The conditioning of the pharmacological actions of cocaine with environmental stimuli is thought to be a critical factor in the longterm addictive potential of this drug. Cocaine-related stimuli may increase the likelihood of relapse by evoking drug craving, and brain-imaging studies have identified the amygdala and nucleus accumbens (NAcc) as putative neuroanatomical substrates for these effects of cocaine cues. To study the significance of environmental stimuli in the recovery of extinguished cocaine-seeking behavior, male Wistar rats were trained to associate discriminative stimuli (S⌬s) with response-contingent availability of intravenous cocaine vs. saline. The rats then were subjected to repeated extinction sessions during which cocaine, saline, and the respective S⌬s were withheld until the animals reached an extinction criterion of <4 responses over three consecutive sessions. Subsequent re-exposure to the cocaine S⌬, but not the nonreward S⌬, produced strong recovery of responding at the previously active lever in the absence of any further drug availability. The efficacy and behavioral selectivity of the cocaine S⌬ remained unaltered throughout an 8-day test period. Exposure to the cocaine S⌬ significantly increased dopamine efflux in the NAcc and amygdala as measured by intracranial microdialysis in a separate group of rats. Dopamine levels remained unaltered in the presence of the nonreward S⌬. The results demonstrate that cocaine-predictive stimuli elicit robust and persistent cocaine-seeking behavior, and that this effect may involve activation of dopamine transmission in the NAcc and amygdala.T he classical conditioning of the pharmacological actions of cocaine with environmental stimuli is thought to have an important role in the long-term addictive potential of this drug. Environmental cues repeatedly associated with the subjective effects of cocaine can elicit drug craving (1-6) and possibly, automatic behavioral responses (7,8) that may lead to relapse in recovering cocaine addicts. Whereas the role of drug-related stimuli in motivating the resumption of drug use is not fully understood, such learned responses may be among the most important factors responsible for the high rates of relapse associated with cocaine and other drug addiction (9).Consistent with the well-established conditioned reactivity to cocaine cues in humans, classically conditioned behavioral responses to cocaine can be readily elicited in animals (10-14). However, it has been more difficult to demonstrate motivating effects of stimuli conditioned to cocaine in animal models of relapse. Stimuli paired contiguously with cocaine infusions in self-administering rats can reinstate responding following extinction (15-17), but these stimuli often produce only weak and transient effects (16,17), or fail to elicit cocaine-seeking behavior (18,19). The lack of robust and enduring behavioral effects of cocaine cues in many ''reinstatement'' studies appears inconsistent with the presumed strength and persistence of the motivating effe...

Guinea‐pigs were sensitized with 3 injections of ovalbumin (OA) (1 or 10 μg per animal) using Al(OH)3 and pertussis vaccine as adjuvants at two week intervals. Sensitized guinea‐pigs were challenged with an aerosol of OA (0.1%) over a one hour period and both airway reactivity and cellular content of bronchoalveolar lavage (BAL) fluid were assessed at intervals for up to 7 days. Guinea‐pigs sensitized with 1 μg of ovalbumin responded to an aerosol of OA with increased pulmonary airway eosinophilia, which was evident 1 day after challenge and was present for up to 7 days. Airway hyperreactivity was not detectable in these animals. Guinea‐pigs sensitized with 10 μg of ovalbumin responded to an aerosol of OA with increased pulmonary airway neutrophilia and eosinophilia and with increased airway reactivity which was maximal between 8 and 24 h after exposure to OA. Depletion of circulating platelets or neutrophils, by use of selective antisera, did not alter either the magnitude of eosinophilia or the intensity of airway reactivity in sensitized guinea‐pigs (10 μg) exposed to an aerosol of OA. Pretreatment of sensitized guinea‐pigs (10 μg) for 6 days with AH 21–132, aminophylline, dexamethasone or ketotifen inhibited pulmonary airway eosinophilia, but did not diminish airway hyperreactivity. Neither eosinophil accumulation nor development of airway hyperreactivity was influenced by treatment with mepyramine or salbutamol over a 6 day period before OA inhalation. Although eosinophilia may occur in association with increased airway reactivity in this animal model, there is no evidence of a causal relationship.

The role of pro-inflammatory cytokines in an animal model of allergic lung disease was examined by use of an interleukin-1 receptor antagonist (IL-1ra) and a specific bioassay for tumor necrosis factor (TNF). Ovalbumin-sensitized guinea pigs exhibit a marked bronchial hyperreactivity (assessed by airway responsiveness to intravenous histamine) and pulmonary eosinophil accumulation (assessed by bronchoalveolar lavage) 24 h after challenge with aerosolized antigen. Exposure of animals to an aerosol of IL-1ra (50 micrograms over 30 min) immediately before antigen challenge resulted in a marked protection against bronchial hyperreactivity and pulmonary eosinophil accumulation compared with IL-1ra vehicle-pretreated animals. Additionally, we report for the first time generation of TNF bioactivity in the bronchoalveolar lavage of antigen-challenged animals, which was significantly reduced in animals exposed to aerosolized IL-1ra before challenge. These studies point to a key role for the cytokines IL-1 and possibly TNF in the pulmonary changes observed during allergic airway disease.