Exposure to tobacco smoke during pregnancy is associated with a range of adverse Outcomes in offspring, including cognitive deficits and increased incidence of attention deficit-hyperactivity disorder (ADHD), but there is considerable controversy concerning the causal role of tobacco smoke in these outcomes. To determine whether developmental exposure to the primary psychoactive ingredient in tobacco smoke, nicotine, may cause long-lasting behavioral alterations analogous to those in ADHD, male Sprague-Dawley rats underwent a chronic neonatal nicotine administration regimen which models third-trimester human exposure. Male rat pups were administered nicotine (6 mg/kg/day) by oral gastric intubation on postnatal days 1–7. In adulthood, rats were tested in two decision-making tasks (risky decision making and delay discounting) as well as in free-operant responding for food reward and the elevated plus maze (EPM). Chronic neonatal nicotine attenuated weight gain during nicotine exposure, but there were no effects on performance in either decision-making task, and only a modest decrease in arm entries in the EPM in one sub-group of rats. These data are consistent with previous findings that developmental nicotine exposure has no effect on delay-discounting, and they extend these findings to risky decision making as well. They further suggest that at least some neurocognitive alterations associated with prenatal tobacco smoke exposure in humans may be due to genetic or other environmental factors, including non-nicotine components of tobacco smoke.

Repeated administration of haloperidol and olanzapine causes a progressively enhanced disruption of conditioned avoidance response (CAR) and a progressively enhanced inhibition of phencyclidine (PCP)-induced hyperlocomotion in rats (termed antipsychotic sensitization). Both actions are thought to reflect intrinsic antipsychotic activity. The present study examined to the extent to which antipsychotic-induced sensitization in one model (e.g. CAR) can be transferred or maintained in another (e.g. PCP hyperlocomotion) as a means of investigating the contextual and behavioral controls of antipsychotic sensitization. Well-trained male Sprague-Dawley rats were first repeatedly tested in the CAR or PCP (3.2 mg/kg, sc) hyperlocomotion model under haloperidol or olanzapine for five consecutive days. Then they were switched to the other model and tested for the expression of sensitization. Finally, all rats were switched back to the original model and retested for the expression of sensitization. Repeated haloperidol or olanzapine treatment progressively disrupted avoidance responding and decreased PCP-induced hyperlocomotion, indicating a robust sensitization. When tested in a different model, rats previously treated with haloperidol or olanzapine did not show a stronger inhibition of CAR or PCP-induced hyperlocomotion than those treated with these drugs for the first time; however, they did show such an effect when tested in the original model in which they received repeated antipsychotic treatment. These findings suggest that the expression of antipsychotic sensitization is strongly influenced by the testing environment and/or selected behavioral response under certain experimental conditions. Distinct contextual cues and behavioral responses may enter an association with unconditional drug effects via a Pavlovian conditioning process. They may also serve as occasion-setters to modulate the expression of sensitized responses. Because antipsychotic sensitization mimics clinical effects of antipsychotic treatment, understanding the neurobiological mechanisms of antipsychotic sensitization and its contextual control would greatly enhance our understanding of the psychological and neurochemical nature of antipsychotic treatment in the clinic.

Ethanol exposure during perinatal development can cause cognitive abnormalities including difficulties in learning, attention, and memory, as well as heightened impulsivity. The purpose of this study was to assess performance in spatial learning and impulsive choice tasks in rats subjected to an intragastric intubation model of binge ethanol exposure during human third trimester-equivalent brain development. Male and female Sprague–Dawley rat pups were intubated with ethanol (5.25 g/kg/day) on postnatal days 4–9. At adolescence (between postnatal days 35–38), these rats and sham intubated within-litter controls were trained in both spatial and cued versions of the Morris water maze. A subset of the male rats was subsequently tested on a delay-discounting task to assess impulsive choice. Ethanol-exposed rats were spatially impaired relative to controls, but performed comparably to controls on the cued version of the water maze. Ethanol-exposed rats also showed greater preference for large delayed rewards on the delay discounting task, but no evidence for altered reward sensitivity or perseverative behavior. These data demonstrate that early postnatal intermittent binge-like ethanol exposure has prolonged, detrimental, but selective effects on cognition, suggesting that even relatively brief ethanol exposure late in human pregnancy can be deleterious for cognitive function.

Delta opioid receptors represent a promising target for the development of novel analgesics. A number of tools have been developed recently that have significantly improved our knowledge of delta receptor function in pain control. These include several novel delta agonists with potent analgesic properties, as well as genetic mouse models with targeted mutations in the delta opioid receptor gene. Also, recent findings have further documented the regulation of delta receptor function at cellular level, which impacts on the pain-reducing activity of the receptor. These regulatory mechanisms occur at transcriptional and post-translational levels, along agonist-induced receptor activation, signaling and trafficking, or in interaction with other receptors and neuromodulatory systems. All these tools for in vivo research, as well as proposed mechanisms at molecular level, have tremendously increased our understanding of delta receptor physiology, and contribute to designing innovative strategies for the treatment of chronic pain and other diseases such as mood disorders.

Eating high fat food can alter sensitivity to drugs acting on dopamine systems; this study examined whether eating high fat food alters sensitivity to a drug acting on serotonin (5-HT) systems. Sensitivity to (+)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide (8-OH-DPAT; 5-HT1A receptor agonist)-induced lower lip retraction was examined in separate groups (n=8-9) of rats with free access to standard (5.7% fat) or high fat (34.3% fat) chow; sensitivity to quinpirole (dopamine D3/D2 receptor agonist)-induced yawning was also examined. Rats eating high fat chow gained more body weight than rats eating standard chow and, after 6 weeks of eating high fat chow, they were more sensitive to 8-OH-DPAT (0.01-0.1 mg/kg)-induced lower lip retraction and quinpirole (0.0032-0.32 mg/kg)-induced yawning. These changes were not reversed when rats that previously ate high fat chow were switched to eating standard chow and sensitivity to 8-OH-DPAT and quinpirole increased when rats that previously ate standard chow ate high fat chow. These data extend previous results showing changes in sensitivity to drugs acting on dopamine systems in animals eating high fat chow to a drug acting at 5-HT1A receptors and they provide support for the notion that eating certain foods impacts sensitivity to drugs acting on monoamine systems.

Food and drugs can activate brain dopamine systems and sensitivity to the effects of drugs acting on those systems is influenced by amount and content of food consumed. This study examined the effects of drinking sucrose on behavioral effects of the directly-acting dopamine receptor agonist quinpirole. Male Sprague-Dawley rats (n=6/group) had free access to water or 10% sucrose and quinpirole dose-response curves (yawning and hypothermia) were generated weekly for 8 weeks. Subsequently, all rats drank water for 8 weeks with quinpirole dose-response curves determined on weeks 9, 10, and 16. In rats drinking sucrose, the ascending (D3 receptor-mediated), but not descending (D2 receptor-mediated), limb of the yawning dose-response curve shifted leftward. The D3 receptor-selective antagonist PG01037 shifted the ascending limb of the dose-response curve to the right in all rats. When rats that previously drank sucrose drank water, their sensitivity to quinpirole did not return to normal. Quinpirole-induced hypothermia was not different between groups. These data show that drinking sucrose increases sensitivity to a dopamine D3, but not D2, receptor-mediated effect and that this change is long lasting. Dopamine receptors mediate the effects of many drugs and the actions of those drugs are likely impacted by dietary factors.

To begin to characterize the temporal profile of behavioral sensitization to the amphetamine derivative MDMA, rats were treated with either saline or MDMA (5.0 mg/kg) twice daily for 5 days, followed by a challenge injection of MDMA (2.5 mg/kg) either 15 or 100 days later. Because we found previously that contextual drug associations are important to the expression of behavioral sensitization to MDMA following relatively short withdrawal periods, rats received the repeated injections in either their home cages (unpaired group) or the activity monitors that were used for tests of sensitization on challenge day (paired group). Locomotor sensitization was evident at 15 days of withdrawal, but only in the paired MDMA-treated group. Interestingly, however, sensitization was apparent at 100 days of withdrawal in both paired and unpaired rats, but the form of sensitization differed between groups. Thus, sensitization in paired rats was expressed as an increase in stereotypy, whereas sensitization in unpaired rats was expressed as an increase in locomotion, paralleling locomotion levels in paired animals at 15 days of withdrawal. These results suggest that the neural changes that underlie behavioral sensitization to MDMA are quite enduring but involve an interaction between withdrawal time and the context of drug administration.

The present study examined the effects of the mGluR1 antagonist JNJ16259685 (JNJ) and the mGluR5 antagonist MPEP alone and in combination with morphine in two acute pain models (hotplate, warm water tail-withdrawal), and a persistent, inflammatory pain model (capsaicin). In the hotplate and warm water tail-withdrawal procedures, JNJ and MPEP were ineffective when administered alone. In both procedures, JNJ potentiated morphine antinociception. In the hot plate procedure, MPEP potentiated morphine antinociception at the highest dose examined, whereas in the warm water tail-withdrawal procedure MPEP attenuated morphine antinociception at a moderate dose and potentiated morphine antinociception at a high dose. For both JNJ and MPEP, the magnitude of this morphine potentiation was considerably greater in the hotplate procedure. In the capsaicin procedure, the highest dose of MPEP produced intermediate levels of antihyperalgesia and also attenuated the effects of a dose of morphine that produced intermediate levels of antihyperalgesia. In contrast, JNJ had no effect when administered alone in the capsaicin procedure and did not alter morphine-induced antihyperalgesia. The present findings suggest that the effects produced by mGluR1 and mGluR5 antagonists alone and in combination with morphine can be differentiated in models of both acute and persistent pain.

Despite its abuse potential, methylphenidate (MPH) is widely prescribed for treatment of attention deficit hyperactivity disorder (ADHD). The purpose of the present study was to examine MPH self-administration in a rat model of ADHD. Experiment 1 examined the acquisition of MPH self-administration and assessed the MPH dose-effect curve in spontaneously hypertensive rats (SHR), an inbred rat model of ADHD, Wistar Kyotos (WKY), the progenitor strain for SHR, and Sprague-Dawleys (SD), an outbred control strain. Experiment 2 replicated Experiment 1, but replaced MPH infusions with sucrose pellets. Initial acquisition of MPH self-administration was greater in SHR and SD than WKY. With extended training using an incrementing fixed ratio schedule, however, SHR and WKY did not differ in responding for MPH using the training dose (0.3 mg/kg/infusion) or other unit doses, except that SHR showed greater responding than WKY at 0.1 mg/kg/infusion. SHR also showed greater acquisition and maintenance of sucrose-reinforced responding compared to both WKY and SD. Greater initial acquisition of MPH self-administration in SHR than WKY may not be due to a strain specific difference in sensitivity to the reinforcing effect of MPH.

Monoamine releasers constitute one class of candidate medications for treatment of cocaine abuse, and concurrent cocaine-versus-food choice procedures are potentially valuable as experimental tools to evaluate the efficacy and safety of candidate medications. This study assessed choice between cocaine and food by rhesus monkeys during treatment with five monoamine releasers that varied in selectivity to promote release of dopamine and norepinephrine (DA/NE) vs. serotonin (5HT) [m-fluoroamphetamine, (+)-phenmetrazine, (+)-methamphetamine, napthylisopropylamine and (±)-fenfluramine]. Rhesus monkeys (n=8) responded under a concurrent-choice schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0 – 0.1 mg/kg/inj, fixed-ratio 10 schedule). Cocaine choice dose-effect curves were determined daily during continuous seven-day treatment with saline or each test compound dose. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice, and the highest cocaine doses (0.032 – 0.1 mg/kg/inj) maintained almost exclusive cocaine choice. Efficacy of monoamine releasers to decrease cocaine choice corresponded to their pharmacological selectivity to release DA/NE vs. 5HT. None of the releasers reduced cocaine choice or promoted reallocation of responding to food choice to the same extent as substituting saline for cocaine. These results extend the range of conditions across which DA/NE-selective releasers have been shown to reduce cocaine self-administration.

Food restriction and hypoinsulinemia can affect the synthesis, turnover and receptor function of serotonin (5-HT) in brain. This study explored the effects of food restriction and streptozotocin treatment on behavioral effects related to 5-HT1A (8-OH-DPAT) and 5-HT2A (DOI) receptor activation. Lower lip retraction and flat body posture (8-OH-DPAT) and head twitching (DOI) were measured in rats during free feeding, food restriction, after treatment with streptozotocin, and finally after insulin replacement. 8-OH-DPAT induced lower lip retraction and flat body posture whereas DOI induced head twitching. One week of food restriction (10 g/day) decreased 8-OH-DPAT induced lower lip retraction, 8-OH-DPAT induced flat body posture, and DOI-induced head twitching. Subsequently, one week of free access to food restored sensitivity to 8-OH-DPAT and DOI-induced behavioral effects. Finally, one week after streptozotocin, 8-OH-DPAT induced flat body posture and DOI-induced head twitching were markedly reduced whereas 8-OH-DPAT induced lower lip retraction was unchanged. One week of insulin replacement restored sensitivity to 8-OH-DPAT and DOI-induced behavioral effects. These results show that modest food restriction or experimentally-induced diabetes can profoundly affect sensitivity to drugs acting at 5-HT1A or 5-HT2A receptors; these results could be relevant to understanding the comorbidity of depression and diabetes.

During adulthood, associative learning is necessary for the expression of one-trial behavioral sensitization; however, it is uncertain whether the same associative processes are operative during the preweanling period. Two strategies were used to assess the importance of associative learning for the one-trial behavioral sensitization of preweanling rats. In the initial experiments, we varied both the sequence and time interval between presentation of the conditioned stimulus (CS, novel environment) and unconditioned stimulus (US, cocaine). In the final experiment, we determined whether ECS-induced retrograde amnesia would disrupt one-trial behavioral sensitization. Results showed that robust sensitized responding was apparent regardless of the sequence in which cocaine and the novel environment (the presumptive CS) were presented. Varying the time between CS and US presentation (0, 3, or 6 h) was also without effect. Results from Experiment 3 showed that single or multiple ECS treatments did not alter the expression of the sensitized response. Therefore, these data indicated that the one-trial behavioral sensitization of preweanling rats was exclusively mediated by nonassociative mechanisms and that associative processes did not modulate sensitized responding. These findings are in contrast to what is observed during adulthood, because adult rats exhibit one-trial behavioral sensitization only when associative processes are operative.

The monogamous prairie vole displays developmental sensitivity to early pharmacological manipulation in a number of species-typical social behaviors. The long-term consequences of altering the neonatal dopamine system are not well characterized. The present study examined whether early manipulation of the dopamine system, a known mediator of adult prairie vole social behavior, during neonatal development would affect adult aggressive and attachment behaviors. Eight-day-old pups were given a single treatment with either 1mg/kg SKF38393 (D1 agonist), quinpirole (D2 agonist), SCH23390 (D1 antagonist), eticlopride (D2 antagonist), or saline vehicle. As adults, subjects received tests for intrasexual aggression and partner preference. Activation of D1-like receptors in pups impaired partner preference formation but had no effect on aggression. Other neonatal treatments had no effect on their behavior as adults. To determine if D1 activation in pups induced changes in dopamine receptor expression, we performed autoradiography on striatal tissue from a second cohort of saline and SKF38393 treated animals. Although sex differences were observed, we found no treatment differences in D1 or D2 receptor binding in any striatal sub-region. This study shows that exposure to a single early pharmacological alteration of dopamine receptor activity may have long-term effects on the social behavior of prairie voles.

There is increasing concern about abuse of propofol, a widely-used surgical anesthetic and sedative that is currently not a controlled substance. The purpose of the present study was to establish a rat model of the psychoactive effect of sub-anesthetic doses of propofol that could be useful for confirming abuse liability and studying mechanisms of propofol abuse. Sprague-Dawley rats were trained to discriminate propofol (10 mg/kg, i.p.) from vehicle (2% methylcellulose). Carisoprodol (100 mg/kg), chlordiazepoxide (10 mg/kg) and dizocilpine (0.1 mg/kg) were tested for substitution for the discriminative-stimulus effects of propofol (10 mg/kg), whereas pentylenetetrazol (10 mg/kg) was tested for antagonism of the discriminative-stimulus effects. Propofol (10 mg/kg) was tested for substitution in rats trained to discriminate carisoprodol from vehicle. Carisoprodol produced 59% propofol-appropriate responding, chlordiazepoxide 65%, and dizocilpine 34%. Pentylenetetrazol decreased propofol-appropriate responding to 41%. Propofol produced 52% carisoprodol-appropriate responding. Mortality rate during training of 10 mg/kg propofol was 38%. Post-mortem examination revealed cardiovascular abnormalities similar to those observed in propofol-infusion syndrome in humans. The results demonstrate that propofol can be trained as a discriminative stimulus. Its discriminative-stimulus effects were more similar to compounds promoting GABA-A receptor activity than to a compound inhibiting NMDA receptor activity. Because propofol has discriminative-stimulus effects similar to known drugs of abuse and occasions a high mortality rate, its potential for continued abuse is of particular concern.

Associations between drugs and the stimuli paired with drugs have been proposed as primary factors in drug addiction and relapse. Previous research has found cues paired with drug infusions are important for many classes of drugs. The purpose of the present experiment was to determine if a cue light was necessary to engender reliable self-administration of methylphenidate (MPH), which is a widely prescribed drug for Attention Deficit Hyperactivity Disorder. Rats were given access to MPH (0.3 mg/kg/infusion) or saline for self-administration. Half of the rats in each group had infusions paired with a cue light, whereas the other half did not. Two additional groups of rats received MPH infusions non-contingently; one group’s lever pressing turned on the cue light, and the other group’s lever pressing had no consequence. Both MPH and the cue functioned as weak reinforcers on their own. The group that lever pressed for MPH paired with a cue light pressed significantly more for MPH than any other group, indicating that the cue and MPH had a synergistic effect on self-administration when combined. Taken together, these results indicate that MPH has reinforcing properties on its own, but that environmental cues also play an important role in enhancing MPH self-administration.

Intracranial self-stimulation (ICSS) is one procedure used to evaluate abuse liability of drugs. The mu opioid receptor agonist morphine is an acknowledged drug of abuse, and the present study examined factors that may influence expression of abuse-related morphine effects on ICSS in rats. Adult male rats were equipped with intracranial electrodes targeting the medial forebrain bundle, and 10 stimulus frequencies (56-158 Hz in 0.05 log increments) were available during each daily session under a continuous reinforcement schedule. The primary dependent variable was ICSS rate at each frequency. Under control conditions, ICSS rate increased with frequency. After acute morphine (1-10 mg/kg), rate-decreasing effects predominated at early pretreatment times (10-30 min), and rate-increasing effects predominated at later pretreatment times (100-180 min). Acute morphine effects dissipated after 300 min. Repeated morphine (3.2-18 mg/kg/day × 7 days at each dose) produced tolerance to rate-decreasing effects, enhanced expression of rate-increasing effects, and enhanced rate-dependency of morphine effects. Withdrawal from repeated morphine produced small but significant dose-dependent decreases in ICSS. These results show that the magnitude and valence of morphine effects on rates of ICSS in rats are strongly influenced by morphine dose and pretreatment time, history of morphine exposure, and baseline ICSS rate.

Δ9-Tetrahydrocannabinol (THC) discrimination in rodents is a behavioral assay that has been used to probe differences among classes of cannabinoids in rats. The purpose of this study was to determine whether traditional and anandamide-like cannabinoids were distinguishable in cannabinoid discrimination procedures in mice. Male mice were trained to discriminate 30 mg/kg THC or 70 mg/kg methanandamide from vehicle in a two-lever milk-reinforced drug discrimination procedure. After acquisition, agonist tests with THC, methanandamide, CP55,940, and anandamide were conducted, as were antagonism tests with rimonabant. Substitution (agonism) and antagonism tests were also performed in female mice trained to discriminate THC. THC and CP55,940 fully substituted in THC-trained mice of both sexes. Further, THC substitution was rimonabant reversible. In contrast, mice injected with methanandamide or anandamide failed to respond substantially on the THC lever, even up to doses that decreased overall responding. In methanandamide-trained mice, methanandamide fully generalized to the methanandamide training dose. Rimonabant did not reverse this generalization. Although THC, CP55,940 and anandamide also increased responding on the methanandamide lever, the magnitude of substitution was less than for methanandamide. These results suggest incomplete overlap in the underlying mechanisms mediating endocannabinoid pharmacology and marijuana intoxication. Further, they suggest that methanandamide discrimination may involve a non-CB1 receptor mechanism that is particularly prominent at higher doses.

In light of the adverse side effects of opioids, cannabinoid (CB) receptor agonists may provide an effective alternative for the treatment of cancer pain. The present study examined the potency and efficacy of synthetic CB1 and CB2 receptor agonists in a murine model of tumor pain. Intraplantar (i.pl) injection of the CB1 receptor agonist ACPA (ED50 of 18.4 µg) reduced tumor-related mechanical hyperalgesia by activation of peripheral CB1 but not CB2 receptors. Similar injection of the CB2 receptor agonist AM1241 (ED50 of 19.5) reduced mechanical hyperalgesia by activation of peripheral CB2 but not CB1 receptors. Both agonists had an efficacy comparable to that of morphine (i.pl), but their analgesic effects were independent of opioid receptors. Isobolographic analysis of the co-injection of ACPA and AM1241 determined that the CB1 and CB2 receptor agonists interacted synergistically to reduce mechanical hyperalgesia in the tumor-bearing paw. These data extend our previous findings that the peripheral cannabinoid receptors are a promising target for the management of cancer pain and mixed cannabinoid receptor agonists may have a therapeutic advantage over selective agonists.

Activation of the dopaminergic system underlies the behavioral effects of (+)-amphetamine, and plays the major role in its discriminative stimulus properties. Although serotonin receptors modulate dopamine levels in the brain, and 5-HT1A and 5-HT2 receptor agonists do not mimic (+)-amphetamine, pretreatment with 5-HT2A/2C agonists significantly potentiates the (+)-amphetamine cue. Further, 5-HT2 antagonists do not modify the discriminative stimulus effect of (+)-amphetamine, but 5-HT1A antagonists have never been tested in (+)-amphetamine-trained rats. The present study sought to characterize the effects of the 5-HT1A antagonist WAY 100635 on (+)-amphetamine-induced discriminative stimulus effects. Male Sprague-Dawley rats were trained in a two-lever, fixed ratio (FR) 50, food-reinforced task with (+)-amphetamine sulfate (1.0 mg/kg, i.p., 30 min pretreatment time) as the discriminative stimulus. Substitution and combination tests with WAY 100635 were then performed. WAY 100635 did not produce substitution in amphetamine-trained rats, but significantly increased behavioral disruption. In combination tests 0.4 and 5.4 mg/kg doses of WAY 100635 potentiated the amphetamine cue. We suggest that low doses of WAY 100635 potentiated the (+)-amphetamine cue by blockade of 5-HT1A receptors, but stimulation of the dopamine D4 receptor by higher doses of WAY 100635 may be responsible for potentiation of amphetamine-induced behavioral sensitization. The high percentage of behavioral disruption in substitution tests might suggest that rats trained to discriminate (+)-amphetamine from saline show behavioral sensitization that is not detectable by the drug discrimination assay but may be expressed as hyperactivity and stereotypic behavior that disrupts operant behavior.

Drug discrimination has been an important technique in behavioural pharmacology for at least 40 years. The characteristics of drug-produced discriminative stimuli are influenced by behavioural and pharmacological variables, including the doses used to establish discriminations. This review covers studies on the effects of varying the training dose of a drug in a search for general principles that are applicable across different drug classes and methodological approaches. With respect to quantitative changes, relationships between training dose and rate of acquisition or magnitude of stimulus control were found for most drug classes. Acquisition accelerated with dose up to a point beyond which drug-induced impairments of performance had a deleterious impact. Sensitivity to the training drug as measured by ED50 values typically increased when the training dose was reduced. Qualitative changes were more complex and appeared to fall into three categories: (i) changes in profiles of generalisation between partial and full agonists; (ii) reduced specificity of some discriminations at small training doses and (iii) changes in the relative salience of actions mediated through different neurotransmitter systems or from central and peripheral sites. Three-lever discrimination procedures incorporating ‘drug versus drug’ or “dose versus dose” contingencies enabled detection of more subtle differences than the simple ‘drug versus no drug’ approach when applied to the opioid, hallucinogen and barbiturate classes of drugs. These conclusions have implications for the interpretation of data from studies that utilise either within- or between-subject designs for studying the discriminative stimulus effects of drugs.

This study explored the involvement of N-methyl-D-aspartate (NMDA) in the effects of mu opioid agonists. A hot plate procedure was used to assess antinociception and tolerance in mice in which the NR1 subunit of the NMDA receptor was reduced (knocked down, KD) to approximately 10% and in mice treated with the NMDA antagonist, LY235959 [(−)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboylic acid]. The mu opioid agonists, morphine, l-methadone and fentanyl, were approximately 3-fold less potent in the NR1 KD mice than in wild type (WT) controls; however, the development of morphine tolerance and dependence did not differ markedly in the NR1 KD and WT mice. Acute administration of the NMDA antagonist, LY235959 produced dose-dependent, leftward shifts in the morphine dose-effect curve in WT mice, but not in the NR1 KD mice. Chronic administration of LY235959 during the morphine tolerance regimen did not attenuate the development of tolerance in the NR1 KD nor the WT mice. These results indicate that the NR1 subunit of the NMDA receptor does not play a prominent role in mu opioid tolerance.

The acute and chronic effects of certain drugs can often be opposite. For example, in congestive heart failure acute administration of β-adrenoceptor agonists results in a beneficial improvement in symptoms of the disease, but their chronic use increases mortality. Conversely, certain β-adrenoceptor antagonists/inverse agonists (β-blockers) initially cause a detrimental response by decreasing cardiac contractility in congestive heart failure, while chronic treatment with the same β-blockers improves contractility and survival. Furthermore, this time-dependent reversal of outcomes occurs in non-pharmacologic interventions such as exercise and can even be observed in the response of plants to pruning or other stressors with the results being a different short-term versus long-term effect. Here we review some of these phenomena with a special emphasis on the temporal dissociation of pharmacological effects. While Francis Colpaert used this knowledge to lead a drug discovery project for an analgesic compound that initially produced hyperalgesia, we will focus on examples outside the central nervous system (CNS).

Methadone is a long-acting opioid used in the treatment of various pain states and substitution therapy in heroin addiction. Extensive behavioral characterization has been carried out utilizing the racemate, but limited investigation has been performed with the individual isomers. While the l-isomer is a potent opioid agonist, the d-isomer has weak μ opioid activity and has also been shown to possess N-methyl-d-aspartate (NMDA) antagonist properties in vitro. The acute antinociceptive effects of the isomers were evaluated in rats using a warm water tail withdrawal procedure at two stimulus intensities (50° and 55° C). Increasing dose ratios of d- to l-methadone were administered chronically to determine the ability of the d-isomer to modulate antinociceptive tolerance to the l-isomer. Acutely, both l- (0.1-5.6 mg/kg, sc) and d- (3.0-56.0 mg/kg, sc) methadone produced antinociception though the efficacy of the d-isomer was limited at 55° C. These effects were dose-dependently blocked by naltrexone (0.01-1.0 mg/kg, sc). Administered chronically, d-methadone (1.7-10 mg/kg, sc) dose-dependently blocked tolerance development to the l-isomer (1.7 mg/kg, sc). These findings support the antinociceptive effects of the isomers being opioid receptor mediated with the l-isomer functioning as a full efficacy agonist whereas the d-isomer appears to have lower efficacy. The ability of nonracemic doses of the d-isomer to prevent tolerance development to the l-isomer may be attributed to partial μ agonist activity however NMDA antagonist activity cannot be discounted.

This study compared fixed-ratio (FR) and fixed-interval (FI) schedules to investigate the discriminative stimulus properties of mu- and/or kappa-opioid receptor agonists. Pigeons were trained to discriminate among morphine (mu agonist), U50,488 (kappa agonist), the combination, and saline under an FR 20 or FI-300 s schedule. After training, correct-key responding averaged 94.4% (FR) and 66.5% (FI) after administration of training drugs. Dose-response curves were generally quantal under the FR and graded under the FI schedules, but highly variable among subjects under the FI. Under the FR schedule, the dose of naltrexone that blocked morphine's discriminative stimuli also blocked U50,488. Combining high doses of morphine with low doses of U50,488 produced responding on the morphine key and combining high doses of U50,488 with low doses of morphine produced responding on the U50,488 key. Combining high doses of both drugs produced responding on the drug-combination key. Increasing d,l-pentazocine doses shifted responding from the saline key to the U50,488 key, then to the morphine key, and finally to the drug-combination key. Butorphanol and ethylketocyclazocine produced similar effects, except responding on the morphine key increased before responding on the U50,488 key. The four-choice procedure under the FR schedule has potential for determining the discriminative stimulus effects of mixed agonists.

There is accumulating evidence that sex plays a critical role in drug abuse. Female sex hormones have been shown to affect central nervous system function and modulate the effects of drugs of abuse. For example, GABAA receptor function is positively modulated by progesterone metabolites. There is evidence from preclinical in vitro and in vivo studies as well as some clinical research suggesting that progesterone and its metabolites may enhance the behavioral effects of benzodiazepines, which also serve as positive modulators of GABAA receptors. The purpose of this experiment was to determine the independent and combined discriminative stimulus, subjective and psychomotor effects of progesterone and triazolam in healthy adult premenopausal women. Oral micronized progesterone (100 mg), triazolam (0.06, 0.12 and 0.25 mg/70 kg) and placebo were administered to healthy, premenopausal women (n =9) under conditions of low circulating sex hormones. Triazolam alone functioned as a discriminative stimulus and produced prototypical sedative-like effects (e.g., performance impairment, enhanced reports of sedative effects). Progesterone alone produced sedative-like effects on several subjective and performance measures and the dose combination effects of progesterone and triazolam on several subjective measures of drug effect were similar to the summation of the two drug effects in isolation. Progesterone did not substitute for or modify the discriminative stimulus effects of triazolam. These results suggest that the parent hormone, progesterone, and triazolam have discordant neuropharmacological mechanisms of action. Additional research is necessary to determine the degree to which neurosteroids influence sex differences in benzodiazepine use and abuse.