The ontogenetic profile of psychostimulant-induced one-trial behavioral sensitization has not been determined. The purpose of this study was to systematically assess the ontogeny of methamphetamine- and cocaine-induced behavioral sensitization across the preweanling and adolescent periods. To this end, rats were injected with methamphetamine, cocaine, or saline in either an activity chamber or home cage during the preweanling (PD 12, PD 16, or PD 20), preadolescent (PD 24), or adolescent (PD 34) periods. One day later, rats were challenged with the same psychostimulant and locomotion was measured in an activity chamber. Results showed that methamphetamine produced one-trial locomotor sensitization on PD 13 and PD 17; whereas, cocaine-induced behavioral sensitization was only evident on PD 21. The sensitized responding of preweanling rats was not influenced by environmental context. Interestingly, preadolescent and adolescent rats did not exhibit locomotor sensitization. The latter result is generally consistent with past studies showing that rats from the middle and late adolescent periods do not exhibit cocaine-induced one-trial behavioral sensitization. The present results show that methamphetamine, as well as cocaine, can produce one-trial context-independent behavioral sensitization during early ontogeny, but sensitized responding is only apparent within a narrow developmental window.
behavioral sensitization; ontogeny; methamphetamine; cocaine
Reinforcement magnitude modulates the effects of the antidepressants fluvoxamine and desipramine in the pigeon. Increasing reinforcement magnitude diminishes the rate-dependent effects of these drugs. Whether this is also the case in other species is unknown. Rats were trained to respond under a multiple fixed-interval (FI 300-s) schedule of reinforcement. In one FI component, rats earned 2 food pellets, and in the other component they earned 10 food pellets when they completed the FI requirement. The effects of fluvoxamine (3, 5.6, 10, and 17.8 mg/kg) or desipramine (1, 3, 5.6, 10, 30 mg/kg) given 30-min, presession (i.p.) on overall response rate were examined. Local rates of responding (during each tenth of the component) increased throughout the FI as is typical, and were higher during the component reinforced with 10-pellets. Fluvoxamine and desipramine decreased overall response rates similarly in both components. Both drugs exerted limited rate dependent effects, demonstrated by a negative slope for the regression of LOG[drug rate/control rate] on LOG[control rate] using data from each tenth of the FI. However, the slope for the 2-pellet condition was significantly steeper than the slope for the 10-pellet condition following 3 and 10 mg/kg fluvoxamine and following 30 mg/kg desipramine. This result is consistent with those obtained in pigeons and demonstrates that reinforcement magnitude can modulate rate-dependent effects of fluvoxamine and perhaps desipramine in rats.
behavioral momentum; rate-dependent; antidpressant
Social-learning theories of substance use propose that members of peer groups influence the drug use of other members by selectively modeling, reinforcing, and punishing either abstinence-related or drug-related behaviors. The objective of the present study was to examine social influences on cocaine self-administration in isolated and socially housed rats, with the caveat that the socially housed rats were tested simultaneously with their partner in the same chamber. To this end, male rats were obtained at weaning and housed in isolated or pair-housed conditions for 6 weeks. Rats were then implanted with intravenous catheters and cocaine self-administration was examined in custom-built operant conditioning chambers that allowed two rats to be tested simultaneously. For some socially housed subjects, both rats had simultaneous access to cocaine; for others, only one rat of the pair had access to cocaine. An econometric analysis was applied to the data, and the reinforcing strength of cocaine was measured by examining consumption (i.e., quantity demanded) and elasticity of demand as a function of price, which was manipulated by varying the dose and ratio requirements on a fixed ratio schedule of reinforcement. Cocaine consumption decreased as a function of price in all groups. Elasticity of demand did not vary across groups, but consumption was significantly lower in socially housed rats paired with a rat without access to cocaine. These data suggest that the presence of an abstaining peer decreases the reinforcing strength of cocaine, thus supporting the development of social interventions in drug abuse prevention and treatment programs.
cocaine; consumption; demand; elasticity; rat; reinforcing strength; self-administration; social; social learning; unit price
Bipolar disorder is a terrible and debilitating disease with limited treatment options. Circadian rhythm disruptions are prominent in bipolar subjects, and studies have shown that rhythm stabilization through psychosocial interventions can improve their symptoms. Furthermore, mice with a mutation in one of the central circadian proteins, CLOCK, have severely disrupted rhythms along with a behavioral profile that closely resembles human mania. A compound has been developed (CK01, similar to PF-670462) that inhibits the activity of casein kinase 1 (CK1), a critical protein involved in the timing of the molecular clock. Previous studies have shown that PF-670462 and other similar compounds are capable of entraining and stabilizing rhythms in arrhythmic animals. Here we show that chronic administration of CK01 leads to a reversal of the anxiety-related behavior, and partial reversal of the depression-related phenotypes of the Clock mutant mouse. This drug had no significant effects on the behavior of wild-type mice at the doses tested. These results suggest that CK1ε/δ inhibitors could be viable drugs for the treatment of bipolar disorder.
anxiety; bipolar disorder; circadian rhythms; depression; mouse
Only a sub-group of human drug users progress from initial drug-taking to drug addiction. An important aspect of this progression is the influence of the learned association between the effects of the drug and the environment in which it is experienced on continued drug-taking and-seeking. These associations can be modeled using the conditioned place preference (CPP) paradigm, although no current method of CPP analysis allows for identification of within-group variability among subjects. In the present study, we adapted a “criterion” method of analysis to separate “CPP expressing” from “non-CPP expressing” rats, in order to study more directly within-group variability in the CPP paradigm. Male Sprague-Dawley rats were conditioned with cocaine (5, 10, 20 mg/kg) or saline in an unbiased three-chamber CPP apparatus in either a single- or four-trial CPP procedure. A classification and regression tree analysis of time spent in the cocaine-paired chamber established a time of 324 s spent in the cocaine-paired chamber as the criterion for cocaine CPP expression. This criterion effectively discriminated control from cocaine-conditioned rats and was reliable for rats trained in both a single- and four-trial CPP procedure. The criterion method showed an enhanced ability to detect effective doses of cocaine in the single trial procedure and a blockade of CPP expression by MK 212 (0.125 mg/kg) treatment in a sub-group of rats. These data support the utility of the criterion analysis as an adjunct to traditional methods that compare group averages in CPP.
classical conditioning; statistical analysis; classification and regression tree analysis; serotonin 2C receptor; animal model; rat
Dipyrone is a common nonopioid analgesic and antipyretic, which, in many countries, is available over the counter and is more widely used than paracetamol or aspirin. However, the exact mechanisms by which dipyrone acts remain inconclusive. Two novel arachidonoyl-conjugated metabolites are formed in mice following the administration of dipyrone that are dependent on the activity of fatty acid amide hydrolase (FAAH), which also represents the major catabolic enzyme of the endogenous cannabinoid ligand anandamide. These arachidonoyl metabolites not only inhibit cyclooxygenase (COX-1/COX-2) but also bind to cannabinoid receptors at low micromolar concentrations. The relative contributions of cannabinoid receptors and FAAH in the overall behavioral response to dipyrone remain untested. Accordingly, the two primary objectives of the present study were to determine whether the behavioral effects of dipyrone would (a) be blocked by cannabinoid receptor antagonists and (b) occur in FAAH−/− mice. Here, we report that thermal antinociceptive, hypothermic, and locomotor suppressive actions of dipyrone are mediated by a noncannabinoid receptor mechanism of action and occurred after acute or repeated administration irrespective of FAAH. These findings indicate that FAAH-dependent arachidonoyl metabolites and cannabinoid receptors are not requisites by which dipyrone exerts these pharmacological effects under noninflammatory conditions.
analgesia; antinociception; CB1 and CB2 cannabinoid receptors; dipyrone; fatty acid amide hydrolase; mouse; thermal regulation
Comparatively few studies over the past 30 years have used pharmacological manipulations as a means of understanding processes underlying feeding behavior of nonhuman primates. In the 1970s and early 1980s, four laboratories provided data on the anorexigenic effects of a range of drugs on rhesus monkeys and baboons, and a fifth laboratory studied the effects of neuropeptides on feeding behavior of baboons. There were differences in the way anorexigenic drugs altered eating topography, and those that increased dopamine levels had greater abuse liability than those that increased serotonin levels. Studies in the 1980s and 1990s used foraging models and principles of behavioral economics to understand food–drug interactions. Experimenter-given anorexigenic drugs did not function as economic substitutes for food. Recent studies have examined the effects of a range of drugs on consumption of highly palatable food and model diet-induced obesity. Although some drugs, including stimulants, N-methyl-D-aspartate antagonists, and a cannabinoid antagonist increased the latency to standard food consumption, there was little evidence for a selective effect of any drug on highly palatable food consumption. Results obtained in nonhuman primates did not always confirm those observed in rodents. Future studies looking at sex differences and social factors may provide insight into factors related to human obesity.
amphetamine; anorectic; anorexigenic; baboon; binge eating; dexfenfluramine; diazepam; eating; nonhuman primate; rhesus monkey; topography
Some doses of fluvoxamine can decrease ethanol-maintained behavior more than food-maintained behavior. This might be explained by differences in reinforcement magnitude. In a previous study, fluvoxamine’s effects on Fixed-Ratio responding did not depend upon reinforcement magnitude. However, response rates differed with reinforcement magnitude. These differences in response rate might explain the failure to observe differences in the potency of fluvoxamine with changes in reinforcement magnitude.
We examined if the effects of fluvoxamine and desipramine depend on reinforcement magnitude and response rate by administering these drugs to pigeons responding under a multiple Fixed-Interval schedule in which responding in three components was maintained by differing durations of food presentation (2-, 4-, & 8-sec).
Fluvoxamine and desipramine’s effects depended jointly on control rate, reinforcement magnitude, and dose. Low fluvoxamine doses had rate-dependent effects in all three components, --increasing lower rates more than higher rates; as dose increased these rate-dependent effects became greater for components maintained by 2- or 4-sec of food presentation, while declining in the component maintained by 8-sec. Low desipramine doses had rate-dependent effects only in the component maintained by 2-sec; whereas higher doses had rate-dependent effects in components maintained by 2- or 4-sec. Still higher doses had rate-dependent effects in all three components.
While the effects of fluvoxamine and desipramine may not depend upon reinforcement magnitude when studied under Fixed-Ratio schedules, reinforcement magnitude can modulate their effects when studied over a wider range of control response rates.
fluvoxamine; desipramine; fixed-interval; rate-dependency; reinforcement magnitude
Despite the efficacy and widespread use of methylphenidate (MPH) as a treatment for Attention Deficit Hyperactivity Disorder (ADHD), clinical and preclinical findings indicate it has abuse potential. Environmental enrichment reduces susceptibility to cocaine and amphetamine self-administration, and decreases impulsive behavior, but its effects on MPH self-administration are unknown. The present experiments sought to determine the influence of environmental enrichment on MPH self-administration. Male rats were raised in an enriched condition (EC) or isolated condition (IC). They were trained to self-administer MPH (0.3 mg/kg/infusion) and then exposed to varying doses of MPH on either a fixed ratio (FR; Experiment 1) or progressive ratio (PR; Experiment 2) schedule of reinforcement. EC rats earned significantly fewer infusions of MPH at low doses (0.03 and 0.056 mg/kg/infusion) than IC rats under both schedules; however, no differences were observed at high unit doses (0.1–1.0 mg/kg/infusion). During saline substitution at the end of MPH self-administration, EC rats also responded less for saline than IC rats, indicative of more rapid extinction. As with other stimulant drugs with different mechanisms of action, environmental enrichment during development protects against self-administration of MPH at low unit doses, but not at high unit doses.
Environmental enrichment; methylphenidate; self-administration; rat; progressive ratio
Tolerance to the analgesic effects of opioids has been demonstrated in laboratory animals after repeated drug administration, yet this effect has been studied less frequently under controlled laboratory conditions in humans. This within-subject, double-blind, placebo-controlled study was designed to determine if tolerance developed to the analgesic, subjective, and physiological effects of the commonly prescribed opioid oxycodone when it was administered daily for 5 days. The effects of oxycodone’s (0, 5, and 20 mg/70 kg, p.o.) were compared, using a within-session cumulative dosing procedure, on the 1st and 5th days of the ‘daily’ dosing phase to assess for tolerance; active oxycodone was administered on the 2nd-4th days of the daily dosing phase. Changes in the effects of oxycodone were also compared when the medication was only administered on the 1st and 5th day of a 5-day ‘intermittent’ dosing phase; placebo medication was administered on the 2nd–4th days of the intermittent dosing phase. A 9-day ‘washout’ period occurred between phases when no medication was administered. Healthy volunteers (N=10) with no history of drug dependence or current drug use participated in this outpatient study. Analgesia was assessed using the Cold-Pressor Test (CPT), pain and drug effects were measured using a variety of questionnaires, and pupil diameter was monitored as an index of physiological effects. When administered daily, no differences were observed in oxycodone-induced analgesia between the 1st and 5th days, but tolerance did develop to some of the positive subjective effects of oxycodone. In contrast, oxycodone-induced analgesia and participant ratings of some positive subjective drug effects were greater on the 5th day compared to the 1st day of the intermittent dosing phase. No differences in the miotic effects of oxycodone between the 1st and 5th days of either dosing phase were detected. Though obtained under limited experimental conditions, these findings suggest that tolerance may not develop to the analgesic effects of therapeutic doses of oxycodone under short-term daily dosing conditions, even though some of its subjective effects may decrease. These data also suggest that intermittent administration may enhance the analgesic effects of oxycodone, while also increasing some of the drug’s positive subjective effects related to abuse liability.
Analgesia; Tolerance; Opioid; Oxycodone; Abuse Liability; Subjective Effects; human
Dehydroepiandrosterone (DHEA), 7-keto DHEA, and several comparison drugs (ethanol, chlordiazepoxide, rauwolscine, and RO15-4513) were administered to male rats responding under a multiple schedule of food and ethanol presentation to determine their selectively for decreasing ethanol-maintained responding. DHEA and 7-keto DHEA significantly decreased both ethanol- and food-maintained responding, compared to control, while also decreasing blood ethanol concentration (BEC). Acute ethanol administration also decreased responding for both food and ethanol; however, ethanol-maintained responding was more potently decreased than food-maintained responding. BEC remained relatively stable after increasing ethanol doses. Among the other drugs tested, RO15-4513 was the most selective for decreasing ethanol-maintained responding compared to food-maintained responding, and it decreased BECs as ethanol-maintained responding decreased. The largest dose of rauwolscine significantly decreased responding for food, while not affecting ethanol-maintained responding compared to control. Low to intermediate doses of rauwolscine produced small, non-significant increases in ethanol-maintained responding and BECs. Chlordiazepoxide produced significant decreases in food-maintained responding and the dose of ethanol presented, but only at the highest dose tested. Although DHEA and 7-keto DHEA did not decrease ethanol-maintained responding as selectively as ethanol or RO15-4513 under the multiple schedule, these neurosteroids may be valuable pharmacological tools in the development of new treatments for alcohol abuse and dependence.
ethanol; dehydroepiandrosterone; rauwolscine; RO15-4513; operant responding; rat
Dopamine D3-preferring agonists are commonly used to treat Parkinson’s disease and restless leg syndrome; however, laboratory animal studies suggest that they may possess a moderate abuse potential. These studies aimed to compare the highly-selective, full D3 agonist PF-592,379 to that of the less selective D3 agonist 7-OH-DPAT, and the indirect dopamine agonist cocaine in drug self-administration and discrimination assays. Although rats readily acquired high rates of fixed ratio (FR)1 responding for cocaine, experimentally naïve rats failed to acquire responding when 7-OH-DPAT or PF-592,379 were made available during an 18-session acquisition period. Cocaine also maintained dose-dependent levels of responding when available under an FR5 or progressive ratio (PR) schedule of reinforcement. Although, 7-OH-DPAT maintained modest levels responding when substituted under an FR5, it failed to maintain significant levels of PR responding. PF-592,379 maintained saline-like rates of responding when substituted under FR5 or PR schedules of reinforcement. Similar behavioral profiles were observed in cocaine discrimination assays, with 7-OH-DPAT partially substituting for cocaine, and PF-592,379 producing saline-like effects over a wide range of doses. Together, the results of these studies predict that highly selective D3 agonists, such as PF-592,379, will have low abuse potential in humans.
Drug Self-administration; Drug Discrimination; cocaine; PF-592,379; Dopamine D3; Dopamine D2; Rat
Previous studies demonstrated effectiveness of selective sigma-receptor (σR) agonists (DTG, PRE-084) as reinforcers in rats trained to self-administer cocaine. Like cocaine, these drugs increased nucleus accumbens shell dopamine levels, and effects of DTG, but not PRE-084, on dopamine appeared to be mediated by σRs. Additionally, σR antagonists blocked self-administration of σR agonists, but were inactive against reinforcing and neurochemical effects of cocaine. Thus pharmacologically distinct mechanisms likely underlie the reinforcing and neurochemical effects of σR agonists and cocaine. The present study further examined the cocaine-like effects of σR agonists in rats trained to discriminate injections of cocaine from saline to assess the similarity of their subjective effects. Standard dopamine-uptake inhibitors (WIN 35,428, methylphenidate), but neither σR agonist (PRE-084, DTG) produced full cocaine-like discriminative-stimulus effects. The lack of effects of σR agonists was obtained regardless of route of administration (i.p., s.c. or i.v.) or pretreatment time (5- or 30-min before sessions). The present results demonstrate differences in the discriminative-stimulus effects of cocaine and selective σR agonists, indicating that an overlap of subjective effects is not necessary for σR agonist self-administration. The previously found differences in neurochemical effects of cocaine and σR agonists may contribute to their different subjective effects.
cocaine; discriminative-stimulus effects; σ receptor; dopamine uptake inhibitor; DTG; PRE-084; WIN 35,428; methylphenidate
Benzodiazepines negatively affect motor coordination and balance and produce myorelaxation. The aim of the present study was to examine the extent to which populations of GABAA receptors containing α1 and α5 subunit contribute to these motor-impairing effects in rats. We used the nonselective agonist diazepam and the α1-selective agonist zolpidem, as well as nonselective, α1- and α5-subunit-selective antagonists flumazenil, βCCt and XLi093, respectively. Ataxia and muscle relaxation were assessed by rotarod and grip strength tests performed 20 minutes after i.p. treatment. Diazepam (2 mg/kg) induced significant ataxia and muscle relaxation which were completely prevented by pretreatment with flumazenil (10 mg/kg) and βCCt (20 mg/kg). XLi093 antagonized the myorelaxant, but not ataxic actions of diazepam. All three doses of zolpidem (1, 2 and 5 mg/kg) produced ataxia, but only the highest dose (5mg/kg) significantly decreased the grip strength. These effects of zolpidem were reversed by ßCCt at doses of 5 and 10 mg/kg, respectively. The present study demonstrates that α1 GABAA receptors mediate ataxia and indirectly contribute to myorelaxation in rats, while α5 GABAA receptors contribute significantly, although not dominantly, to muscle relaxation but not ataxia.
ataxia; muscle relaxation; rotarod; grip strength; rat
Progesterone decreases cocaine self-administration in women and in female rats. In a previous study using rats selectively bred for high (HiS) and low (LoS) saccharin intake, HiS rats escalated their cocaine intake compared to LoS rats. Our goal was to examine the effects of progesterone on the escalation of cocaine self-administration in HiS and LoS rats. Four groups of female rats were compared: HiS P (progesterone-treated), LoS P, HiS VEH (vehicle-treated), and LoS VEH. Rats were trained to self-administer 0.8 mg/kg cocaine i.v. under a fixed-ratio 1 (FR 1) schedule during daily short-access (ShA) 2-h sessions. Rats then self-administered 3 randomly-presented doses of cocaine (0.2, 0.4, 1.6 mg/kg) and then had daily 6-h long-access (LgA) sessions with 0.4 mg/kg cocaine for 21 days. Cocaine intake was then reassessed with the 4 doses under the ShA condition. Throughout the experiment, rats were treated with daily s.c. injections of P (0.5 mg/kg) or an equal volume of VEH 30 min prior to each session. During the initial ShA condition, HiS rats earned more cocaine infusions than LoS rats at all doses, and during the subsequent LgA condition, HiS rats escalated cocaine intake, while the LoS rats maintained a steady rate. Progesterone treatment potentiated escalation of cocaine intake in the HiS rats but had an opposite effect on LoS rats, attenuating their cocaine self-administration. Results from the post-LgA dose-response ShA condition, indicated that both LoS and HiS VEH and P-treated rats earned more infusions than pre-LgA, but mainly at low doses. These results suggest that genetic differences in drug abuse vulnerability contribute differentially to treatment outcomes during escalation, a critical phase of the drug abuse process.
Selective breeding; Saccharin intake; Progesterone; Escalation; Cocaine self- administration; rat
We tested the hypothesis that the irreversible gamma-amino butyric acid (GABA) transaminase inhibitor, γ-vinyl GABA (Vigabatrin; VGB) would reduce ethanol reinforcement and enhance the discriminative stimulus effect of ethanol, effectively reducing ethanol intake. The present studies used adult C57BL/6J (B6) mice in well-established operant, two-bottle choice consumption, locomotor activity and ethanol discrimination procedures, to examine comprehensively the effects of VGB on ethanol-supported behaviors. VGB dose-dependently reduced operant responding for ethanol as well as ethanol consumption for long periods of time. Importantly, a low dose (200 mg/kg) of VGB was selective for reducing ethanol responding without altering intake of food or water reinforcement. Higher VGB doses (>200 mg/kg) still reduced ethanol intake, but also significantly increased water consumption and, more modestly, increased food consumption. While not affecting locomotor activity on its own, VGB interacted with ethanol to reduce the stimulatory effects of ethanol on locomotion. Finally, VGB (200 mg/kg) significantly enhanced the discriminative stimulus effects of ethanol as evidenced by significant left-ward and up-ward shifts in ethanol generalization curves. Interestingly, VGB treatment was associated with slight increases in blood ethanol concentrations. The reduction in ethanol intake by VGB appears to be related to the ability of VGB to potentiate the pharmacological effects of ethanol.
alcohol; mouse; reward; ethanol drinking; interoceptive cue
Kappa opioid receptor (KOPr) activation antagonizes many cocaine-related behaviors but adverse side effects such as sedation, dysphoria and depression limit their therapeutic use. Recently, salvinorin A (Sal A), a naturally occurring KOPr agonist, has been shown to attenuate cocaine-induced drug-seeking in a model of relapse in rats. The present study evaluated the effects of acute Sal A exposure on cocaine-induced hyperactivity and cocaine sensitization in rats. Acute treatment with the dose of Sal A that decreased drug-seeking in a previous study (0.3 mg/kg), significantly attenuated the expression of cocaine sensitization. This dose of Sal A failed to affect spontaneous locomotion or to produce a conditioned taste aversion to a novel-tasting saccharin solution. However, Sal A decreased climbing and swimming time and increased time spent immobile in the forced swim test. These findings indicate that Sal A, just like traditional KOPr agonists, attenuates cocaine-induced behavioral sensitization but does not produce the adverse effect of conditioned aversion, suggesting improved potential compliance. However, pro-depressive effects were also produced and these effects may limit the therapeutic potential.
Salvinorin A; kappa opioid agonist; behavioural sensitization; conditioned taste aversion; forced swim test; depression; rat
The selective serotonin reuptake inhibitor fluvoxamine reduces responding for ethanol at lower doses than responding for food when each is available in separate components or separate groups of rats. However, when both are available concurrently and deliveries earned per session are equal, this apparent selectivity inverts and food-maintained behavior is more sensitive than ethanol-maintained behavior to rate-decreasing effects of fluvoxamine. Here, we investigate further the impact concurrent access to both food and ethanol has on the potency of fluvoxamine. Fluvoxamine (5.6-17.8 mg/kg) potency was assessed under conditions where food and ethanol were available concurrently and response rates were equal (average variable intervals (VI) 405-s and 14-s for food and ethanol, respectively), as well as when density of food delivery was increased (average VI 60-s food & VI 14-s ethanol). The potency of fluvoxamine was also determined when only ethanol was available (food extinction and average VI 14-s ethanol) and under a multiple VI (VI 30-s food and ethanol) where either food or ethanol was the only programmed reinforcer available during each component. Fluvoxamine was less potent at decreasing ethanol self-administration when food was available concurrently (ED50 [95% C.L.]: 8.2 [6.5-10.3] & 10.7 [7.9-14.4]) versus when ethanol was available in isolation (ED50: 4.0 [2.7-5.9] & 5.1 [4.3-6.0]). Effects on food were similar under each condition where food was available. The results demonstrate that the potency of fluvoxamine to reduce ethanol-maintained behavior depends on whether ethanol is available in isolation or in the context of concurrently scheduled food reinforcement.
alcoholism; SSRI; concurrent; reinforcement; selective; pharmacotherapy; Fluvoxamine; ethanol; food; reinforcement schedule; rat
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.
Haloperidol; Olanzapine; Conditioned avoidance response; Phencyclidine; Time course of antipsychotic effect; Behavioral sensitization, rat
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.
alcohol; binge ethanol exposure; delay discounting; hippocampus; impulsivity; Morris water maze; rat; spatial learning
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.
delta opioid receptor; analgesia; pain; mouse genetic model; rat; regulation; mechanism
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.
Serotonin; 8-OH-DPAT; high fat chow; quinpirole; rat; dopamine; lower lip retraction; yawning
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.
quinpirole; yawning; sucrose; dopamine receptor; hypothermia; rat