Contingent Tolerance Research Articles

Response topography in behavioral tolerance to cocaine with rats

Research conducted with rats has shown tolerance to the behavioral effects of psychomotor stimulants to be contingent on chronic drug administration occurring before the experimental session. Recent experiments with pigeons, however, resulted in tolerance when drug administration followed the experimental session. We hypothesized that the apparent species differences in tolerance may be a function of different operantly conditioned response topographies used in these experiments. Specifically, we propose that operantly reinforced consummatory responses, like pecking with pigeons, are less likely to reveal contingent tolerance. This experiment involved rats in a manner that paralleled earlier experiments with pigeons. Rats were subjected to daily sessions that required 20 licking responses to obtain 2.5-s access to water. Acute effects of cocaine were determined by administering precession doses ranging from 1.0 to 30.0 mg/kg, with dosing occurring every fifth day. Rats were then divided into two groups. One group received 17.0 mg/kg cocaine before the session and the other received 17.0 mg/kg cocaine after the session. After 30 daily sessions, the effects of the cocaine-dose range were reassessed. Tolerance to the rate-decreasing effects of cocaine was evident in both the groups, regardless of the temporal relationship between drug administration and the experimental session. The results support the hypothesis that operantly reinforced consummatory responses are less likely to show contingent tolerance.

Environmental and pharmacological factors in the development of noncontingent tolerance to cocaine in pigeons.

Previous research with rats and monkeys has shown that tolerance to behavioral effects of cocaine developed if the drug was administered before behavioral test sessions but not if it was administered after sessions, a finding known as contingent tolerance. In contrast, a recent experiment using pigeons found that they showed tolerance resulting from postsession drug administration (noncontingent tolerance). The 4 experiments reported in this article were conducted to examine that result more fully. Experiment 1 found that immediate presession administration of cocaine to pigeons reliably led to tolerance to effects on food-reinforced operant key pecking and that immediate postsession administration of cocaine also led to tolerance in half the subjects, those whose key pecking was not suppressed by postsession dosing. Experiment 2 showed that eating in the home cage under the effects of postsession cocaine was not necessary for tolerance to develop to effects of postsession cocaine and that the majority of subjects developed tolerance from postsession cocaine administration. Experiment 3 found that mere drug exposure in the home cage without exposure to an experimental session did not reliably produce tolerance during the behavioral session. Experiment 4 showed that tolerance from postsession cocaine administration could be observed even when daily dosing was discontinued during dose-response curve assessment. Therefore, the combined results showed that pigeons often developed tolerance to effects of cocaine during the behavioral session when cocaine was administered postsession and that this tolerance was not the result of feeding under effects of the drug.

Expression of c-fos mRNA in the basal ganglia associated with contingent tolerance to amphetamine-induced hypophagia

Tolerance to the hypophagic effect of psychostimulants is contingent on having access to food while intoxicated. Rats given chronic injections of such drugs with access to food learn to suppress stereotyped movements, which interfere with feeding. In contrast, controls given the drug after food access do not learn to suppress stereotypy and, therefore, do not become tolerant. To determine the role of the basal ganglia in this phenomenon, we used in situ hybridization to measure the expression of c-fos mRNA, a marker for neural activation, in the brains of tolerant and nontolerant rats. Rats given chronic amphetamine injections prior to food access learned to suppress stereotyped movements, whereas yoked controls given the drug after feeding did not. Following an acute injection of amphetamine, both of these groups had higher levels of c-fos mRNA than saline-treated controls throughout the striatum, in the nucleus accumbens core, the ventral pallidum and layers V–VI of the motor cortex. In contrast, tolerant rats, which had learned to suppress stereotypy, had higher levels of c-fos mRNA than both amphetamine- and saline-treated controls in the entopeduncular nucleus, globus pallidus, subthalamic nucleus, pedunculopontine nucleus, nucleus accumbens shell, olfactory tubercle, somatosensory cortex, and layers II–IV of motor cortex. These data suggest that the learned suppression of amphetamine-induced stereotypy involves the activation of dorsal striatal pathways previously implicated in response selection as well as the ventral striatum, long implicated in appetitive motivation and reinforcement.

Is Tolerance to Antiepileptic Drugs Clinically Relevant?

Is Tolerance to Antiepileptic Drugs Clinically Relevant?

Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders.

Based on the mood-stabilizing properties of carbamazepine and valproate, new anticonvulsants have been explored for use in bipolar disorders. One such agent, lamotrigine, has a novel clinical profile in that it may "stabilize mood from below," as it appears to maximally impact depressive symptoms in bipolar disorders. In this paper, we review the mechanisms of action of lamotrigine in an effort to understand the basis of its distinctive clinical use in the management of bipolar disorders as well as its diverse antiseizure effects. We consider lamotrigine mechanisms, emphasizing commonalities and dissociations among actions of lamotrigine, older mood stabilizers, and other anticonvulsants. Although ion channel effects, especially sodium channel blockade, may importantly contribute to antiseizure effects, such actions may be less central to lamotrigine thymoleptic effects. Antiglutamatergic and neuroprotective actions are important candidate mechanisms for lamotrigine psychotropic effects. Lamotrigine has a variable profile in kindling and contingent tolerance experiments and does not appear to have robust gamma-aminobutyric acid or monoaminergic actions. Lamotrigine intracellular signaling effects warrant investigation. Although lamotrigine mechanisms overlap those of other mood-stabilizing anticonvulsants, important dissociations suggest candidate mechanisms, which could contribute to lamotrigine's distinctive psychotropic profile.

Behavioral Tolerance (Contingent Tolerance) isMediated in Part by Variations in Regional Cerebral Blood Flow

Concepts and experimental results taken frombehavioral pharmacology, functional brain imaging,brain physiology, and behavioral neuroscience, wereused to develop the hypothesis that behavioraltolerance can, in part, be attributed to cellulartolerance. It is argued that task specific activationof circumscribed neuronal populations gives rise tocorresponding increases in regional cerebral bloodflow such that neurons related to task performance areexposed to higher effective doses of blood-borne drugthan neuronal groups not highly activated by thebehavioral task. Through this cerebral hemodynamicregulatory mechanism cellular tolerance phenomena canat least partially account for behavioral tolerance(i.e., tolerance conferred through drugged practice).

Development of the contingent tolerance to midazolam in FR30 reinforcement schedule

Development of the contingent tolerance to midazolam in FR30 reinforcement schedule

Noncontingent Drug Exposure Facilitates the Development of Contingent Tolerance to the Anticonvulsant Effects of Ethanol and Diazepam in Kindled Rats

Tolerance to anticonvulsant drug effects on kindled convulsions can result from drug exposure alone, but convulsive activity during drug exposure has a substantial facilitatory effect on tolerance development. Tolerance produced by drug exposure in the absence of a criterion response (in this case convulsions) has been termed pharmacologic tolerance (10); tolerance produced by drug exposure with concomitant performance of the criterion response has been termed contigent tolerance (1). The present study examines whether noncontingent drug exposure facilitates the development of contingent tolerance to the anticonvulsant effects of ethanol and diazepam. Amygdala-kindled, Long–Evans rats were treated with either ethanol (5.0 g/kg once daily for 21 days) or diazepam (5.0 mg/kg three times daily for 10 days) in the absence of convulsive stimulation to produce pharmacologic tolerance—control rats received treatments of vehicle. Then, all of the rats were rendered contingently tolerant by a series of “bidaily” (once every 2 days) injections (ethanol 2.0 g/kg or diazepam 2.0 mg/kg), each 1 h prior to a kindled convulsion. The rats that had received noncontingent exposure to ethanol or diazepam developed contingent tolerance significantly faster than the control rats. These results suggest that the mechanisms underlying pharmacologic and contingent tolerance to anticonvulsant drug effects are additive.

Contingent tolerance, compensatory responses, and physical dependence in diazepam-treated amygdala-kindled rats.

Three groups of amygdala-kindled rats received 10 bidaily treatment trials: On each trial, the drug-before group received a diazepam (2.5 mg/kg i.p.) injection 1 hr before a convulsive stimulation, the drug-after group received a diazepam injection 1 hr after a stimulation, and the vehicle control group received a vehicle injection either 1 hr before or 1 hr after a stimulation. After treatment, only the drug-before group displayed significantly longer forelimb clonus under the influence of diazepam (that is, they displayed contingent tolerance to diazepam's anticonvulsant effect) and significantly longer forelimb clonus while drug free. Following a 14-day retention period, the rats in the drug-before group retained significant levels of contingent tolerance but did not display significant increases when tested drug free. These data suggest that compensatory responses do not play a causal role in the expression of contingent tolerance.

Contingent tolerance, compensatory responses, and physical dependence in diazepam-treated amygdala-kindled rats.

Contingent tolerance, compensatory responses, and physical dependence in diazepam-treated amygdala-kindled rats.

GABA and epileptogenesis.

GABA and epileptogenesis.

Failure of chronic treatment with abecarnil to induce contigent and noncontingent tolerance in pentylenetetrazol-kindled rats.

We examined the effect of chronic treatment with abecarnil, a selective agonist at gamma-aminobutyric acid(A) (GABA(A)) receptors, on the development of tolerance to its anticonvulsant effect in pentylenetetrazole (PTZ)-kindled rats. We used two different experimental protocols to differentiate between pharmacological (noncontingent) and contingent tolerance. In one group of animals, kindling was suspended and abercarnil (1mg/kg intraperitoneally, i.p.) was administered three times daily for 15 days. In a second group of rats, PTZ-kindling was continued during chronic treatment with abecarnil. Tolerance to the anticonvulsant effect of a subsequent challenge dose of abecarnil (0.5 mg/kg i.p.) did not develop in either experimental group.

Reversal of overshadowing in a drug mixture discrimination in rats.

Previous studies have suggested that in some circumstances, learning processes such as overshadowing may determine the effects that one drug has upon the response to another. The experiments described here examined overshadowing in rats trained to discriminate mixtures of nicotine plus midazolam in two-lever operant procedures with food reinforcement. After training for 60 sessions, midazolam (0.32 mg/kg SC) overshadowed nicotine (0.32 mg/kg SC) so that the discriminative stimulus effect of nicotine seen in control rats trained with nicotine alone was abolished (n = 8-10). In the next phase of the study, the discriminative response to midazolam in one group of mixture-trained rats was devalued by means of an extinction procedure which weakened the relationship between administration of midazolam and the response that was reinforced. Dose-response determinations then showed that the devaluation procedure had indeed attenuated the response to midazolam, whereas the previously overshadowed response to nicotine was restored. Post-session injections of drugs were used to equate the pharmacological histories of the groups and the effects seen were therefore attributable to training with the drugs and not simply to repeated exposure to them. Additionally, in the control rats trained with nicotine only (with midazolam given post-session), midazolam markedly reduced response rates, whereas in the three groups of rats trained with the mixture, midazolam had little response rate-depressant effect; this observation suggests that behaviourally contingent tolerance had developed to the response rate-reducing effect of midazolam. Application of devaluation procedures in studies of the discriminative stimulus effects of single drugs with multiple effects may provide a means for manipulating the characteristics of the discriminations obtained and for identifying individual elements of the drug-produced stimulus complex.

Contingent drug tolerance: Differential tolerance to the anticonvulsant, hypothermic, and ataxic effects of ethanol

The kindled-convulsion model of epilepsy was used to study contingent tolerance to ethanol's (1.5 g/kg; IP) anticonvulsant, hypothermic, and ataxic effects in adult male rats. In the present experiments, three groups of amygdala-kindled rats received a series of bidaily (one every 48 h) convulsive stimulations: one group received ethanol 1 h before each stimulation; one group received ethanol l h after each stimulation; and another group served as the saline control. Tolerance to ethanol's anticonvulsant effect (Experiments 1 and 2) was greatest in those rats that received ethanol before each convulsive stimulation; whereas, tolerance to ethanol's hypothermic (Experiments 1 and 2) and ataxic (Experiments 2) effects developed in both groups that received ethanol. These results were predicted on the basis of the drug-effect theory of drug tolerance: the theory that functional drug tolerance is an adaptation to the disruptive effects of drugs on concurrent patterns of neural activity, not to drug exposure per se.

Dissipation of contingent tolerance to the anticonvulsant effect of diazepam: Effect of the criterion response

The effect of convulsive stimulations on the dissipation of tolerance to the anticonvulsant effect of diazepam was investigated using the kindled-convulsion model. Amygdala-kindled rats were rendered tolerant to diazepam's anticonvulsant effect by 25 “bidaily” (one/48 h) diazepam injections (2.5 mg/kg), each followed 1 h later by a convulsive stimulation. They were then divided into nine groups for the tolerance-dissipation phase of the experiment. Of the nine groups, three received bidaily control handling for one trial, or seven trials; three received bidaily saline injections, each 1 h before a convulsive stimulation, for one, three, or seven trials; and three received bidaily diazepam injections, each 1 h after a convulsive stimulation, for one, three, or seven trials. Finally, each rat received a tolerance-retention test (i.e., a diazepam injection followed 1 h later by a convulsive stimulation) 48 h after its last tolerance-dissipation trial. The tolerance dissipated gradually but completely over the 4-, 8-, and 16-day test intervals in the rats that received a convulsive stimulation before each injection during the tolerance-dissipation phase, whether they were injected with saline or diazepam; in contrast, tolerance did not dissipate in the rats that received saline injections but no stimulations. Remarkably, the discontinuance of the bidaily diazepam injections, evem for 16 days, was not sufficient to dissipate the tolerance that had developed to diazepam's anticonvulsant effect; nor was the continuation of the bidaily diazepam injections sufficient to keep tolerance from dissipating. The] present findings support previous assertions that the performance of the criterion response while undrugged is the key factor in the dissipation of contingent drug tolerance and they provide the first controlled demonstration of the time course of the dissipation.

Analysis of the hippocampal GABA A receptor system in kindled rats by autoradiographic and in situ hybridization techniques: contingent tolerance to carbamazepine

Tolerance to the anticonvulsant effects of carbamazepine (CBZ) in the amygdala kindling paradigm is a contingent process, since it only develops in rats treated with CBZ before the kindling stimulation and not in those animals treated after the stimulation. The present study was designed to investigate the GABA A receptor system in CBZ contingent tolerance. Receptor autoradiography utilizing various radioligands that bind to different components of the GABA A receptor system and in situ hybridization with oligonucleotides that recognize different subunits of the GABA A receptor were performed. Kindling increased binding to benzodiazepine, picrotoxin, and GABA recognition sites selectively in the dentate gyrus of the hippocampus. Kindling also increased levels of mRNA for the α 4, β 1, and β 3 subunits but did not change α 1, α 2, or γ 2 subunit levels. Rats tolerant to CBZ showed decreased [ 3H]muscimol binding, diazepam-insensitive [ 3H]Ro 15-4513 binding, and decreased α 4 subunit mRNA content compared to non-tolerant rats, whereas [ 3H]flunitrazepam binding, [ 35S]TBPS binding, and the levels of β 1 and β 3 subunit mRNAs remained elevated. The data suggest an indirect interaction of CBZ with the GABA A receptor system, since CBZ reportedly does not bind to this receptor system.

Contingent tolerance to carbamazepine: alterations in TRH mRNA and TRH receptor binding in limbic structures

Tolerance to carbamazepine's anticonvulsant effects on amygdala kindled seizures occurs contingently, that is, only when carbamazepine is given prior to, but not after the seizure occurs. Biological correlates of contingent tolerance were examined using in situ hybridization and receptor binding techniques for thyrotropin-releasing hormone (TRH) mRNA and TRH receptor binding. Rats were fully kindled and given daily injections of carbamazepine (15 mg/kg, i.p.) either 15 min before (CBZ-before) or after (CBZ-after) amygdala stimulation until the CBZ-before rats became tolerant. Kindled rats were matched so that the two groups had an equal number of seizures and doses of CBZ. Three other groups were also used for comparison: kindled rats that received vehicle injections, and sham-kindled animals treated with either vehicle or CBZ. Rats were sacrificed 4 h after the last seizure or sham stimulation. Both sham-kindled rat groups had barely detectable levels of TRM mRNA. In the CBZ-after (non-tolerant) and vehicle-kindled rats, TRH mRNA levels were increased in the dentate gyrus, pyriform, entorhinal, and perirhinal cortices. In contrast to the other kindled animals, the CBZ-before rats (tolerant) had dramatically diminished TRH mRNA levels bilaterally in the dentate gyrus and pyriform cortex, and ipsilateral to the stimulation in the entorhinal cortex. Decreases in TRH receptor binding were demonstrated autoradiographically in the dentate gyrus and perirhinal cortex in all of the kindled groups with no differences between tolerant and non-tolerant rats. The reported TRH mRNA alterations are, thus, specifically associated with the development of contingent tolerance and are not attributable to either the occurence of seizures or repeated drug exposure alone. The role of TRH inn carbamazepine's anticonvulsant effects and the functional consequences of the failure of CBZ-tolerant animals to show seizure-induced increases in TRH mRNA warrants further investigation.

Anticonvulsant tolerance to clonazepam in amygdala kindled rats: Clonazepam concentrations and benzodiazepine receptor binding

The relationship between anticonvulsant tolerance to clonazepam and benzodiazepine receptor changes was studied in amygdala kindled rats. Fully kindled rats were given 1 mg/kg clonazepam (clonazepam treated) or vehicle (kindled control) orally three times per day for 4 weeks. During chronic treatment, amygdala stimulation was given twice per week, 30 min after a single protective dose of clonazepam (0.5 mg/kg, i.p.) was injected to both groups of rats. As measured by seizure stage, clonazepam treated rats showed a greater degree of tolerance than kindled control rats; contingent tolerance to the anticonvulsant effects of clonazepam developed in kindled control rats, while clonazepam treated rats shows contingent plus pharmacologic tolerance. There were no significant differences between clonazepam treated and kindled control rats in “peak” plasma clonazepam concentrations 40 min after clonazepam injections. Benzodiazepine receptor assays showed no significant difference in maximal binding capacity ( B max), dissociation constant ( K d) or γ-aminobutyric acid (100 μM) enhancement of benzodiazepine receptor binding between clonazepam treated and kindled control rats. These data suggest that pharmacologic tolerance to anticonvulsant action of clonazepam is not related to either plasma clonazepam concentrations or benzodiazepine receptor changes.

Effects of variation in chronic dose of cocaine on contingent tolerance as assessed in a milk-drinking task.

Tolerance to the suppressive effects of cocaine on milk drinking by rats was studied using a contingent tolerance experimental design. Three separate groups (n = 6) of rats received 8.0, 16.0, or 32.0 mg/kg cocaine daily 15 min before a 15-min period of access to sweetened condensed milk for 20 days. Three additional groups of six rats each received the same chronic doses 15 min after access to milk. Milk, water, and food intake as well as body weight were measured daily. Tolerance effects were assessed by comparing initial acute dose-effect determinations with a probe dose-effect redetermination in which all rats again received doses of cocaine pre-session after having experienced the differential pre- or post-session chronic treatment. Behavioral tolerance on the milk intake measure was observed for the 8.0 mg/kg and 16.0 mg/kg doses, but not for the 32.0 mg/kg chronic treatment, even though the latter group exhibited evidence of tolerance in the water intake measure. Chronic treatment with 8.0 and 16.0 mg/kg produced different outcomes in that chronic exposure to 16.0 mg/kg in the presence of milk resulted in generalization of tolerance to both a lower (8.0 mg/kg) and a higher dose (32.0 mg/kg), but the group receiving 8.0 mg/kg did not exhibit generalization of tolerance to higher doses. Modest sensitization effects were observed in the rats treated post-session with either 8.0 or 16.0 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Contingent tolerance to midazolam-induced elevation of operant response force

Contingent tolerance to midazolam-induced elevation of operant response force