Nifedipine blocks the development of tolerance to the anticonvulsant effects of ethanol.
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Animals↗
Biomedical subjects
J P Pinel
Publications and source records attributed to J P Pinel.
Tolerance to the anticonvulsant effects of carbamazepine, diazepam, and sodium valproate in kindled rats.
We assessed the development of tolerance to the anticonvulsant effects of carbamazepine (CBZ), diazepam (DZP), and sodium valproate (VPA) on convulsions elicited by amygdala stimulation in kindled rats in three similar experiments. In each experiment, amygdala-kindled rats were assigned to a drug group or to a corresponding vehicle control group. The rats in the three drug groups received a total of 10 bidaily (one every 48 h) IP injections of CBZ (70 mg/kg), DZP (2 mg/kg) or VPA (250 mg/kg) at a dose that initially blocked the forelimb clonus elicited by an amygdala stimulation (400 microA, 60 Hz, 1 s) administered 1 h after the injection. The rats in the three vehicle control groups were similarly treated except that they received injections of the saline vehicle. The drug tolerance test occurred 48 h after the final tolerance-development trial; the rats from each drug group and the corresponding vehicle control group received an injection of the appropriate drug followed 1 h later by the administration of a convulsive stimulation. The drug tolerance test revealed almost total tolerance in each of the three drug groups but no tolerance in any of the three vehicle control groups. Such large tolerance effects are inconsistent with the less dramatic effects reported in previous studies; possible reasons for this inconsistency were considered.
Amygdala↗
Tolerance to the anticonvulsant effects of phenobarbital, trimethadione, and clonazepam in kindled rats: cross tolerance to carbamazepine.
The kindled-convulsion model was used to assess the development of tolerance and cross tolerance to the anticonvulsant effects of antiepileptic drugs. In Experiment 1, tolerance developed to the anticonvulsant effects of bidaily (one every 48 h) IP injections of phenobarbital, trimethadione, and clonazepam on convulsions elicited 1 h after each injection in kindled rats by amygdala stimulation. In Experiment 2, kindled rats that were tolerant to the anticonvulsant effects of phenobarbital, trimethadione, or clonazepam received bidaily IP injections of carbamazepine, each followed 1 h later by a convulsive amygdala stimulation. There was a statistically significant transfer of tolerance from phenobarbital to carbamazepine, but not from either trimethadione or clonazepam to carbamazepine. Apparently, tolerance to anticonvulsant drugs is most likely to transfer between drugs that are effective against similar kinds of clinical and experimental seizures and have similar putative mechanisms of action.
Amygdala↗
Contingent tolerance to the anticonvulsant effects of carbamazepine, diazepam, and sodium valproate in kindled rats.
The effect of convulsive stimulation during periods of drug exposure on the development of tolerance to the anticonvulsant effects of carbamazepine (CBZ), diazepam (DZP), or sodium valproate (VPA) was studied in three similar experiments. In each experiment, amygdala-kindled rats were assigned to one of three groups: one group received a drug injection (CBZ, 70 mg/kg, IP; DZP, 2 mg/kg, IP; VPA, 250 mg/kg, gavage) 1 h before each of a series of 10 bidaily (one every 48 h) convulsive stimulations, a second group received the same dose of the drug 1 h after each of the 10 stimulations, and a third group served as a vehicle control. The drug tolerance test occurred in each experiment 48 h after the 10th tolerance-development trial; every rat received the appropriate dose of CBZ, DZP, or VPA 1 h before being stimulated. In each experiment, only the rats from the drug-before-stimulation group displayed a significant amount of tolerance to the drug's anticonvulsant effect. Thus the development of tolerance to the anticonvulsant effects of CBZ, DZP, and VPA was not an inevitable consequence of drug exposure; the development of tolerance was contingent upon the occurrence of convulsive stimulation during the periods of drug exposure. These results support the idea that functional drug tolerance is an adaptation to a drug's effects on ongoing patterns of neural activity, rather than to drug exposure per se.
Amygdala↗
Bidirectional contingent cross tolerance between the anticonvulsant effects of pentobarbital and ethanol.
In Experiment 1, two groups of kindled rats received a pentobarbital injection (15 mg/kg, IP) and a convulsive amygdala stimulation once every 48 h. In one group, pentobarbital was injected 1 h before each stimulation; in the other, it was injected 1 h after each stimulation. Only the rats that received pentobarbital before each stimulation became tolerant to pentobarbital's anticonvulsant effect. Cross tolerance to the anticonvulsant effect of ethanol (1.5 g/kg, IP) was also found to be greater in the pentobarbital-before-stimulation rats. Experiment 2 was designed to assess the transfer of tolerance in the opposite direction, that is, from ethanol to pentobarbital, and the results mirrored those of Experiment 1: convulsive stimulation during the periods of ethanol exposure facilitated the development of tolerance to the anticonvulsant effect of ethanol and its transfer to pentobarbital. These results support the theory that functional drug tolerance and cross tolerance are adaptations to the effects of drugs on concurrent patterns of neural activity rather than to drug exposure per se.
Amygdala↗
Contingent tolerance to the disruptive effects of alcohol on the copulatory behavior of male rats.
Sexually active male rats received five 30-min copulation tests with sexually receptive females, one every 4 days. One group of rats received alcohol (1 g/kg, IP) 45 min before, and an equivalent volume of saline 45 min after, each test; a second group received saline before and alcohol after each test; and a third, control group received saline both before and after. Four days after the last of the five tolerance-development trials, each rat received an injection of alcohol (1 g/kg, IP) 45 min before a copulation test so that the development of tolerance in the three groups could be compared. Tolerance to the disruptive effects of alcohol on mount, intromission, and ejaculation latencies, and on the duration of the postejaculatory interval was found to be significantly greater in the rats injected with alcohol before each copulation test than it was in the rats in the other two groups. These results constitute the first experimental evidence that tolerance develops to the disruptive effects of alcohol on male sexual behavior, and they support the theory that tolerance is an adaptive response to the disruptive effects of drugs on concurrent patterns of neural activity, rather than to drug exposure per se.
Animals↗
Linguistic analogies and behavior: the finite-state behavioral grammar of food-hoarding in hamsters.
Rodger and Rosebrugh (1979) developed a method for identifying sets of rules by which discrete responses are combined to form functional sequences of behavior. In the present study, this so-called finite-state behavioral grammar method was used to analyze the food-hoarding behavior of Syrian golden hamsters (Mesocricetus auratus). Specifically, it was used to analyze 127 videotaped food-hoarding sequences that were observed in 14 male, adult hamsters in an apparatus that comprised a home compartment, a foraging area, and a connecting tunnel. An integral part of grammar derivation is the development of hypotheses about the function of the observed response patterns to guide the grammar derivation. Two such hypotheses guided the present analysis: first, we hypothesized that behaviors observed in the foraging area after the hamsters' cheek pouches were filled served an exploratory function; second, we hypothesized that behaviors observed in the home compartment prior to the hamsters emptying their cheeck pouches served to assess potential food deposition sites. In addition to generating these two hypotheses and the grammars for the hoarding sequences, this study demonstrates how the finite-state grammar method can be used as a productive means of gaining insights into the organization of consummatory response sequences.
Animals↗
Pirenperone does not attenuate morphine analgesia in spinal rats.
The selective serotonin type-2 (S2) receptor blocker pirenperone (0.24 mg/kg, SC) attenuates morphine-produced tail-flick antinociception in intact rats, but not in rats with transected spinal cords. These results suggest that S2 receptor blockade does not affect intraspinal opioid antinociception. Together with evidence that there are virtually no S2 receptors in the dorsal spinal cord, supraspinal S2 receptors are implicated in the mediation of morphine-produced antinociception.
Analgesics↗
Defensive burying, nest relocation, and pup transport in lactating female rats.
A wire-wrapped wooden dowel was inserted through the wall of the nest compartment of a two-compartment box. There were four conditions. Some lactating female rats were shocked by the dowel when they first touched it, and some were not, after which the dowel was either immediately withdrawn from the chamber or left in place for the duration of the ensuing 30-min test period. Three defensive behaviours were observed during the tests: the mothers buried the shock source with bedding from the floor of the chamber, they transported their pups to the adjoining "safe" chamber, and they built a new nest in the safe chamber from material salvaged from their original nest. The shocked mothers that were confronted with the shock source throughout the test period displayed significantly more of each of these three defensive behaviours than did the mothers in the other three conditions. The methods used in this study provide a simple, reliable, safe paradigm for studying maternal defensive behaviour; the results indicate that the defensive capacities of the rat extend far beyond stereotypical flight, freeze, and fight responses, which have been the focus of most research on rodent defense.
Animals↗
Development of defensive burying in Rattus norvegicus: experience and defensive responses.
Rats (Rattus norvegicus) deprived of the opportunity to interact with particulate matter until they were young adults engaged in defensive burying after they were shocked by a wire-wrapped dowel in a test chamber that held bedding material. Interacting with a particulate substrate during development is not necessary for the expression of defensive burying in adulthood. However, interacting with a particulate substrate early in the rats' lives did have a substantial effect on the emergence and maintenance of burying behavior. Defensive burying developed at a later age and declined at an earlier age in rats maintained on wire mesh from birth until testing than it did in rats raised until weaning on bedding and housed on mesh thereafter. Because defensive burying is a complex, flexible, yet reliable response sequence that cannot be performed without the appropriate substrate, it has considerable potential as a model for the study of the development of species-specific defense responses.
Animals↗
Attenuation of morphine analgesia by the S2 antagonists, pirenperone and ketanserin.
The involvement of serotonin type-2 (S2) receptors in morphine-induced analgesia was assessed by challenging the effect of 10 mg/kg of morphine sulphate (IP) with the S2 receptor blockers, pirenperone and ketanserin. Tail-flick latencies were assessed at 0, 30, 60, 90 and 120 min after injections by measuring the time that it took each rat to remove its tail from a 52 degrees C water bath. Pirenperone, at 0.08, 0.16, and 0.24 mg/kg (SC) attenuated morphine-induced antinociception. In contrast, only the high 10 mg/kg (SC) dose of ketanserin attenuated the effect of morphine. Because pirenperone easily enters the central nervous system whereas ketanserin does not, these results indicate the involvement of central S2 receptors in morphine-induced antinociception. The 10 mg/kg dose of ketanserin, however, did not attenuate the antinociception produced by 100 mg/kg of ketamine. Thus, the antianalgesic effect of S2 receptor blockers may be specific to opioid-mediated analgesia.
Analgesia↗
Response contingency and the dissipation of ethanol tolerance.
Ethanol (1.5 g/kg) administered intraperitoneally to kindled rats blocks the seizures normally elicited by electrical stimulation of the amygdala. Tolerance to this anticonvulsant effect develops following a series of ethanol injections delivered at 48-hr intervals only when an amygdaloid stimulation is administered during each period of ethanol intoxication. In the present study, the response contingency was shown to also play a critical role in the dissipation of tolerance. There was no significant loss of tolerance over a 14-day retention interval in rats that received: 1) bidaily ethanol injections each followed 1 hr later by a convulsive stimulation; or 2) bidaily ethanol injections but no stimulation; or 3) neither ethanol nor stimulation. In contrast, tolerance dissipated completely in rats that received: 1) bidaily stimulations but no ethanol; or 2) convulsive stimulation 1 hr before each bidaily ethanol injection. Accordingly, the cessation of ethanol exposure was neither necessary nor sufficient for the dissipation of tolerance to the anticonvulsant effect of ethanol. The critical factor in the decline of tolerance was the elicitation of seizures in the absence of ethanol.
Animals↗
Tolerance to alcohol's anticonvulsant effect is not under Pavlovian control.
Tolerance to the anticonvulsant effect of alcohol has been shown to be contingent on the presence of convulsive stimulation during the period of intoxication. In the present experiments, manipulation of the environmental stimuli associated with alcohol administration had no effect on the development of tolerance to alcohol's anticonvulsant effect in kindled rats. Such tolerance was found not to be specific to the alcohol-predictive environment, nor was its development retarded by pre-exposing the subjects to an environment that was subsequently associated with alcohol administration. Moreover, an injection of saline to tolerant subjects in the alcohol-predictive environment did not elicit a conditioned compensatory increase in seizure duration. Thus, the Pavlovian theory of drug tolerance cannot account for the contingent tolerance that develops to alcohol's anticonvulsant effect.
Amygdala↗
Increased susceptibility to kindled seizures in rats following a single injection of alcohol.
After 2 or 2.5 g of alcohol, rats previously subjected to low-intensity electrical stimulation of the amygdala showed first a suppression followed by a potentiation of motor seizures and afterdischarges.
Amygdala↗
Rat defensive behavior: burying noxious food.
In Experiment 1, rats living in chambers containing bedding material were injected with a toxicosis-producing dose of lithium chloride shortly after their initial taste of sweetened condensed milk. They consumed no additional milk and used the bedding to bury the spout through which the milk had been delivered, although they did not bury a concurrently available water spout. In another control condition, rats did not bury a spout containing a novel solution (saccharin) not paired with toxicosis. In Experiment 2, rats did not bury a milk spout until milk consumption was followed by toxicosis. In Experiment 3, rats buried a spout containing Tabasco pepper sauce but not a concurrently available water spout. Thus, burying the food source appears to be an integral component of the rat's defensive reaction to noxious food.
Animals↗
Experimental epileptogenesis: kindling-induced epilepsy in rats.
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Amygdala↗
Electrode placement and kindling-induced experimental epilepsy.
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Amygdala↗
Increased susceptibility to the epileptic effects of alcohol withdrawal following periodic electroconvulsive shocks.
There was a progressive intensification (kindling) of the motor seizure pattern when electroconvulsive shocks (ECSs) were administered to rats at 3-day intervals, but not when the inter-ECS interval was 1 hr. Similarly, the incidence of convulsive symptoms elicited by subsequent alcohol exposure and withdrawal was a function of the number of antecedent ECSs administered at 3-day, but not at 1-hr, intervals. Significant ECS-produced intensification of the alcohol withdrawal syndrome persisted for 3 weeks following ten periodic ECSs and occurred even when the motor seizures elicited by the antecedent ECSs were pharmacologically suppressed.
Animals↗