Cocaine-induced conditioned taste avoidance over extended conditioned stimulus-unconditioned stimulus intervals.

Although long-delay learning has been demonstrated numerous times in the conditioned taste avoidance procedure, the empirical evidence showing this is almost exclusively limited to studies using emetics. Given that compounds outside the emetic class (e.g. drugs of abuse) are also effective in inducing conditioned taste avoidances, the present study assessed the ability of cocaine, a non-emetic psychoactive compound, to support long-delay conditioning as the unconditioned stimulus in conditioned taste avoidance preparation. Using saccharin as the conditioned stimulus, two taste-drug pairings were followed by six extinction trials during which saccharin was presented without subsequent injections of cocaine. During the two conditioning trials, animals were injected subcutaneously with cocaine (32 mg/kg) at different conditioned stimulus-unconditioned stimulus intervals, that is, 10, 60, 120, 180, 240, 300, 420 and 540 min. A control group of animals was given an equi-volume injection of the drug vehicle at the 10-min conditioned stimulus-unconditioned stimulus interval. After two conditioning trials, all treatment groups consumed significantly less saccharin than controls, with the magnitude of the effect decreasing as the conditioned stimulus-unconditioned stimulus interval increased. After six extinction trials, animals injected with cocaine at 10, 60 and 120 min conditioned stimulus-unconditioned stimulus intervals still consumed significantly less than controls. These results with cocaine suggest that taste avoidance learning over long delays is not limited to classical emetic compounds and may, in fact, be characteristic of taste avoidance learning in general.

The inability of CCK to block (or CCK antagonists to substitute for) the stimulus effects of chlordiazepoxide.

To further examine the relationship between cholecystokinin (CCK) and GABA, the present study assessed the ability of the CCK-A antagonist devazepide and the CCK-B antagonist L-365,260 to substitute for the stimulus effects of chlordiazepoxide (CDP), as well as the ability of CCK-8s to block these effects, in female Long-Evans rats within the conditioned taste aversion baseline of drug discrimination learning. Both devazepide and L-365,260 failed to substitute for the discriminative stimulus properties of CDP, and CCK-8s failed to block its stimulus effects. The benzodiazepine diazepam did substitute for, and the benzodiazepine antagonist flumazenil did block, the stimulus effects of CDP. This suggests that the lack of substitution for, or antagonism of, CDP by the CCK antagonists and CCK-8s, respectively, was not due to the inability of the present design to assess such effects. Possible bases for the current findings, e.g., necessity of an anxiogenic baseline, drug and receptor specificity, as well as the dose-response nature of the interaction, were discussed. Given that a relationship between CCK and GABA has been reported in other designs, the present results suggest that such a relationship may be preparation specific.

Morphine-induced conditioned taste aversions in the LEW/N and F344/N rat strains.

Previous reports have shown that the LEW/N and F344/N inbred rat strains display a differential sensitivity to cocaine in a number of preparations, with the LEW/N rats displaying an increased sensitivity to both the reinforcing and aversive effects of cocaine (relative to the F344/N rats). Given that the LEW/N rats are also more sensitive to the reinforcing effects of morphine than the F344/N strain, the present experiment examined the ability of morphine to condition taste aversions in the LEW/N and F344/N strains to determine if the general sensitivity to cocaine generalizes to another drug of abuse. Specifically, on four conditioning trials, 35 LEW/N and 33 F344/N female rats were allowed access to a novel saccharin solution and then injected with varying doses of morphine (0, 10, 32 and 56 mg/kg). On intervening recovery days, subjects were allowed 20-min access to water. Following the fourth trial, a final aversion test was administered. The F344/N rats, but not the LEW/N rats, rapidly acquired morphine-induced taste aversions at all doses of morphine. Pharmacokinetic differences between the strains were also assessed. Specifically, 10 mg/kg morphine (or vehicle) was administered to subjects of both strains and plasma morphine levels were analyzed at 0.5, 2 and 4 h postinjection. No differences in plasma levels between the strains were observed. Unlike with cocaine, the LEW/N rats do not seem generally sensitive to morphine (relative to the F344/N rats). Rather, the differential sensitivity of the two strains to these compounds seems to be preparation dependent. Possible mechanisms underlying the differential sensitivity evident in the strains were discussed.

Effects of cross fostering on open-field behavior, acoustic startle, lipopolysaccharide-induced corticosterone release, and body weight in Lewis and Fischer rats.

Lewis (LEW/N) and Fischer (F344/N) rats differ on a myriad of behavioral and physiological endpoints, some of which have been reported to be affected by maternal experience in outbred rats and other strains. To assess whether epigenetic factors contribute to the differential behavioral responses to stress and pro-inflammatory challenges in these strains, the effects of cross fostering on open-field, acoustic startle, and glucocorticoid reactivity to lipopolysaccharide (LPS) were examined in the present experiment. In the open-field test, although in-fostered female LEW/N and F344/N strains did not differ, female LEW/N rats displayed significantly greater activity than female F344/N rats in the cross-fostered condition. Differences between males of the two strains were increased by cross fostering, with the LEW/N strain displaying greater total activity. In acoustic startle, there was little strain difference between in-fostered or cross-fostered female rats. On the other hand, in-fostered male LEW/N rats had a significantly greater startle response than in-fostered male F344/N rats, an effect that was dramatically reduced by cross fostering. In-fostered female LEW/N rats displayed a blunted corticosterone response relative to in-fostered female F344/N rats, an effect that was reduced by cross fostering. Conversely, although there was no strain difference between male in-fostered rats, cross-fostered male F344/N rats displayed a significantly greater corticosterone response to LPS than cross-fostered male LEW/N rats. Finally, body weight differences between in-fostered LEW/N and F344/N rats were reduced by cross fostering. Together, these data illustrate that maternal factors play a role in the behavioral and physiological responses to stress between the two strains.

Assessment of SNC 80 and naltrindole within a conditioned taste aversion design.

Although compounds with relative selectivity for the mu and kappa opiate receptors subtypes have been reported to condition taste aversions, it is not known whether systemically administered delta compounds have the ability to produce aversions. To that end, female Long-Evans rats were adapted to water deprivation and were given pairings of a novel saccharin solution and various doses of the selective delta agonist SNC 80 (0.32-10.0 mg/kg; Experiment 1) or the selective delta antagonist naltrindole (1.0-18.0 mg/kg; Experiment 2). For comparison, the relatively selective mu agonist morphine (Experiment 1) and mu antagonist naloxone (Experiment 2) were assessed under identical conditions. Both SNC 80 (Experiment 1) and naltrindole (Experiment 2) were effective as unconditioned stimuli within this design, inducing dose-dependent taste aversions with repeated conditioning trials. Although at no dose did animals injected with SNC 80 differ from those injected with morphine, aversions induced by SNC 80 were acquired at a faster rate than those induced by morphine. Subjects injected with naloxone drank significantly less than those injected with naltrindole at the 10 mg/kg dose, and aversions induced by naloxone at 5.6 and 10 mg/kg were acquired at a faster rate than those induced by naltrindole. Although the basis for opioid agonist- and antagonist-induced taste aversions is not known, the differences between aversions induced by SNC 80 and naltrindole and those induced by morphine and naloxone, respectively, may be a function of their relative selectivity for specific opiate receptor subtypes.

Morphine discriminative control is mediated by the mu opioid receptor: assessment of delta opioid substitution and antagonism.

Morphine is an effective training drug in drug discrimination procedures. In subsequent generalization tests in which other opioids are administered, mu opioid agonists selectively substitute for the training drug. Given the relative selectivity of morphine for the mu receptor, such substitution patterns suggest that the mu opioid receptor is mediating the discriminative control of this compound. The present study assessed this selective mediation by examining the ability of the delta opioid agonist SNC80 to substitute for (and the delta opioid antagonist naltrindole to antagonize) morphine stimulus effects in rats trained to discriminate morphine from its vehicle in the conditioned taste aversion baseline of drug discrimination learning. Although morphine and methadone produced dose-related substitution for morphine (10 mg/kg), there was no evidence of substitution for morphine by SNC80 at any dose tested. Further, although naloxone (3.2 mg/kg) completely blocked the discriminative effects of morphine, naltrindole (3.2-10 mg/kg) did not significantly affect the morphine stimulus. These data suggest that the discriminative control established to morphine is mediated by its activity at the mu, but not the delta, receptor.

The interaction of cocaethylene and cocaine and of cocaethylene and alcohol on schedule-controlled responding in rats.

RATIONALE: Cocaethylene is a unique metabolite of cocaine, produced only in the presence of alcohol. This metabolite is pharmacologically, physiologically and behaviorally active. Further, it has been reported to interact pharmacokinetically with both cocaine and alcohol, an interaction that may mediate, in part, the interaction of cocaine and alcohol. Although cocaethylene has been shown to interact with both cocaine and alcohol, behavioral assessments of these interactions are limited. OBJECTIVES: To examine directly the behavioral interactions between cocaethylene and cocaine and between cocaethylene and alcohol, the present study assessed the effects produced by these combinations on schedule-controlled responding. METHODS: Rats were first administered cumulative doses of cocaethylene, cocaine and alcohol to assess their effects alone on responding. Following this, doses of cocaethylene were combined with cumulative doses of cocaine or alcohol. Additionally, doses of cocaine or alcohol were given in combination with cumulative doses of cocaethylene. RESULTS: When administered alone, cocaethylene, cocaine and alcohol produced dose-related decreases in responding. Further, cocaethylene shifted the dose-response functions for both cocaine and alcohol to the left and down, while cocaine and alcohol shifted the dose-response function for cocaethylene to the left and down. An isobolographic analysis revealed that these interactions were additive in nature. CONCLUSIONS: The present study suggests behavioral interactions between cocaethylene and cocaine and between cocaethylene and alcohol. The contribution of cocaethylene to the enhanced effects produced by the co-administration of cocaine and alcohol was discussed.

Nalorphine's ability to substitute for morphine in a drug discrimination procedure is a function of training dose.

Rats trained to discriminate the mu agonists fentanyl or morphine from their respective vehicles generalize to the partial mu agonist nalorphine incompletely and inconsistently. Any number of factors may influence the generalization patterns obtained, one of which being the specific dose of the full opioid agonist used during training, a factor reported to influence generalization with other partial opioid agonists. To assess if training dose influences stimulus generalization to nalorphine and to support its role in the aforementioned variability across studies, in the present experiments rats were trained to discriminate either a low (5.6 mg/kg) or a high (10 mg/kg) dose of morphine from distilled water within the taste aversion baseline of drug discrimination learning. Subjects were then given a range of doses of morphine, nalorphine, methadone, or naloxone to assess the degree of substitution (if any) of these compounds for the training dose of morphine. For all subjects, morphine fully substituted for itself, and the opioid antagonist naloxone failed to substitute for the morphine cue. Rats generalized the morphine cue to nalorphine in subjects trained at the lower dose but not in subjects trained at the higher dose. Rats generalized the morphine cue to methadone in the latter group (the high dose group), indicating that the failure to generalize to nalorphine in this group was not a general inability of an opioid agonist to substitute for morphine. Naloxone blocked morphine stimulus control in all subjects and nalorphine control in the low-dose group for which nalorphine substituted for morphine, suggesting that morphine control (and the nalorphine substitution) was based on opioid activity. These results indicate that the substitution patterns of nalorphine in morphine-trained subjects are a function in part of the dose of morphine used in training and support the position that nalorphine is a partial opioid agonist with intermediate efficacy.

Cocaine preexposure fails to sensitize the acquisition of cocaine-induced taste aversions.

In two separate experiments, rats were given either an intraperitoneal (IP) injection of 10 mg/kg cocaine once a day for 10 consecutive days (Experiment 1) or a single IP injection of 40 mg/kg of cocaine (Experiment 2) prior to receiving repeated pairings of a novel saccharin solution with cocaine (32 mg/ kg; subcutaneous; SC). Although vehicle-preexposed subjects given saccharin-cocaine pairings readily acquired an aversion to the cocaine-associated saccharin solution, subjects preexposed to cocaine (whether 10 times or only once) displayed a retarded acquisition of the aversion. That is, cocaine preexposure attenuated the acquisition of cocaine-induced taste aversions. There was no difference in the degree of attenuation between the two preexposure conditions. Thus, under conditions that are effective in inducing sensitization within other behavioral preparations there was no evidence of sensitized cocaine-induced taste aversions. The results from the present investigation are similar to reports from this laboratory and others demonstrating that preexposure to cocaine, as with a range of other psychoactive drugs, results in weaker taste aversions. The basis for the attenuating effects of cocaine preexposure was discussed in terms of an adaptation to the aversive effects of cocaine.

Assessment of cocaethylene lethality in Long-Evans female and male rats.

Cocaethylene, the metabolite of cocaine produced only in the presence of alcohol, produces a number of pharmacological, physiological, and behavioral effects. It also has a range of toxicological consequences, the most severe being lethality. Given that the assessments of cocaethylene lethality have been limited to mice, the present study assessed the lethality of cocaethylene in rats. Further, because of within-species sex differences with its parent compound, cocaine, cocaethylene lethality was also examined in both females and males. Specifically, female and male rats were injected IP with 75, 87, 100, 115, and 133 mg/kg cocaethylene and observed over a 24-h period. Deaths were dose dependent and occurred within 30 min for both females and males. For females, the LD50 was 96 mg/kg; for males, the LD50 was 70 mg/kg. The percentage of rats displaying severe effects (i.e., seizure and death) increased with dose across all postinjection times. Further, these effects occurred earlier as dose increased. Differences in the LD50 for rats and mice, as well as the greater sensitivity to cocaethylene in male rats, are discussed.

The effects of cocaine preexposure on the acquisition of cocaine-induced taste aversions.

In separate experiments, rats received either five intraperitoneal or five subcutaneous injections of cocaine (once daily or spaced every fourth day) prior to receiving repeated saccharin-cocaine pairings (during taste aversion conditioning). Both spaced and massed subcutaneous cocaine preexposure attenuated the subsequent acquisition of taste aversions induced by cocaine. Specifically, aversions in the preexposed subjects were acquired at a slower rate and/or to a lesser degree than those acquired by subjects preexposed to the cocaine vehicle and injected with cocaine during conditioning. Spaced and massed intraperitoneal cocaine preexposure had only a weak or no effect, respectively, on the subsequent acquisition of cocaine-induced taste aversions. Specifically, subjects receiving spaced intraperitoneal injections of cocaine during preexposure differed from nonpreexposed subjects on only a single conditioning trial, and subjects receiving massed intraperitoneal injections of cocaine during preexposure displayed aversions comparable to those of nonpreexposed subjects. Although the effects of subcutaneous cocaine preexposure were similar to those reported with other drugs within the aversion design, it is clear that the preexposure effect with cocaine is dependent upon the specific parameters of preexposure. Several possibilities for these differential effects of cocaine preexposure were discussed, including the influence of changing the route of administration from preexposure to conditioning (i.e., from i.p. to s.c.) and the differential masking of the aversive effects of cocaine during conditioning by differential sensitization to cocaine's reinforcing properties following s.c. and i.p. preexposure. Although the present series of experiments did not directly address the mechanism(s) underlying the attenuating effects of cocaine preexposure on aversion learning, several possibilities were noted, including adaptation or tolerance to the aversive effects of cocaine and sensitization to its rewarding effects.

Cocaine and alcohol synergism in taste aversion learning.

Female Long-Evans rats were given 20-min access to saccharin followed by injections of alcohol and cocaine, alone and in combination. Although there was no significant interaction between alcohol and cocaine when cocaine was given intraperitoneally (IP), aversions induced by the drug combination when cocaine was administered subcutaneously (SC) were significantly greater than those induced by either drug alone. Further, the aversions induced by the combination were significantly greater than the summed effects of the individual drugs administered alone, indicating a synergistic interaction between cocaine and alcohol. It was suggested that this synergism might result from a summation of the effects of alcohol, cocaine, and cocaethylene, a unique and toxic metabolite of cocaine produced when alcohol is coadministered. To assess the role of cocaethylene in the present design, additional taste aversion assessments were performed in which saccharin was paired with either IP or SC injections of cocaethylene. Although cocaethylene was found to induce aversions, the summed changes in consumption from baseline produced by cocaine, alcohol, and cocaethylene were significantly less than the changes produced by cocaine and alcohol in combination. These results indicate that the synergistic interaction between cocaine and alcohol in the present design cannot be attributed solely to summation of the effects of the individual drugs and the metabolite cocaethylene. Additional mechanisms by which cocaethylene might contribute to the synergistic interaction between cocaine and alcohol, as well as the role pharmacokinetic interactions between cocaine and alcohol might have in the interaction, were discussed.

Effects of mu- and delta-opioid-receptor antagonists on the stimulus properties of cholecystokinin.

Melton and Riley recently reported that the relatively selective mu-opioid-antagonist naloxone potentiated the stimulus properties of the gut peptide cholecystokinin (CCK). To assess whether such opioid potentiation is limited to activity at the mu-receptor subtype, in the present experiment the effects of the highly selective delta-antagonist naltrindole on CCK's stimulus properties were examined. Because in the initial report of naloxone's potentiation of CCK a relatively high, nonphysiologic dose of CCK (i.e., 13 micrograms/kg) was used as the training drug, in the current analysis subjects were trained to discriminate 5.6 micrograms/kg CCK from its vehicle and the assessments and comparisons of the effects of naloxone and naltrindole were based on this dose. Specifically, rats were administered 5.6 micrograms/kg CCK before saccharin-LiCl pairings and the CCK vehicle before saccharin alone. With such training, they rapidly acquired the drug discrimination, avoiding saccharin consumption when it was preceded by CCK and consuming the same saccharin solution when it was preceded by its vehicle. In subsequent generalization tests, doses of CCK that were ineffective in suppressing saccharin consumption (i.e., did not substitute for the training dose of CCK) did result in the suppression of saccharin consumption when combined with doses of the mu antagonist naloxone that alone had no effect on saccharin intake. On the other hand, the highly selective delta-opioid-receptor antagonist naltrindole was ineffective in potentiating the effects of CCK. Specifically, when naltrindole was combined with ineffective doses of CCK, subjects drank at control levels. The ability of naloxone to potentiate CCK's stimulus effects is consistent with a range of other demonstrations of the role of the mu-opioid-receptor subtype in CCK-opioid interactions, although the specific basis for the interaction remains unknown. Given recent findings on the effects of delta agonists and antagonists on CCK-induced activity, the failure of naltrindole to potentiate CCK's stimulus effects may be due to the absence of delta activity within this preparation, rather than the absence of delta mediation of CCK-opioid interactions in general.

The interaction of cocaine and alcohol on schedule-controlled responding.

Within a number of physiological preparations, the effects of alcohol and cocaine in combination are reported to be greater than the effects of either drug given alone. Little has been reported, however, on the behavioral effects of the interaction. The present study investigated this issue by assessing the effects of cocaine and alcohol (alone and in combination) on schedule-controlled responding. Specifically, rats were trained to respond on an FR20 schedule for a water reinforcer. They were then administered cumulative doses of cocaine or alcohol. Following this, subjects were administered ineffective doses of alcohol prior to further dose-response assessments with cocaine and with ineffective doses of cocaine prior to further dose-response assessments with alcohol. Cocaine and alcohol alone produced dose-related decreases in responding. Furthermore, the dose-response function for cocaine was shifted to the left by alcohol and the dose-response function for alcohol was shifted to the left by cocaine. An isobolographic analysis revealed that the interaction between cocaine and alcohol was additive in nature. The possible bases for the interaction (e.g., changes in cocaine pharmacokinetics by alcohol and the formation of cocaethylene following co-administration of cocaine and alcohol) were discussed.

Dopamine D1/D2 antagonist combinations as antagonists of the discriminative stimulus effects of cocaine.

Although data suggest that the dopaminergic system mediates the discriminative stimulus effects of cocaine, neither selective D1 or D2 dopamine agonists nor selective D1 or D2 antagonists substitute reliably for or consistently block these effects. These findings suggest that concurrent activity at these receptor subtypes may underlie this discrimination. Accordingly, it would be expected that simultaneous blockade of these receptors may be necessary to block it fully. The ability of various combinations of the D1 antagonist, SCH 23,390, and the D2 antagonist, haloperidol, were tested for their ability to block the cocaine stimulus in rats trained to discriminate cocaine (7.5, 10, or 13 mg/kg) from vehicle. Antagonist combinations decreased the percentage of cocaine-appropriate responses 10-95% below the cocaine baseline at doses of the antagonist that were inactive when given separately. These findings support the position that activity at D1-like and D2-like receptor subtypes may account for more of the pharmacological action of cocaine than activation of a single dopamine receptor subtype.

Discriminative stimulus effects of dopaminergic agents in rhesus monkeys.

Recent reports have shown that treatment with dopamine reuptake inhibitors can selectively decrease responding maintained by low doses of cocaine in rhesus monkeys. This may occur because response-independent delivery of a reuptake inhibitor and response-dependent cocaine have common effects. One behavioral effect that dopamine reuptake inhibitors and cocaine share is their ability to serve as a discriminative stimulus. To compare discriminative effects of several dopaminergic agents with their ability to attenuate cocaine-maintained responding, three rhesus monkeys were first trained to discriminate intravenous injections of cocaine (0.1 mg/kg) from saline. Following generalization testing with various doses of cocaine (0.001-1.0 mg/kg), the relative potencies of phentermine (0.03-1.0 mg/kg), d-amphetamine (0.01-1.0 mg/kg), GBR 12,909 (0.01-1.0 mg/kg), and buspirone (0.03-0.56 mg/kg) to substitute for cocaine were assessed. Each drug except buspirone resulted in predominantly cocaine-appropriate responding at doses that were generally without rate-decreasing effect. The ED50 for the ability of these drugs to substitute for cocaine exhibited the same rank order as that for their effectiveness in decreasing cocaine-maintained responding. Thus, the current results show that the potencies of dopaminergic drugs to decrease cocaine-maintained responding and substitute for cocaine in a drug discrimination paradigm are related.

The effects of chronic morphine on the generalization of buprenorphine stimulus control: an assessment of kappa antagonist activity.

Rats trained to discriminate the mixed mu agonist/kappa antagonist buprenorphine from its vehicle generalize buprenorphine control to morphine. Buprenorphine, however, does not generalize to MR2266. The generalization to morphine suggests that buprenorphine's mu agonist properties mediated in part its discriminative control. The failure to generalize to MR2266, a compound reported to block kappa-mediated effects, however, suggests that its kappa antagonist activity was not involved in its discriminative effects. The ability of buprenorphine's mu (but not kappa) activity to establish stimulus control may be a function of the overshadowing of the kappa properties of buprenorphine by its concurrent mu activity. To test this possibility, in the present experiment rats were chronically exposed to morphine prior to buprenorphine discrimination training. This procedure has been reported to result in tolerance to buprenorphine's mu agonist effects and a more pronounced display of its kappa antagonist properties. The rats were then tested for the generalization of buprenorphine control to morphine, MR2266, and pentobarbital. As expected, buprenorphine failed to generalize to the nonopioid pentobarbital. Although subjects were tolerant to morphine (as evidenced by reductions in morphine-induced behavioral effects and a rightward shift in the doses of morphine substituting for buprenorphine), buprenorphine still failed to generalize to MR2266. The failure of buprenorphine to generalize to MR2266 under conditions that should have allowed for the development of stimulus control by buprenorphine's kappa antagonist activity was discussed in terms of the general inability of kappa antagonist activity to support discrimination learning.

The contribution of within-session averaging of drug- and vehicle-appropriate responding to the graded dose-response function in drug discrimination learning.

Prior work within the taste aversion baseline of drug discrimination learning has demonstrated that the generalization function for individual rats is graded in nature. In such work, intermediate doses of the training drug produced intermediate levels of drug-appropriate responding. Under some conditions, such graded responding has been reported to be due to an averaging of quantal drug- and vehicle-appropriate responding at different periods within the session. The present experiment assessed the contribution of such averaging to the graded responding within the aversion design. Rats were first trained to discriminate either 1mg/kg naloxone or 10mg/kg pentobarbital from distilled water. They were then administered various doses of the training drug (or a different drug), and the within-session pattern of licking was monitored minute by minute over the 20min session. Responding within the session was primarily either drug- or vehicle-appropriate. The specific pattern of drug- or vehicle-appropriate responding was presumably dependent upon the onset and/or offset of the drug stimulus. Thus, for the aversion baseline the graded response function for individual rats appears to be a function of the within session averaging of quantal (either drug- or vehicle-appropriate) responding.

Interagency coordination: the key to mainstreaming children with special needs into day care.

While the need for mainstreamed day-care services continues to increase, many barriers remain that prevent or delay providers from enrolling children with special needs. The suggestions in this article to coordinate local resources will help programs begin to provide initial necessary services to children with special needs. The use of volunteers will help supplement the staffing needs of a day-care center and allow for more individualized care of the children. Unfortunately, the absence of public funds for child day care continues to be a major barrier to creating appropriate programs for children with special needs. State and federal policies need to be expanded to support day care in general and children with special needs specifically. Part H of PL 99-457 (now Part H of IDEA PL102-119) is a national impetus to promote interagency collaboration at state and local levels. This is a beginning, but more state and federal funding is needed. In addition, regulations need to be developed that will make it easier rather than more difficult for local agencies to participate. Day-care providers and professionals in every community must work together to provide appropriate services to children with special needs. The most effective services use interdisciplinary teams to work together to plan and implement the care. Let us pick up the challenge of this mandate and develop programs that will help future generations recognize and accept the differences between individuals as well as see the similarities.

Nalorphine as a stimulus in drug discrimination learning: assessment of the role of mu- and kappa-receptor subtypes.

Using the conditioned taste aversion baseline of drug discrimination learning, animals were trained to discriminate nalorphine from distilled water. In subsequent generalization tests, the mu-opiate agonist morphine substituted for the nalorphine stimulus in a dose-dependent manner, while the kappa-opiate agonist U50,488H and the mu-opiate antagonists naloxone and naltrexone failed to do so. That the mu-agonist morphine substituted for the nalorphine stimulus while a kappa-agonist and mu-antagonists failed to substitute indicate that the discriminative control that was established with nalorphine in the present study was mu-agonist receptor-mediated. The basis for this selective control by the mu-receptor subtype may be related to the relative salience of receptor activity in opiate-naive animals. The present results suggest that discriminative control by compounds with activity at multiple receptor sites is not uniformly mediated by specific activity at all of those sites. The specific site mediating discriminative control appears to be a function of the specific training drug.