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The finding that the performance of a response during periods of drug exposure facilitates the development of tolerance to the effects of the drug on that response is commonly referred to as contingent drug tolerance. Contingent tolerance is typically demonstrated in before-and-after design experiments. One group of subjects receives drug before the performance of the criterion response (drug-before-test condition) and a second group of subjects receives drug after the performance of the criterion response (the drug-after-test condition). The usual finding is that substantial tolerance develops in the drug-before-test condition, but no tolerance whatsoever develops in the drug-after-test condition. Such demonstrations of contingent tolerance have led to the drug-effect theory of tolerance: the theory that tolerance to a particular drug effect is an adaptive response to the experience of that particular drug effect. The purpose of this thesis was to clarify the relation between drug exposure, drug effects, and the development of tolerance. Several experiments have demonstrated that no tolerance whatsoever develops to anticonvulsant drug effects if convulsive stimulation is administered prior to each drug injection (drug-after-test condition), rather than afterwards (drug-before-test condition). Be that as it may, a different experimental design was used in Experiments 1 and 2 to show that small amounts of tolerance develop in the absence of concurrent convulsive stimulation. Rats that received either 3 intraperitoneal injections of diazepam (5.0 mg/kg) per day for 10 days (Experiment 1) or 1 gastric intubation of ethanol (5 g/kg) for 21 days (Experiment 2) were significantly more tolerant than vehicle controls; however, the tolerance could be detected only by a sensitive savings measure. The purpose of Experiment 3 was to test a novel interpretation for the inconsistency between Experiments 1 and 2 on the one hand and the repeated failure to observe tolerance to anticonvulsant drugs following drug exposure without concurrent convulsive stimulation in the drug-after-test condition of before-and-after experiments on the other. This hypothesis is that small amounts of tolerance do develop following each drug injection in the drug-after-test condition but that it is dissipated the next day by the convulsive activity experienced in the absence of the drug. To test this hypothesis, one group of amygdala-kindled rats received 15 diazepam injections (2.5 mg/kg) each before a convulsive stimulation, one group received 15 diazepam injections each after a convulsive stimulation, one group received 15 diazepam injections with no convulsive stimulation, and one group received 15 vehicle injections either with or without convulsive stimulations. The drug-before-stimulation rats developed substantial tolerance as has been frequently reported, and the hypothesis was confirmed by the finding that the drug-only rats developed tolerance significantly faster than the rats in the drug-afterstimulation group and the rats in the vehicle-control group. The results of these experiments make two important points. First, tolerance develops following drug exposure even when the criterion response is not performed during drug exposure —albeit substantially less than when it is performed. Presumably, this is because a few of the neural circuits that are active during a convulsion are spontaneously active following the drug administration. Second, the reason why the subjects in the drug-after condition display no evidence of tolerance is because the drug-free performance of the criterion response prior to each drug exposure causes any tolerance that has developed to dissipate.

We investigated the role of metabotropic glutamate receptors (mGluRs), and related intracellular second messengers, in the development of morphine tolerance and dependence. The mGluRs are divided into three groups: group I mGluRs are positively coupled to phosphatidylinositol (PI) hydrolysis, while group II and III mGluRs are negatively coupled to cyclic adensoine-3$ sp prime$,5$ sp prime$-monophosphate (cAMP) production. Opioid receptors are also coupled to these same systems, and have been shown to elicit changes in these messenger systems during chronic treatment. / We showed that chronic intracerebroventricular (i.c.v.) administration of selective group II and III mGluR antagonists concurrently with subcutaneous (s.c.) morphine significantly reduced the severity of precipitated withdrawal symptoms. Conversely, acute i.c.v. injection of a selective group II mGluR antagonist just prior to the precipitation of withdrawal significantly exacerbated the severity of abstinence symptoms. In addition, acute i.c.v. injection of a selective group II mGluR agonist just prior to the precipitation of withdrawal significantly reduced abstinence symptoms. From these results we hypothesized that chronic opioid treatment may induce a desensitization of group II mGluRs. / We also demonstrated that chronic i.c.v. infusion of a selective group I mGluR antagonist concurrently with s.c. morphine significantly attenuated the precipitated withdrawal syndrome. In addition, we showed that chronic i.c.v. antagonism of $ delta$-opioid receptors with a highly selective antagonist also decreased the development of morphine dependence, as well as tolerance. Since both group I mGluRs and $ delta$-opioid receptors are positively coupled to PI hydrolysis, further evidence for a role of products of PI hydrolysis in the development of morphine dependence was obtained when we showed that selective chronic inhibition of protein kinase C (PKC) activation, as well as selective chronic inhibition of intracellular Ca$ sp{2+}$ release, concurrently with morphine treatment significantly reduced the severity of abstinence symptoms. Thus, compensatory changes usually elicited by chronic opioid treatment may be counteracted by antagonizing receptors positively coupled to PI hydrolysis, as well as by inhibiting products of PI hydrolysis. / In the General Discussion, we propose a model based on the possible interaction of mGluRs and opioid receptors, via related intracellular second messengers, to explain the development of morphine dependence.

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It was hypothesized that a metabolite of morphine, morphine-3-glucuronide (M3G), contributes to the expression of symptoms seen during withdrawal from morphine. To test this hypothesis, the behaviors observed during precipitated withdrawal from morphine and sufentanil were compared. Sufentanil was chosen because, like morphine, it acts primarily at the mu opioid receptor, but has different metabolites. Differences in the abstinence syndromes produced by the two drugs may therefore be attributable to the actions of metabolites, rather than the primary opioid actions of morphine and sufentanil. Although there were some differences in the occurrence of symptoms, morphine and sufentanil withdrawal were very similar. Therefore, the evidence was inconclusive as to the contribution of metabolites during withdrawal. / Systemic administration of M3G alone and in combination with morphine produced no withdrawal-like behaviors. However, when these drugs were given centrally, withdrawal-like behaviors were observed in conjunction with seizures. The seizures were not attenuated by naloxone (but were alleviated by an anti-convulsant), indicating that they were not mediated by opioid receptors. The behaviors resembled those seen by previous investigators following high doses of morphine. The results suggest that M3G may play a role in the toxic effects of high doses of morphine.