Amphetamines--Physiological effect

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 cocaine exposure and maternal deprivation on subsequent voluntary ingestion of cocaine and amphetamine was investigated in 7-day-old rat pups in order to further our understanding on the development of drug addiction. Maternally deprived and non-deprived pups were pre-exposed to a cocaine solution masked with 5% orange Tang solution. Four hours later, experimental pups were tested for subsequent cocaine self-administration (SA) (Exp. 1) or amphetamine SA, (Exp. 2), following a second deprivation period. Control pups were not deprived during this interval. Pups in both experiments were assessed for dose self-administered and for general activity. Results indicate that cocaine pre-exposure increased cocaine and amphetamine SA, and activity significantly increased after pre-exposure and testing sessions. Lastly, sensitization of the motor effects of cocaine was observed in pups pre-exposed to cocaine. This study provides a potential drug SA animal model not yet investigated in developing animals.

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 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.