the opioid antagonist naltrexone by treating them once weekly with cumulative doses of the drug (1, 3, 10, 30 and 100 mg/kg). Sensitization was monitored by measuring salivation following naltrexone administration. During the first week of treatment, no salivation was noted following any dose of naltrexone. Over a period of 8 weeks, however, increasing amounts of salivation were noted, with the most salivation occurring at the higher doses. Animals treated for 8 weeks with saline never salivated following injections. Following the development of sensitivity to naltrexone, the rats were sacrificed and their brains were assayed for GABA receptor function. GABA-stimulated chloride uptake, a measure of GABA receptor function, was unchanged in the cortex, but was increased in the cerebellum. These results suggest that the effects of naltrexone on cerebellar GABA receptors may be involved in the development of enhanced sensitivity to opioid antagonists.     

Alteration of ethanol self-administration by naltrexone

The effect of naltrexone HC1 (NLTRX) on the reinforcing properties of ethanol (EtOH) was evaluated with intravenous self-administration (IVSA). Eight drug-naive, male, 3.5–5.0 Kg rhesus monkeys ($\text{M. mulatta}$) were selected for: spontaneous acquisition of EtOH IVSA, consumption of at least 1.0 gm/Kg/day of EtOH during daily 4 hr. IVSA test sessions, and extremely low daily variability (10%) of EtOH intake during a 30 day control period. The selected subject group received intramuscular injections of either saline (SAL) (1.0 ml) or NLTRX (1, 3, 5 mg/Kg) 30 minutes before each test session. SAL was administered for 10 consecutive days and each NLTRX dose for 15 consecutive days. SAL phases were alternated with the NLTRX phases. NLTRX pretreatment produced lower levels of EtOH IVSA than those observed during SAL pretreatment phases. The magnitude of the suppression of EtOH IVSA corresponded to the NLTRX dose and was statistically significant following both 3 mg/Kg (p<0.05) and 5 mg/Kg (p<0.01) doses. NLTRX pretreatment produced transient increases in EtOH IVSA during the first 5 days of treatment, followed by significant decreases for the next 10 days. These data suggest that the blockade of opiate receptors by NLTRX in rhesus monkeys apparently decreases the reinforcing effects of EtOH measured with IVSA techniques.     

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.     

Operant behavior in transition reflects neonatal exposure to cadmium

Male Long-Evans rats were injected with 0, 1, 3, or 6 mg/kg of cadmium chloride on the first day of life. Animals free of morphological stigmata at weaning were selected for study. Tissue concentrations of cadmium and operant behavior under various fixed-ratio (FR) schedules of reinforcement were evaluated when these rats were adults. Dose-related increases in cadmium were present in the brains, livers, and kidneys. Dose-related differences in behavior were most evident during the transition from fixed ratio 25 (FR 25 or 25 responses/reinforcer) to FR 75. An inverted U describes the relationship between response output during the transition to FR 75 and cadmium chloride dose response output increased at 3 mg/kg and decreased at 6 mg/kg. The rate decreases were not correlated with weight loss that appeared after some of the animals exposed to 6 mg/kg reached 60 days of age. Challenge doses of d-amphetamine revealed no interaction between neonatal exposure to cadmium and d-amphetamine. The occurrence of alterations in operant behavior in animals that appeared normal on a number of preweaning evaluations suggests that operant behavior in transition was sensitive to subtle effects not observed with other commonly used tests. The data provide evidence for delayed effects in the adult that are due to neonatal exposure to cadmium.     

Interaction of MIF-I or alpha-MSH with D-amphetamine or chlorpromazine on thermoregulation and motor activity of rats maintained at different ambient temperatures

Administration of several doses of MIF-I or alpha-MSH did not modify colonic temperature or the level of motor activity of rats in ambient temperatures of 4 degree or 20 degrees C. However, the thermoregulatory but not motor effects of the interaction between MIF-I or alpha-MSH with d-amphetamine were dependent upon ambient temperature. At 4 degree C, 1.0 mg/kg of both peptides enhanced the d-amphetamine-induced hypothermia, but at 20 degrees C both peptides blocked the hyperthermic effects of d-amphetamine. The hypothermic effect of chlorpromazine (CPZ) at 4 degree C and 20 degrees C was blocked by 1.0 mg/kg MIF-I but not by 1.0 mg/kg alpha-MSH. No linear dose response relationships between various doses of MIF-I or alpha-MSH and thermal responses were found. Administration of melanin or the use of hypophysectomized rats did not alter the significant interactions observed after peripheral injections.     

Ondansetron amelioration of scopolamine induced cognitive deficits in three-panel runway apparatus in rats

Effect of ondansetron (5-HT3-receptor antagonist) was studied on the working memory deficits induced by scopolamine, a muscarinic receptor antagonist in rats using a three-panel runway apparatus. Varying doses of scopolamine (0.1-0.56mg/kg, ip) were administered alone or in combination with ondansetron (0.01-1.0 mg/kg, ip) and memory errors and latency period of the session were recorded on a three-panel runway apparatus. Treatment with scopolamine (0.56 mg/kg) produced working memory deficits in rats. Treatment with ondansetron (1.0 mg/kg) significantly reduced the scopolamine-induced working memory deficits.     

An analysis of D-amphetamine produced facilitation of avoidance acquisition in rats and performance changes subsequent to drug termination

In Experiment I rats were trained on a discriminated Y-maze active avoidance task following administration of saline or one of three dosages (.75, 1.50 or 3.0 mg/kg) of d-amphetamine. The six measures recorded simultaneously during each session indicated that the avoidance facilitation produced by d-amphetamine was due to attenuation of shock-induced behavioral suppression resulting in a behavioral baseline more compatible with the animal's associating running with shock avoidance. Results from Experiment II showed that the avoidance decrement following drug termination is dependent on training dosage and whether the drug is abruptly or gradually withdrawn. This experiment further suggested that the disruption is due to dissociation between the drug and non-drug states and could be attenuated by gradually withdrawing the drug over training sessions.     

Inhibition of luteinizing hormone secretion by delta9-tetrahydrocannabinol in the ovariectomized rat: effect of pretreatment with neurotransmitter or neuropeptide receptor antagonists.

Acute treatment with delta9-tetrahydrocannabinol [delta9-THC; 0.5 or 1.0 mg/kg b.w. intravenously (i.v.)], the major psychoactive constituent of marijuana, produces a dose-related suppression of pulsatile luteinizing hormone (LH) secretion in ovariectomized rats. To determine whether delta9-THC produces this response by altering neurotransmitter and/or neuropeptide systems involved in the regulation of LH secretion, ovariectomized rats were pretreated with antagonists for dopamine, norepinephrine, serotonin, or opioid receptors, and the effect of delta9-THC on LH release was determined. Pretreatment with the D2 receptor antagonists butaclamol (1.0 mg/kg b.w., intraperitoneally) or pimozide [0.63 mg/kg, subcutaneously (s.c.)], the opioid receptor antagonists naloxone (1-4 mg/kg, i.v.) or naltrexone (2 mg/kg, i.v.), the noradrenergic alpha2-receptor antagonist idazoxan (10 microg/kg, i.v.), or the serotonin 5-HT(1C/2) receptor antagonist ritanserin (1 or 5 mg/kg b.w., i.p.), did not alter delta9-THC-induced inhibition of pulsatile LH secretion. Pretreatment with a relatively high dose of the beta-adrenergic receptor blocker propranolol (6 mg/kg, i.v.) attenuated the ability of the low THC dose to inhibit LH release; however, lower doses of propranolol were without effect. Furthermore, the ability of a relatively nonspecific serotonin 5-HT(1A/1B) receptor antagonist pindolol (4 mg/kg, s.c.) or the specific 5-HT1A receptor antagonist WAY-100635 (1 mg/kg, s.c.) to significantly attenuate THC-induced LH suppression indicates that activation of serotonergic 5-HT1A receptors may be an important mode by which THC causes inhibition of LH release in the ovariectomized rat.     

Comparison between multiple behavioral effects of peripheral ethanol administration in rats: sedation, ataxia, and bradykinesia

Although low doses of systemic ethanol stimulate locomotion in mice, in rats the typical response to peripheral ethanol administration is a dose-dependent suppression of motor activity. In the present study, male rats received acute doses of ethanol IP (0.0, 0.25, 0.5, 1.0 or 2.0 g/kg) and were tested on several behavioral tasks related to the motor suppressive or sedative effects of the drug. This research design allowed for comparisons between the effects of ethanol on different behavioral tasks in order to determine which tasks were most sensitive to the drug (i.e., which tasks would yield deficits that appear at lower doses). In the first two experiments, rats were evaluated on a sedation rating scale, and ataxia/motor incoordination was assessed using the rotarod apparatus. Administration of 2.0 g/kg ethanol produced sedation as measured by the sedation scale, and also impaired performance on the rotarod. In a third experiment, ethanol reduced locomotion in the stabilimeter at several doses and times after IP injection, with 0.25 g/kg being the lowest dose that produced a significant decrease in locomotion. Finally, experiment four studied the effects of ethanol on operant lever pressing reinforced on a fixed ratio 5 (FR5) schedule for food reinforcement. Data showed suppressive effects on lever pressing at doses of 1.0, and 2.0 g/kg ethanol. Analysis of the interresponse time distribution showed that ethanol produced a modest slowing of operant responding, as well as fragmentation of the temporal pattern of responding and increases in pausing. Taken together, these results indicate that rats can demonstrate reduced locomotion and slowing of operant responding at doses lower than those that result in sedation or ataxia as measured by the rotarod. The detection of subtle changes in different motor test across a broad range of ethanol doses is important for understanding ethanol effects in other cognitive, motivational or sensory processes.     

Muscarinic antagonists attenuate dizocilpine-induced hypermotility in mice.

Pretreatment of mice with the muscarinic receptor antagonists scopolamine and atropine attenuated the hypermotility (but not the depression of rearing) induced by a low dose of dizocilpine maleate [(+)-MK-801; 0.1 mg/kg, i.p.], a non-competitive NMDA antagonist. In contrast, the muscarinic blockers failed to affect hypermotility induced by equieffective doses of phencyclidine (1 mg/kg, i.p.) or d-amphetamine (2 mg/kg, i.p.). These results suggest differences between the mechanism of behavioral activation produced by dizocilpine and phencyclidine, and demonstrate the potential of muscarinic blockade for diminishing the behavioral toxicity of NMDA antagonists.     

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.     

Reversal of amphetamine induced polysome dissociation by neuroleptic agents in rat brain

Administration of d-amphetamine to rats causes the dissociation of brain polysomes in a dose-dependent manner. Further, the dose of d-amphetamine required to induce a stereotypic state in rats coincides with the dose needed to cause polysome dissociation. The enantiomeric form, i.e. 1-amphetamine, is ineffective in inducing both the behavioral and biochemical changes even at a dose as high as 30 mg/kg. Clinically potent neuroleptics such as haloperidol and chlorpromazine can effectively reverse the polysome dissociation as well as the behavioral changes induced by a near toxic dose of d-amphetamine (15 mg/kg).     

Analeptic and antianaleptic effects of naloxone and naltrexone in rabbits.

Naloxone (5 mg/kg), but not naltrexone, shortened the duration of anaesthesia in rabbits pretreated with pentobarbital. This analeptic effect was blocked by atropine, but not by methylatropine; it thus appears that a central cholinergic mechanism is involved. In contrast, smaller doses of both naloxone and naltrexone attenuated the arousal property of thyrotropin releasing hormone (TRH). Naloxone, but not naltrexone, also antagonized the analeptic property of d-amphetamine. In conscious animals naloxone potentiated, whereas naltrexone attenuated, the excitatory effects of TRH and d-amphetamine.     

CGS8216 noncompetitively antagonizes the discriminative effects of diazepam in rats

The benzodiazepine antagonist properties of CGS8216 were evaluated in rats trained to discriminate between saline and 1.0 mg/kg of diazepam in a two-choice, stimulus-shock termination procedure. CGS8216 (0.3 to 100 mg/kg) administered alone, either s.c., p.o. or i.p., occasioned only saline-appropriate responding. When administered concomitantly with a constant 1.0 mg/kg dose of diazepam, CGS8216 produced dose-related decreases in drug-appropriate responding. CGS8216 was most potent by the i.p. route, and approximately tenfold less potent by the oral route. CGS8216 was dermatotoxic after s.c. administration. CGS8216 i.p. had a long duration of action. A dose of 30 mg/kg completely antagonized the discriminative effects of the 1.0 mg/kg training dose of diazepam when the antagonist was administered 8 hr before the start of the test session. In order to determine the type of antagonism by CGS8216, the dose-effect curve for diazepam was redetermined in the presence of varying doses of CGS8216 (0.3 to 3.0 mg/kg, i.p.). CGS8216 produced a dose-related rightward shift in the diazepam dose-effect curve, but also decreased the slope and appeared to decrease the maximal effect. These results are consistent with the interpretation that CGS8216 antagonizes diazepam in a noncompetitive manner. It may do so because either it interacts with a subpopulation of benzodiazepine receptors, it functions as a pseudo-irreversible antagonist due to its high affinity, or because it is an antagonist with agonist properties.     

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.     

Effects of intraperitoneal and intraventricular d-amphetamine administration on active avoidance performance in the rat

Intraventricular and intraperitoneal administration of d-amphetamine impaired asymptotic shuttle box avoidance performance in rats. Low ip doses (0.5, 1.0, 1.5, and 2.0 mg/kg) had no effect whereas higher ip doses (2.5, 3.0, 3.5, 4.0 mg/kg) impaired performance in a dose-related fashion. An inverted U-shaped function was obtained with the ivent doses; low dose (25 ug) and high doses (200 and 400 ug) impaired performance whereas intermediate doses (50 and 100 ug) had little effect. The cannulation procedure itself produced only minimal acquisition effects. The data tend to support the contention that amphetamine acts on the brain to cause the deterioration of well learned avoidance responding.