Drug tolerance

There is a growing body of literature indicating that drug effects are influenced by the
context in which they are taken, and that neuroadaptations resulting from chronic drug
use are similarly context dependent. Contingent tolerance to amphetamine-induced
hypophagia is mediated by the learned suppression of stereotyped behaviors, and is an
example of a drug-environment interaction. This form of behavioral tolerance depends
upon instrumental learning, by which rats learn a strategy to suppress drug-induced
stereotypies that interfere with feeding. Considerable progress has been made in
understanding contingent tolerance at the behavioral level; little is known about the
neural mechanisms underlying contingent tolerance. Therefore, the purpose of this study
was to delineate neural circuitry involved in contingent tolerance. The differential
activation of neurons expressing the immediate early gene c-fos was analyzed throughout
the brains of amphetamine-tolerant and non-tolerant rats, using the Before-After
paradigm; the amphetamine tolerant group received injections of amphetamine (2.0
mg/kg) before access to milk, after-amphetamine and after-saline groups (i.e., nontolerant)
received injections of amphetamine after access to milk, and the saline group received saline at both time points. The experimental design permitted us to identify
structures uniquely involved in tolerance from those associated with drinking milk,
having a history of amphetamine, or receiving an injection of amphetamine on the final
test. The unique finding reported here is that when amphetamine is given in an
environment containing food, patterns of c-fos are very different than when the drug is
given in an environment without food. Results showed that amphetamine-tolerant
animals had significant increases in c-fos in a set of interconnected structures throughout
the brain, as compared with non-tolerant and saline rats. These data supported the
hypothesis that structures associated with the dorsal striatum mediate the response
selection of feeding and the inhibition of stereotypies, while the ventral striatum, via
instrumental learning, reinforces the selection and inhibition of competing motor
behaviors. Results also support the idea that the mechanisms of tolerance involve several
neural subsystems that function to modulate motor, motivational, and reward-based
learning. Specifically, the learned suppression of stereotypies involves the tolerance
"Response Selection," "Reinforcement," and "Instrumental Learning" subsystems.

The effects of amphetamine on the milk intake, body weight, and behavioral activity of bottle- and cannula-fed rats was investigated in a before/after paradigm. Dose response determinations were conducted before (DR 1) and after (DR 2) chronic treatment (45 days) with amphetamine (8.0 mg/kg) given either before or after milk tests, to determine whether tolerance developed to the anorexic effect of the drug. Control groups were given saline during the chronic phase. Both cannula- and bottle-fed animals lost a significant amount of weight. Cannula-fed animals drank significantly more than bottle-fed animals throughout the chronic phase. Statistical analysis revealed significant increases in intake from DR 1 to DR 2 for the after and saline cannula-fed groups, and the before, after, and saline bottle-fed groups. All groups showed an increase in intake from DR 1 to DR 2, though the increase of the before cannula-fed group failed to reach statistical significance.

The purpose of this experiment was to determine if tolerance to cocaine-induced hypophagia involves learning to suppress stereotyped movements that interfere with feeding. Milk intake and motor activity were measured in rats fed via bottles or intraoral cannulas. On dose-response 1, the bottle group was more hypophagic than the cannula group at the 8, 16, and 32 mg/kg doses. After 60d of chronic cocaine (16 mg/kg), only the bottle-fed group showed tolerance, indicated by a shift to the right on dose-response 2. Tolerance was accompanied by a decrease in activity, while activity in the cannula-fed groups given 16 or 32 mg/kg showed sensitization. These results suggest that moderate doses of cocaine interfere with feeding primarily by producing incompatible behaviors. Tolerance involves learning to inhibit these behaviors in order to feed.

The purpose of this study was to determine whether prior sensitization of stereotypy interferes with the development and retention of tolerance to amphetamine-induced hypophagia. Rats were given intermittent injections of either amphetamine to induce sensitization of stereotypy, or saline. Both sensitized and nonsensitized groups became tolerant to drug-induced hypophagia to the same degree. Such tolerance was accompanied by a decrease in the frequency of stereotyped movements while milk was available. After a 4 wk drug withdrawal period, both groups lost tolerance and displayed more intense stereotypy than they had prior to drug withdrawal. Therefore, sensitization of stereotypy did not retard the development of tolerance. However, the loss of tolerance following drug withdrawal may have been due to the development of more intense stereotypy and/or the "unlearning" of previously acquired strategies for suppressing stereotypy.

It was hypothesized that animals sensitized to the stereotyped behavioral effects of amphetamine would have a more difficult time developing tolerance to the hypophagic effect of the drug than nonsensitized animals. Although sensitized animals showed more intense stereotypy, they were not impaired in the development of tolerance, or in the amount of tolerance gained, thus showing a dissociation between these two variables. Differential sensitization was also shown to these effects. That is, sensitized animals were not impaired on milk intake, whereas nonsensitized animals became more sensitive to the hypophagic effect of amphetamine. Further, it was found that animals sensitized to the stereotyped behavioral effects of the drug developed tolerance to this effect, and this tolerance was found to occur both in the presence and absence of milk.

Rats that developed tolerance to the anorexic effect of morphine under conditions supportive of associational tolerance were tested for Pavlovian conditioned tolerance. Initially sensitive and nonsensitive rats received chronic morphine injections of 10 and 20mg/kg respectively in the presence of an explicitly paired compound cue until tolerant to the morphine induced suppression of milk intake. In a test for compensatory responding, only nonsensitive rats increased their intake in response to a placebo injection of saline in the presence of the morphine cue. In tests of associative tolerance, morphine injections in the presence of an explicitly unpaired saline cue, or in the absence of either cue, did not produce a loss of tolerance. After the temporal pattern of morphine administration was extinguished, only nonsensitive rats showed both a loss of tolerance in the presence of the saline cue, and tolerance retention in the presence of the morphine cue.

Two experiments were performed to determine whether tolerance to the "anorexigenic" effect of haloperidol is contingent on access to food in the drugged state. In the first experiment groups of rats were given injections of haloperidol (2.5 or 5 mg/kg) either before or after a 30-min drinking session for 53 days. Control groups were given saline injections. On Day 54 all groups were given the drug before milk access to determine the level of tolerance. Rats which had received the drug after milk were found to be more tolerant than rats given the drug chronically before milk on Day 54. In the second experiment the length of drug administration was shortened to 14 days. Findings suggested that rats which received chronic post-test injections of haloperidol continued to develop tolerance with repeated injections of the drug, while the development of such tolerance was suppressed after Day 15 in rats given repeated pre-test injections of the drug. (Abstract shortened with permission of author.)