The objective of this study was to report on the prevalence and correlates of anxiety and mood problems among 9- to 14- year-old children with Asperger syndrome (AS) and high-functioning autism. Children who received a diagnosis of autism (n 40) or AS (n 19) on a diagnostic interview when they were 4 to 6 years of age were administered a battery of cognitive and behavioural measures. Families were contacted roughly 6 years later (at mean age of 12 years) and assessed for evidence of psychiatric problems including mood and anxiety disorders. Compared with a sample of 1751 community children, AS and autistic children demonstrated a greater rate of anxiety and depression problems. These problems had a significant impact on their overall adaptation. There were, however, no differences in the number of anxiety and mood problems between the AS and autistic children within this high-functioning cohort. The number of psychiatric problems was not correlated with early autistic symptoms but was predicted to a small extent by early verbal/non-verbal IQ discrepancy scores. These data indicate that high-functioning PDD children are at greater risk for mood and anxiety problems than the general population but the correlates and risk factors for these comorbid problems remain unclear.

The Pavlovian conditioning analysis of drug tolerance emphasizes that cues present at the time of drug administration become associated with drug-induced disturbances. These disturbances elicit unconditional responses that compensate for the pharmacological perturbation. The drug-compensatory responses eventually come to be elicited by drug-paired cues. These conditional compensatory responses (CCRs) mediate tolerance by counteracting the drug effect when the drug is administered in the presence of cues previously paired with the drug. If the usual predrug cues are presented in the absence the drug, the unopposed CCRs are evident as withdrawal symptoms. Recent findings elucidate intercellular and intracellular events mediating CCRs and indicate the importance of internal stimuli (pharmacological cues and interoceptive cues inherent in self-administration) to the acquisition of drug tolerance and the expression of withdrawal symptoms. Early chroniclers of drug effects noted that responsivity to drugs often decreased as a function of experience with the drug. For example, in 1612, Jean Mousin, physician to the King of France, wondered why individuals sometimes became progressively more sober while they were continuing to drink alcoholic beverages. Although the term tolerance was not used until some years later, it appears that Mousin observed the phenomenon now termed acute tolerance-decreased responsiveness to a drug within the course of a single administration (Kalant, 1998). Acute Tolerance and Withdrawal Acute tolerance has been investigated extensively with respect to ethanol (e.g., see LeBlanc, Kalant, & Gibbins, 1975) as well as other drugs, such as opiates. For example, over the course of a single, long administration of morphine, accomplished by gradual infusion via an implanted morphine pellet, the analgesic effect of the drug decreases (e.g., see Tilson, Rech, & Stolman, 1973; Wei & Way, 1975). The existence of acute tolerance is evidence that pharmacological stimulation initiates adaptive responses that compensate for the primary drug effect (

Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence.

On the basis of a conditioning analysis of drug tolerance, drug-associated cues become associated with the drug effect. These cues elicit conditional compensatory responses and modulate the expression of tolerance. Although there are many findings consistent with the conditioning analysis of tolerance, there also are contrary findings. The results of these experiments suggest that some of the apparently contradictory findings result because interoceptive pharmacological cues, as well as exteroceptive environmental cues, are paired with a drug effect. That is, within each administration, early drug-onset cues may become associated with the later, larger drug effect, and these pharmacological cues may overshadow simultaneously present environmental cues. We demonstrate the contribution of such intraadministration associations to tolerance to the analgesic effect of morphine and to the expression of conditional compensatory hyperalgesia.

The sequence in which problems of different concepts are studied during instruction impacts concept learning. For example, several problems of a given concept can be studied together (blocking) or several problems of different concepts can be studied together (interleaving). In the current study, we demonstrate that the 2 sequences impact concept induction differently as they differ in the temporal spacing and the temporal juxtaposition of to-be-learned concept problems, and in the cognitive processes they recruit. Participants studied 6 problems of 3 different statistical concepts, and then were tested on their ability to correctly classify new problems on a final test. Interleaving problems of different to-be-learned concepts, rather than blocking problems by concept, enhanced classification performance, replicating the interleaving effect (Experiment 1). Introducing temporal spacing between successive problems decreased classification performance in the interleaved schedule-consistent with the discriminative-contrast hypothesis that interleaving fosters between-concept comparisons-and increased classification performance in the blocked schedule-consistent with the study-phase retrieval hypothesis that temporal spacing causes forgetting and subsequent retrieval enhances memory (Experiment 2). Temporally juxtaposing problems of concepts 3-at-a-time rather than 1-at-a-time improved overall classification performance, particularly in a blocked schedule-consistent with the commonality-abstraction hypothesis that blocking fosters within-concept comparisons (Experiment 3). All participants also completed a working memory capacity (WMC) task, findings of which suggest that the efficacy of the above study sequences may be related to individual differences in WMC.