A pharmacological dose of estradiol can enhance appetites for alcoholic beverages

Each of 30 female Sprague-Dawley rats were given 2 mg of estradiol valerate (EV), 30 others were given placebos. EV is a preparation that delivers estradiol for more than 12 days, but probably less than 20. Fifteen days later, the females had the opportunity to take sweetened alcoholic beverage 24 h a day across 25 days. Subsequently, they could self-administer other alcoholic beverages, including one of only alcohol and water. After a period of abstinence, rats had another opportunity to take sweetened alcoholic beverage (94 to 96 days after the single injection of EV). With every measurement, rats given EV consumed significantly more ethanol than controls. For example, mean of measurements representing daily intake for the fourth week of availability of palatable alcoholic beverage for placebo-treated=5.29 grams of ethanol per kilogram of bodyweight (g'E/kg); for EV-treated=8.13 g'E/kg; P=.003. The data support the conclusion that pharmacological doses of estradiol can induce marked, enduring changes in appetite for alcoholic beverages.     

Estradiol valerate and intake of sweetened water

Recently, it has been shown that female rats receiving very large doses (e.g., 2 mg) of estradiol valerate (EV) take considerably more alcoholic beverage than placebo controls. The question asked, with these procedures, is whether the enhanced appetite for alcoholic beverages was specific to those beverages or was a reflection of a general increase in appetite. Female rats were provided with various sweetened beverages. In one experiment, they were provided a palatable saccharin solution (0.25% solution) and a less palatable one (2% saccharin solution). EV treatment led to more intake of the palatable saccharin solution and reduced intake of the less palatable solution. EV induces changes leading to enhanced appetite for some ingesta (including palatable saccharin solutions and alcoholic beverages), but surely not all ingesta.     

One injection of estradiol valerate induces dramatic changes in rats' intake of alcoholic beverages

A series of experiments investigated the effects of a single injection of estradiol valerate (EV) on female rats' consumption of alcoholic beverages. EV provides sustained release of estradiol. Just after an injection of EV, rats' intake of a palatable alcoholic beverage, which had been taken regularly before, is reduced dramatically. Subsequently, rats' intake of alcoholic beverage returns to baseline levels. With continued opportunity to drink, rats take more ethanol than controls. When EV was given 15 and 31 days before the first opportunity to drink an alcoholic beverage, female rats markedly enhanced their intake of ethanol. Once enhanced intakes emerged, they were observed with different kinds of alcoholic beverages and endured for months.     

Effects of caffeine on alcohol-related changes in behavioural control and perceived intoxication in light caffeine consumers

Rationale

Caffeinated alcoholic beverages have been associated with increased risk of alcohol-related harms. However, few studies have examined these combined effects on behavioural control, which is believed to underlie many of the negative effects of alcohol consumption. In addition, studies have often omitted subjective measures, and none have directly assessed the role of caffeine consumer history.

Objectives

To examine the combined effects of alcohol and caffeine on measures of behavioural control and perceived intoxication in abstinent, light caffeine consumers.

Methods

Participants (n?=?28; 50% male) attended four sessions at which they consumed one of the following beverages in a randomised order: placebo, alcohol alone (0.6?g/kg), caffeine alone (2.0?mg/kg), and alcohol/caffeine. They completed measures of mood, intoxication, anxiety and alcohol craving before and after a task battery comprising measures of behavioural control and reaction time performance.

Results

Caffeine attenuated alcohol-related performance deficits on stop-signal accuracy, had no effect on go–no-go performance deficits, and worsened accuracy on the Stroop task. Caffeine did not influence absolute changes in perceived intoxication but there was suggestion that caffeine may have changed the nature of intoxication with increases in stimulation.

Conclusions

Caffeine appears to have mixed effects on alcohol intoxication that are task-dependent. We found increased stimulation in the alcohol/caffeine condition, supporting the contention that caffeinated alcoholic beverages enable an individual to drink for longer. Future research should model real world drinking behaviour by examining how these effects change across multiple drink administrations.     

Effects of the combination of metyrapone and oxazepam on intravenous nicotine self-administration in rats

Rationale

Despite increased education regarding its dangers, cigarette smoking remains a significant public health concern due to serious associated health consequences such as cancer and respiratory and cardiovascular diseases. Most smokers fail in their attempts to quit smoking, and current pharmacological interventions have relatively low levels of efficacy and are associated with significant adverse events. We have previously reported that combinations of metyrapone and oxazepam, administered at doses that were ineffective when delivered singly, resulted in dose-related decreases in cocaine self-administration in rats while not affecting food-maintained responding during the same sessions.

Objectives

The current study was designed to test the effects of the administration of a metyrapone:oxazepam combination on nicotine self-administration in rats.

Methods

Several dose combinations of metyrapone (12.5, 25 or 50 mg/kg) and oxazepam (5 or 10 mg/kg) were tested in rats trained to intravenously (IV) self-administer nicotine (0.03 mg/kg/infusion) during 1-h self-administration sessions using both fixed-ratio and progressive-ratio (PR) schedules of reinforcement.

Results

The administration of low doses of metyrapone and oxazepam in combination significantly decreased IV nicotine self-administration in rats. At the lowest doses of 12.5 mg/kg of metyrapone and 5 mg/kg of oxazepam, the drugs alone did not decrease IV nicotine self-administration, but the combination was effective. Varenicline was also tested using the fixed-ratio schedule, and reductions in nicotine intake were similar to those seen with the moderate dose of the combination.

Conclusions

The results of this study suggest a potential utility of the combination of metyrapone and oxazepam for smoking cessation in humans.     

The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats

Rationale

There is a focus on developing D3 receptor antagonists as cocaine addiction treatments.

Objective

We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats.

Methods

In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10 mg/kg, IP)-induced locomotor activity, respectively.

Results

SR 21502 produced significant, dose-related (3.75, 7.5 and 15 mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15 mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15 mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity.

Conclusions

SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine’s rewarding, incentive motivational and stimulant effects.     

A computer-automated touchscreen paired-associates learning (PAL) task for mice: impairments following administration of scopolamine or dicyclomine and improvements following donepezil

Rationale

Performance on the Cambridge Neuropsychological Test Automated Battery touchscreen paired-associates learning (PAL) test is predictive of Alzheimer??s disease and impaired in schizophrenia and chronic drug users. An automated computer touchscreen PAL task for rats has been previously established. A pharmacologically validated PAL task for mice would be a highly valuable tool, which could be useful for a number of experimental aims including drug discovery.

Objectives

This study sought to investigate the effects of systemic administration of cholinergic agents on task performance in C57Bl/6 mice.

Methods

Scopolamine hydrobromide (0.02, 0.2, and 2.0?mg/kg), dicyclomine hydrochloride (M₁ receptor antagonist; 2.0, 4.0, and 8.0?mg/kg), and donepezil hydrochloride (cholinesterase inhibitor; 0.03, 0.1, and 0.3?mg/kg) were administered post-acquisition in C57Bl/6 mice performing the PAL task.

Results

Scopolamine (0.2 and 2.0?mg/kg) and dicyclomine (at all administered doses) significantly impaired PAL performance. A significant facilitation in PAL was revealed in mice following donepezil administration (0.3?mg/kg).

Conclusions

The present study shows that mice can acquire the rodent PAL task and that the cholinergic system is important for PAL task performance. M₁ receptors in particular are likely implicated in normal performance of PAL. The finding that mouse PAL can detect both impairments and improvements indicates that this task could prove to be a highly valuable tool for a number of experimental aims including drug discovery.     

High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens

Rationale

Although reports of dextromethorphan (DXM) abuse have increased recently, few studies have examined the effects of high doses of DXM.

Objective

This study in humans evaluated the effects of supratherapeutic doses of DXM and triazolam.

Methods

Single, acute oral doses of DXM (100, 200, 300, 400, 500, 600, 700, and 800 mg/70 kg), triazolam (0.25 and 0.5 mg/70 kg), and placebo were administered to 12 healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Subjective, behavioral, and physiological effects were assessed repeatedly after drug administration for 6 h.

Results

Triazolam produced dose-related increases in subject-rated sedation, observer-rated sedation, and behavioral impairment. DXM produced a profile of dose-related physiological and subjective effects differing from triazolam. DXM effects included increases in blood pressure, heart rate, and emesis; increases in observer-rated effects typical of classic hallucinogens (e.g., distance from reality, visual effects with eyes open and closed, joy, anxiety); and participant ratings of stimulation (e.g., jittery, nervous), somatic effects (e.g., tingling, headache), perceptual changes, end-of-session drug liking, and mystical-type experience. After 400 mg/70 kg DXM, 11 of 12 participants indicated on a pharmacological class questionnaire that they thought they had received a classic hallucinogen (e.g., psilocybin). Drug effects resolved without significant adverse effects by the end of the session. In a 1-month follow-up, volunteers attributed increased spirituality and positive changes in attitudes, moods, and behavior to the session experiences.

Conclusions

High doses of DXM produced effects distinct from triazolam and had characteristics that were similar to the classic hallucinogen psilocybin.     

Psychopharmacology of theobromine in healthy volunteers

Background

Theobromine, a methylxanthine related to caffeine and present in high levels in cocoa, may contribute to the appeal of chocolate. However, current evidence for this is limited.

Objectives

We conducted a within-subjects placebo-controlled study of a wide range of oral theobromine doses (250, 500, and 1,000 mg) using an active control dose of caffeine (200 mg) in 80 healthy participants.

Results

Caffeine had the expected effects on mood including feelings of alertness and cardiovascular parameters. Theobromine responses differed according to dose; it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In secondary analyses, we also examined individual differences in the drug’s effects in relation to genes related to their target receptors, but few associations were detected.

Conclusions

This study represents the highest dose of theobromine studied in humans. We conclude that theobromine at normal intake ranges may contribute to the positive effects of chocolate, but at higher intakes, effects become negative.     

Acute behavioural effects of bupropion and naltrexone, alone and in combination, in non-deprived male rats presented with palatable mash

Rationale

In appetite research, drugs frequently progress to clinical trials on the basis of outcome (reduced food intake/body weight gain) with insufficient attention to process (behavioural analysis). Although bupropion and naltrexone (alone and in combination) reduce food consumption in rodents and humans, their effects on behaviour during feeding tests have not been thoroughly investigated.

Objectives

This study aimed to assess the behavioural specificity of anorectic responses to bupropion, naltrexone and their combination.

Methods

Video analysis was employed to characterise the behavioural effects of acute systemic treatment with bupropion (10.0–40.0 mg/kg), naltrexone (0.1–3.0 mg/kg) and combined bupropion (20 mg/kg) plus naltrexone (0.1–1.0 mg/kg) in non-deprived male rats exposed for 1 h to palatable mash. Particular attention was paid to the behavioural satiety sequence (BSS).

Results

In experiment 1, the anorectic response to 40 mg/kg bupropion was associated with significant psychomotor stimulation and a complete disruption of the BSS. In experiment 2, the anorectic response to 3 mg/kg naltrexone was associated with an accelerated but otherwise normal BSS. In experiment 3, the co-administration of 20 mg/kg bupropion and naltrexone (0.1 and 1.0 mg/kg) not only produced an additive anorectic profile (including a reduced rate of eating), but the addition of the opioid receptor antagonist also concurrently attenuated the psychomotor stimulant response to the atypical antidepressant.

Conclusions

Low-dose co-treatment with naltrexone and bupropion produces a stronger suppression of appetite than that seen with either agent alone and has the additional advantage of reducing some of the unwanted effects of bupropion.     

Altered locomotor and stereotyped responses to acute methamphetamine in adolescent, maternally separated rats

Rationale

Neonatal maternal separation (MS) has been used to model the effects of early life stress in rodents. MS alters behavioral responses to a variety of abused drugs, but few studies have examined its effects on methamphetamine sensitivity.

Objectives

We sought to determine the effects of MS on locomotor and stereotyped responses to low-to-moderate doses of methamphetamine in male and female adolescent rats.

Methods

Male and female rat pups were subjected to 3 h per day of MS on postnatal days (PN) 2–14 or a brief handling control procedure during the same period. During adolescence (approximately PN 40), all rats were tested for locomotor activity and stereotyped behavior in response to acute methamphetamine administration (0, 1.0, or 3.0 mg/kg, s.c.).

Results

MS rats of both sexes exhibited increased locomotor activity in a novel environment, relative to handled controls. MS increased the locomotor response to methamphetamine (METH), and this effect occurred at different doses for male (3.0 mg/kg) and female (1.0 mg/kg) rats. MS also increased stereotyped behavior in response to METH (1.0 mg/kg) in both sexes.

Conclusions

MS enhances the locomotor response to METH in a dose- and sex-dependent manner. These results suggest that individuals with a history of early life stress may be particularly vulnerable to the psychostimulant effects of METH, even at relatively low doses.     

Effects of coincident 5-HT1A receptor stimulation and NMDA receptor antagonism on l-DOPA-induced dyskinesia and rotational behaviors in the hemi-parkinsonian rat

Rationale

Serotonin 1A receptor (5-HT1AR) agonists reduce l-DOPA-induced dyskinesia and enhance motor function in experimental and clinical investigations of Parkinson’s disease (PD). While the mechanism(s) by which these effects occur are unclear, recent research suggests that modulation of glutamate neurotransmission contributes.

Objective

To further delineate the relationship between 5-HT_1A receptors and glutamate, the current study examined the effects of the 5-HT_1AR agonist, ±8-OH-DPAT and the N-methyl-d-aspartic acid receptor (NMDAR) antagonist, MK-801, on l-DOPA-induced motor behavior.

Materials and methods

Unilateral 6-hydroxydopamine lesioned male Sprague–Dawley rats were rendered dyskinetic with 1 week of daily l-DOPA (12 mg/kg, i.p.) + benserazide (15 mg/kg, i.p.). On test days, one group of rats received pretreatments of: ±8-OH-DPAT (0, 0.03, 0.1, 0.3 mg/kg, i.p.) or MK-801 (0, 0.03, 0.1, 0.3 mg/kg, i.p.). A second group was administered combined ±8-OH-DPAT (0, 0.03 or 0.1 mg/kg, i.p.) + MK-801 (0, 0.1 mg/kg, i.p.). Pretreatments were followed by l-DOPA administration, after which, abnormal involuntary movements (AIMs) and rotations were monitored. To investigate effects on motor performance, subthreshold doses of ±8-OH-DPAT (0.03 mg/kg, i.p.) + MK-801 (0.1 mg/kg, i.p.) were administered to l-DOPA-naïve hemiparkinsonian rats before the forepaw adjusting steps test.

Results

Individually, both ±8-OH-DPAT and MK-801 dose-dependently decreased l-DOPA-induced AIMs without affecting rotations. Combined subthreshold doses of ±8-OH-DPAT+MK-801 reduced l-DOPA-induced AIMs and potently enhanced contralateral rotations without altering l-DOPA-induced motor improvements.

Conclusions

The current results indicate a functional interaction between 5-HT_1AR and NMDAR that may improve pharmacological treatment of PD patients.     

Operant, oral alcoholic beer self-administration by C57BL/6J mice: effect of BHF177, a positive allosteric modulator of GABAB receptors

Rationale

With its high palatability, near-beer has been successfully used in rats as a vehicle to induce ethanol oral self-administration.

Objectives

The study aimed to develop an operant model of oral alcoholic beer self-administration promoting a stable intake of pharmacologically relevant amounts of ethanol in free-feeding C57BL/6J mice. It also aimed to assess the model's predictive validity by evaluating the influence of baclofen, a GABA_B agonist, and BHF177, a GABA_B positive allosteric modulator, on alcoholic beer self-administration.

Methods

Mice were trained to self-administer, under a fixed ratio three schedule of reinforcement, 10?μl of beer containing increasing ethanol concentrations (0–18% v/v) in daily 30-min sessions. The effects on motor coordination (rotarod), locomotor activity (open field, automated cages) and anxiety-like behavior (elevated plus maze, EPM) were examined. Baclofen (1.25–5?mg/kg, intraperitoneal, i.p.) and BHF177 (3.75–30?mg/kg, i.p.) were used to see the effects on 9% alcoholic beer and near-beer self-administration.

Results

Near-beer stably maintained operant oral self-administration in mice. Adding ethanol to near-beer reduced the number of active lever presses, while the corresponding amount of ethanol self-administration increased (0.8–1.0?g/kg/session). Motor impairment was observed when more than 1.3?g/kg/session of ethanol was self-administered with beer and slight but consistent hyperlocomotion with more than 0.9–1.0?g/kg/session. BHF177 (15?mg/kg) preferentially reduced 9% alcoholic beer self-administration, while the higher dose (30?mg/kg)—like baclofen 5?mg/kg—also reduced near-beer self-administration.

Conclusions

The operant model of oral alcoholic beer self-administration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction.     

Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task

Rationale

Effort-related motivational symptoms such as anergia and fatigue are common in patients with depression and other disorders. Research implicates pro-inflammatory cytokines in depression, and administration of cytokines can induce effort-related motivational symptoms in humans.

Objectives

The present experiments focused on the effects of the pro-inflammatory cytokine interleukin 1-beta (IL-1β) on effort-related choice behavior.

Methods

Rats were tested on a concurrent fixed ratio 5 lever pressing/chow feeding choice procedure, which assesses the tendency of rats to work for a preferred food (high carbohydrate pellets) in the presence of a concurrently available but less preferred substitute (laboratory chow).

Results

IL-1β (1.0–4.0 μg/kg IP) shifted choice behavior, significantly decreasing lever pressing and increasing intake of the freely available chow. The second experiment assessed the ability of the adenosine A_2A antagonist (E)-phosphoric acid mono-[3-[8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl] propyl] ester disodium salt (MSX-3) to reverse the behavioral effects of IL-1β. MSX-3 attenuated the effort-related impairments produced by IL-1β, increasing lever pressing and also decreasing chow intake. In the same dose range that shifted effort-related choice behavior, IL-1β did not alter food intake or preference in parallel free-feeding choice studies, indicating that these low doses were not generally suppressing appetite or altering preference for the high carbohydrate pellets. In addition, IL-1β did not affect core body temperature.

Conclusions

These results indicate that IL-1β can reduce the tendency to work for food, even at low doses that do not produce a general sickness, malaise, or loss of appetite. This research has implications for the involvement of cytokines in motivational symptoms such as anergia and fatigue.     

Serotonin 5-HT4 receptors in the nucleus accumbens are specifically involved in the appetite suppressant and not locomotor stimulant effects of MDMA (��ecstasy��)

Rationale

3,4-Methylenedioxymethamphetamine (MDMA) abuse is a substantial problem in young adults. Due to a high focus on body image in this population, two main factors that may encourage MDMA use are the appetite suppressant and locomotor stimulant effects of this drug. The nucleus accumbens (NAc) is a brain region associated with the regulation of motivated and locomotor behaviours, and recent evidence suggests that NAc 5-HT4 receptors are likely to be involved in the appetite suppressant effect of MDMA. It has not yet been shown whether 5-HT4 receptors of the NAc are involved in the locomotor stimulant effects of MDMA, which may also contribute to a reduction in food intake.

Objectives

This study aimed to investigate the effect of local antagonism of serotonin 5-HT4 receptors in the NAc in the appetite suppressant and locomotor stimulant effects of MDMA.

Methods

Male hooded Wistar rats underwent surgery for the implantation of bilateral NAc microinjection cannulae under isofluorane anesthesia. Following 5?C7?days of recovery, the rats received bilateral microinjections of the 5-HT4 antagonist RS39604 into the NAc immediately prior to either saline or MDMA administration. Food intake, water intake, body weight and locomotor activity were measured.

Results

RS39604 significantly increased food intake and increased weight loss in MDMA-treated but not saline-treated rats. Measures of MDMA-induced water intake or locomotor activity were not altered by antagonist administration.

Conclusions

These results demonstrate that 5-HT4 receptors in the NAc specifically regulate the appetite suppressant effects of MDMA but not MDMA-induced water intake or locomotor activity.     

Assessing the effects of chronic sazetidine-A delivery on nicotine self-administration in both male and female rats

Rationale

Sazetidine-A is a selective ??4??2 nicotinic receptor desensitizing agent and partial agonist. It has been shown in previous studies to significantly reduce nicotine self-administration in rats after acute or repeated injections. However, the effects of continuous chronic infusions of sazetidine-A on maintenance of nicotine self-administration and relapse after abstinence have yet to be examined.

Objectives

This study evaluated the efficacy of continuous sazetidine-A infusions (sc) over a period of 4?weeks to reduce nicotine self-administration in male and female Sprague-Dawley rats.

Methods

Sazetidine-A was administered via Alzet osmotic minipumps to young adult female and male rats at doses of 0, 2 or 6?mg/kg/day for 4?weeks. The effects of sazetidine-A on IV nicotine self-administration were examined in repeated 3-h sessions over the first 2?weeks of infusion followed by 1?week of forced abstinence from nicotine and 1?week of resumed nicotine access.

Results

The 6?mg/kg/day sazetidine-A dose significantly reduced overall nicotine self-administration compared with vehicle control across the sessions for both male (p?p?p?p?Conclusions The continuing effectiveness of sazetidine-A in reducing nicotine self-administration in both male and female rats supports its promise as a new treatment to help people successfully quit smoking.     

The effects of prenatal cocaine,post-weaning housing and sex on conditioned place preference in adolescent rats

Rationale

Gestational exposure to cocaine now affects several million people including adolescents and young adults. Whether prenatal drug exposures alter an individual’s tendency to take and/or abuse drugs is still a matter of debate.

Objectives

This study sought to answer the question “Does prenatal exposure to cocaine, in a dose-response fashion, alter the rewarding effects of cocaine using a conditioned place preference (CPP) procedure during adolescence in the rat?” Further, we wanted to assess the possible sex differences and the role of being raised in an enriched versus impoverished environment.

Methods

Virgin female Sprague-Dawley rats were dosed daily with cocaine at 30 mg/kg (C30), 60 mg/kg (C60), or vehicle intragastrically prior to mating and throughout gestation. Pups were culled, fostered and, on postnatal day (PND) 23, placed into isolation cages or enriched cages with three same-sex littermates and stimulus objects. On PND43–47, CPP was determined across a range of cocaine doses.

Results

C30 exposure increased sensitivity to the rewarding effects of cocaine in adolescent males, and being raised in an enriched environment further enhanced this effect. Rats exposed to C60 resembled the controls in cocaine CPP. Overall, females were modestly affected by prenatal cocaine and enrichment.

Conclusions

These data support the unique sensitivity of males to the effects of gestational cocaine, that moderate prenatal cocaine doses produce greater effects on developing reward circuits than high doses and that housing condition interacts with prenatal treatment and sex such that enrichment increases cocaine CPP mostly in adolescent males prenatally exposed to moderate cocaine doses.     

Intracranial self-stimulation in rats as a function of various stimulus parameters

The effects of different subcutaneous doses (0.08, 0.16, 0.31, 0.63 and 1.25 mg/kg) of apomorphine on self-stimulation in rats, with monopolar nichrome electrodes, implanted in the medial forebrain bundle at the level of the lateral hypothalamus were studied. Six different selected stimulus parameter combinations inducing different predictable response rates were used. Apomorphine was found to produce a dose-related response stimulation and a dose-related response depression. The highest stimulation was obtained at 0.63 mg/kg, the highest depression at 1.25 mg/kg. The response stimulation with apomorphine was 1. inversely related to the control response rate, i.e. the higher the control response rate, the lower the response stimulation after apomorphine and vice versa, 2. directly related to the control response rate of the individual rats, i.e. the highest response stimulation was obtained with the most sensitive rat and vice versa. The response inhibition with apomorphine was not related to the control response rates but was more pronounced during the first 1/2 h of the session. It is postulated that

1. increased self-stimulation with apomorphine could be the result of an increased motor response output;
2. decreased self-stimulation with apomorphine could be due to non-adaptive behaviour as a result of non-physiological overexcitation with interruption of integrated behaviour;
3. a complex behavioural pattern like intracranial self-stimulation depends on different interacting systems, mediated by different transmitters.

     

Predisposing effects of neonatal visceral pain on abuse-related effects of morphine in adult male Sprague Dawley rats

Rationale

Adverse early life experiences are risk factors for drug abuse and addiction. Changes in brain opioid systems have been demonstrated in response to neonatal visceral pain (NVP), but the impact of these changes on abuse-related effects of morphine are unknown. The NVP procedure used models chronic visceral hyperalgesia persisting across development.

Objectives

Intravenous self-administration, drug discrimination, and locomotor activity were used to compare the abuse-related effects of morphine in NVP and control rats.

Methods

Rats self-administered 0.3 mg/kg/inj morphine under an FR1 schedule, and dose–effect functions for morphine were then established. Separate rats were trained to discriminate 3.2 mg/kg morphine from saline under an FR20 schedule, and morphine dose–effect functions were then determined in the absence and presence of 0.1 mg/kg naltrexone. A third group of rats was tested with a range of morphine doses in an assay of locomotor activity, then injected daily with 10 mg/kg morphine to assess locomotor sensitization.

Results

NVP rats self-administered more morphine than controls at reinforcing doses. Discriminative stimulus effects of morphine were similar between groups, but in the presence of naltrexone, the ED₅₀ for morphine was more than 12× greater in control rats than in NVP animals. Morphine did not stimulate locomotor activity at any tested dose in NVP rats, although significant effects were observed in controls. Finally, significant locomotor sensitization was observed only in NVP rats.

Conclusions

NVP-induced changes in brain opioid systems have persistent pharmacological consequences into adulthood and may increase sensitivity to abuse-related effects of opioids across development.     

Anxiogenic-like profile of Wistar adult rats based on the pilocarpine model: an animal model for trait anxiety?

Rationale

There is extensive evidence indicating the influence of seizures on emotional responses observed in human and animals, but so far few studies are focusing on the behavioral profile of animals that do not have seizures despite being treated with convulsant agents.

Objectives

We aimed to establish the behavioral profile, biochemical, and electrographic features of rats submitted to the pilocarpine model of temporal lobe epilepsy

Methods

Rats treated with pilocarpine (20 to 350 mg/kg, i.p.) that did not develop status epilepticus or spontaneous recurrent seizures were evaluated 1 month later in the elevated plus maze (EPM), T-maze (ETM), open-field (OF), and step-down avoidance tests. Electroencephalographic (EEG), glutamate uptake, and hippocampal neuronal death assays were also performed

Results

Pilocarpine (150 or 350 mg/kg) promoted anxiogenic-like effects in rats evaluated in the EPM, ETM, and OF tests, whereas only the highest dose evoked spike–wave discharges during EEG recordings. Hippocampal theta rhythm was increased by pilocarpine 150 or 350 mg/kg and only the highest dose reduced the l-[³H]-glutamate uptake and cell viability on hippocampal slices.

Conclusions

Subconvulsant doses of pilocarpine promote long-lasting alterations on neural circuitry, reflected by an increased theta activity in the hippocampus and an anxiety-like profile of rats evaluated 1 month after the treatment which is independent of seizure occurrence and is not related to changes in glutamate uptake or hippocampal damage. These results prompt us to suggest that a systemic administration of subconvulsant doses of pilocarpine could be useful as a new tool to model trait anxiety in rats.