The influence of oxytocin administration on responses to infant faces and potential moderation by OXTR genotype

Rationale

Oxytocin is a neuropeptide that is associated with increases in social affiliative behaviors, particularly toward infants. However, no previous study has investigated healthy adults?? responses to infant faces following oxytocin administration. In addition, given that preliminary evidence suggests that a single-nucleotide polymorphism of the oxytocin receptor (OXTR) gene, rs53576, may influence behaviors associated with parental sensitivity, we assessed whether such responses vary according to OXTR rs53576 genotype.

Objectives

The present study assessed the effects of intranasally administered oxytocin and OXTR genotype on human adults?? preferences for infant faces.

Methods

A double-blind, between-groups design was used, with 57 genotyped volunteers randomly assigned to receive intranasally administered oxytocin or placebo. Fifty minutes following the administration of oxytocin or placebo, participants viewed infants?? and adults?? faces showing neutral expressions and assessed how appealing they found each face.

Results

Infants?? faces were more strongly preferred following oxytocin inhalation relative to placebo. When participants were separated according to genotype, this effect was only observed for participants homozygous for the rs53576G allele. Parallel effects were not seen for adults?? faces.

Conclusions

The present results are consistent with the hypothesis that acute oxytocin administration increases sensitivity to reward-relevant features of infants and/or reduces sensitivity to their aversive properties. The results are also consistent with suggestions of more efficient oxytocinergic function in rs53576G homozygotes.     

Effects of intranasal oxytocin prior to encoding and retrieval on recognition memory

Rationale

The neuropeptide oxytocin (OXT) has been shown to modulate a variety of human social behaviors. However, little is known about its impact on emotional memory processing. Previous research demonstrated both memory-enhancing and memory-impairing oxytocinergic effects.

Methods

We investigated the influence of a single (prior to encoding) and a repeated (prior to encoding and retrieval) intranasal administration of OXT on recognition memory for stimuli taken from the International Affective Picture System. In addition, we assessed the interaction of emotion regulation during encoding and OXT-induced memory effects. In a double-blind, placebo-controlled design, 80 healthy young males performed an emotion regulation task followed by a surprising recognition memory task after 60 min.

Results

Results show that repeated OXT administration significantly improved memory certainty for negative social stimuli. Regarding the influence of emotion regulation, the promnestic effect of OXT was more pronounced when participants had been instructed to increase their negative emotions during encoding.

Conclusions

Our findings indicate that OXT facilitates the processing of negative social stimuli during memory encoding and retrieval, possibly by enhancing the perception of aversive aspects in social situations.     

Social instigation and aggression in postpartum female rats: role of 5-Ht1A and 5-Ht1B receptors in the dorsal raph�� nucleus and prefrontal cortex

Rationale

5-HT_1A and 5-HT_1B receptor agonists effectively reduce aggressive behavior in males that has been escalated by social instigation. Important sites of action for these drugs are the receptors in dorsal raphé nuclei (DRN) and the ventral?Corbital prefrontal cortex (VO PFC). DRN and VO PFC areas are particularly relevant in the inhibitory control of escalated aggressive and impulsive behavior.

Objectives

The objectives of this study are to assess the anti-aggressive effects of 5-HT_1A (8-OH-DPAT) and 5-HT_1B (CP-93,129) receptor agonists microinjected into DRN and VO PFC, respectively, and to study the aggressive behavior in postpartum female Wistar rats using the social instigation protocol to increase aggression.

Methods and Results

8-OH-DPAT (0.56???g) in the DRN increased aggressive behavior in postpartum female rats. By contrast, CP-93,129 (1.0???g) microinjected into VO PFC decreased the number of attack bites and lateral threats. 5-HT_1A and 5-HT_1B receptor agonists differed in their effects on non-aggressive activities, the former decreasing rearing and grooming and the latter increasing these acts. When 8-OH-DPAT was microinjected into DRN and CP-93,129 was microinjected into VO PFC in female rats at the same time, maternal aggression decreased. Specific participation of 5-HT_1B receptors was verified by reversal of the anti-aggressive effects using the selective antagonist SB-224,289 (1.0???g).

Conclusions

The decrease in maternal aggressive behavior after microinjections of 5-HT_1B receptor agonists into the VO PFC and DRN of female postpartum rats that were instigated socially supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner, due to activation of 5-HT_1B receptors at the soma and terminals.     

Hindbrain orexin 1 receptors influence palatable food intake, operant responding for food, and food-conditioned place preference in rats

Rationale

Brain orexin 1 receptors (OX1Rs) are involved in food-motivated behavior. Most research has focused on forebrain OX1R populations, but hindbrain OX1Rs affect feeding. We hypothesized that hindbrain OX1Rs affect the reward value of food.

Objectives

We examined the effects of hindbrain OX1R stimulation or blockade on motivation for food, palatable high-fat (HF) food intake, and food-conditioned place preference.

Methods

Rats trained to lever press for sucrose on a progressive ratio (PR) schedule received fourth intracerebroventricular (icv) injections of vehicle, orexin-A (0.1–1 nmol), or the OX1R antagonist SB334867 (10–20 nmol) before operant test sessions. Effects of these treatments on HF food intake during daily 1-h tests were assessed with fourth icv and nucleus of the solitary tract (NTS) injections. We conditioned a place preference by pairing HF food with one side of a two-sided chamber and then examined the effect of 20 nmol fourth icv SB334867 on the expression of that preference.

Results

In ad lib fed rats on the PR schedule, fourth icv orexin-A significantly increased responding and breakpoint relative to the vehicle. In 24-h food-deprived rats, fourth icv SB334867 significantly decreased responding and breakpoint. Orexin-A delivered to the fourth ventricle (0.1 nmol) or NTS (0.01 nmol) increased HF diet intake. Fourth icv SB334867 did not affect HF food intake, but SB334867 delivered either fourth icv (20 nmol) or intra-NTS (5–10 nmol) suppressed chow intake. Expression of HF food-conditioned place preference was inhibited by fourth icv SB334867.

Conclusions

Hindbrain OX1R activity affects food-motivated operant behavior and may play a role in responding to cues that predict palatable food.     

Behavioral and neurochemical characterization of kratom (Mitragyna speciosa) extract

Objective

Mitragyna speciosa and its extracts are named kratom (dried leaves, extract). It contains several alkaloids and is used in traditional medicine to alleviate musculoskeletal pain, hypertension, coughing, diarrhea, and as an opiate substitute for addicts. Abuse and addiction to kratom is described, and kratom has attracted increasing interest in Western countries. Individual effects of kratom on opioidergic, adrenergic, serotonergic, and dopaminergic receptors are known, but not all of the effects have been explained. Pharmacokinetic and pharmacodynamic data are needed.

Methods

The effects of kratom extract on mice behavior were investigated following oral (po), intraperitoneal (ip), and intracerebroventricular (icv) application. Receptor-binding studies were performed.

Results

In μ opioid receptor knockout mice (?/?) and wild type (+/+) animals, the extract reduced locomotor activity after ip and low po doses in +/+ animals, but not after icv administration. The ip effect was counteracted by 0.3 mg/kg of apomorphine sc, suggesting dopaminergic presynaptic activity. An analgesic effect was only found in ?/? mice after icv application. Norbinaltorphimine abolished the analgesic effect, but not the inhibitory effect, on locomotor activity, indicating that the analgesic effect is mediated via κ opioid receptors. Oral doses, which did not diminish locomotor activity, impaired the acquisition of shuttle box avoidance learning. There was no effect on consolidation. Binding studies showed affinity of kratom to μ, δ, and κ opioid receptors and to dopamine D1 receptors.

Conclusions

The results obtained in drug-naïve mice demonstrate weak behavioral effects mediated via μ and κ opioid receptors.     

Cannabidiol potentiates ��9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats

Rationale

The interactions between ??⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) during chronic treatment, and at equivalent doses, are not well characterised in animal models.

Objectives

The aim of this study is to examine whether the behavioural effects of THC, and blood and brain THC levels are affected by pre-treatment with equivalent CBD doses.

Methods

Adolescent rats were treated with ascending daily THC doses over 21?days (1 then 3 then 10?mg/kg). Some rats were given equivalent CBD doses 20?min prior to each THC injection to allow examination of possible antagonistic effects of CBD. During dosing, rats were assessed for THC and CBD/THC effects on anxiety-like behaviour, social interaction and place conditioning. At the end of dosing, blood and brain levels of THC, and CB₁ and 5-HT_1A receptor binding were assessed.

Results

CBD potentiated an inhibition of body weight gain caused by chronic THC, and mildly augmented the anxiogenic effects, locomotor suppressant effects and decreased social interaction seen with THC. A trend towards place preference was observed in adolescent rats given CBD/THC but not those given THC alone. With both acute and chronic administration, CBD pre-treatment potentiated blood and brain THC levels, and lowered levels of THC metabolites (THC-COOH and 11-OH-THC). CBD co-administration did not alter the THC-induced decreases in CB₁ receptor binding and no drug effects on 5-HT_1A receptor binding were observed.

Conclusions

CBD can potentiate the psychoactive and physiological effects of THC in rats, most likely by delaying the metabolism and elimination of THC through an action on the CYP450 enzymes that metabolise both drugs.     

Mesolimbic dopamine D2 receptor plasticity contributes to stress resilience in rats subjected to chronic mild stress

Rationale

Few studies have investigated neurobiological and biochemical differences between stress-resilient and stress-vulnerable experimental animals.

Objectives

We investigated alterations in mesolimbic dopamine D₂ receptor density and mRNA expression level in stressed rats at two time points, i.e. after 2 and 5 weeks of chronic mild stress (CMS).

Methods

We used the chronic mild stress paradigm because it is a well-established animal model of depression. Two groups of stressed rats were distinguished during CMS experiments: (1) stress reactive (70 %), which displayed a decrease in the drinking of a palatable sucrose solution during the stress regimen, and (2) stress resilient (30 %), which exhibited an unaltered drinking profile when compared with the unchallenged control group. [³H]Domperidone was used as a ligand to label dopamine D₂ receptors, and a mixture of three specific oligonucleotides was used to evaluate dopamine D₂ receptor mRNA changes in various regions of the rat brain.

Results

CMS strongly affected the mesolimbic dopamine circuit in stress-resilient group after 2 weeks and stress-reactive group of rats after 5 weeks which exhibited a decrease in the level of dopamine D₂ receptor protein without alterations in D₂ mRNA expression. Stress-resilient animals, but not stress-reactive animals, effectively adapted to the extended stress and coped with it. The increase in D₂ mRNA expression returned the dopamine D₂ receptor density to control levels in stress-resilient rats after 5 weeks of CMS, but not in stress-reactive animals.

Conclusions

These results clearly demonstrate that, despite earlier blunting, the activation of dopamine receptor biosynthesis in the dopamine mesoaccumbens system in stress-resilient rats is involved in active coping with stressful experiences, and it exhibits a delay in time.     

Postsynaptic 5-HT1 receptors and offensive aggression in rats: a combined behavioural and autoradiographic study with eltoprazine.

The present study was designed to assess whether the antiaggressive effects of eltoprazine are mediated via presynaptic and/or postsynaptic 5-HT1 receptors. We describe the effects of central 5-HT depletion 1) on the behaviour of resident TMD-S3 rats in a territorial situation, 2) on the efficacy of eltoprazine to inhibit offensive aggression, and 3) on the 5-HT1A, 5-HT1B and 5-HT1C receptor binding in brains of rats previously used in behavioural studies. Male resident rats were given combined 5,7-dihydroxytryptamine (5,7-DHT) injections into the dorsal and median raphe nuclei. Two to four weeks after the lesions, rats were confronted with an intruder Wiser rat in their home cage for a 10-min period. The 5,7-DHT treatment resulted in a modest reduction of offensive behaviour, while having no effects on other social and nonsocial behaviours. Oral administration of eltoprazine (1 mg/kg) specifically reduced offensive aggression in both sham- and 5,7-DHT-lesioned animals, leaving social interest and exploration intact or even increasing it. A low dose (0.3 mg/kg) of eltoprazine did not affect the behavioural repertoire of sham-operated rats, whereas this dose significantly reduced offense behaviours in the 5,7-DHT-lesioned residents. Quantitative autoradiographic studies 5 weeks after 5,7-DHT treatment revealed a significant increase in radioligand binding to 5-HT1A, 5-HT1B and 5-HT1C sites in many brain regions studied, except for the raphe nuclei where [3H]8-OH-DPAT binding to 5-HT1A sites was markedly reduced. The concentrations of 5-HT and 5-HIAA in frontal cortex were reduced to approximately 10% of controls. The results indicate that serotonin has a stimulatory rather than an inhibitory influence on offensive aggressive behaviour. Central 5-HT depletion does not prevent the antiaggressive effects of eltoprazine, indicating a role for postsynaptic 5-HT1 receptors in the modulation of offensive aggression. The 5,7-DHT-induced overall upregulation of 5-HT1A, 5-HT1B and 5-HT1C binding sites suggests that these three receptor subtypes receive a tonic serotonergic influence. It is conceivable that this postsynaptic 5-HT1 receptor supersensitivity is reflected by the increased efficacy of eltoprazine to inhibit offensive aggression.     

Role of oxytocin receptors in modulation of fear by social memory

Rationale

Oxytocin receptors (Oxtr) are important mediators of social learning and emotion, with bidirectional effects on fear and anxiety. Contrary to the anxiolytic actions of Oxtr in the amygdala, we recently showed that Oxtr in the lateral septum mediate the enhancement of fear conditioning by social defeat in mice.

Objectives

Using positive social interactions, which impair fear conditioning, here we attempted to delineate whether the role of septal Oxtr in fear regulation depends on the valence of the social memory.

Methods

Pharmacological and genetic manipulations of lateral septal Oxtr were combined with the social buffering of fear paradigm, in which pre-exposure to nonfearful conspecifics reduces subsequent contextual fear conditioning, as revealed by decreased freezing behavior.

Results

Antagonism and down-regulation of Oxtr in the lateral septum abolished, while oxytocin (Oxt) administration before pre-exposure to nonfearful conspecifics facilitated the decrease of freezing behavior.

Conclusions

The septal oxytocin system enhances memory of social interactions regardless of their valence, reducing fear after positive and enhancing fear after negative social encounters. These findings explain, at least in part, the seemingly bidirectional role of Oxt in fear regulation.     

Somatostatin antagonist induces catalepsy in the aged rat

Rationale

Extrapyramidal motor signs are the major features of Parkinson’s disease (PD). It is unclear whether there is a link between these signs and such PD-associated factors as brain somatostatin deficiency and aging.

Objectives

This study aimed to examine whether an inhibition of the brain somatostatin system can initiate catalepsy, a model of extrapyramidal disorders, in young and aged rats.

Methods

The animals of 100–110 and 540–560 days of age were used. Catalepsy was measured using the bar test. The inhibition of the brain somatostatin activity was simulated by intracerebroventricular administration of a somatostatin antagonist, cyclosomatostatin.

Results

Cyclosomatostatin dose-dependently induced catalepsy in aged, but not in young rats. The cataleptic response was reversed by a somatostatin analog, octreotide.

Conclusions

The combination of aging and brain somatostatin deficiency can lead to catalepsy in rats. Since both factors are frequently observed in PD patients, the present results might be of relevance for pathogenesis of extrapyramidal signs in this disease.     

JNJ-39220675, a novel selective histamine H3 receptor antagonist, reduces the abuse-related effects of alcohol in rats

Rationale

A few recent studies suggest that brain histamine levels and signaling via H₃ receptors play an important role in modulation of alcohol stimulation and reward in rodents.

Objective

The present study characterized the effects of a novel, selective, and brain penetrant H₃ receptor antagonist (JNJ-39220675) on the reinforcing effects of alcohol in rats.

Methods

The effect of JNJ-39220675 on alcohol intake and alcohol relapse-like behavior was evaluated in selectively bred alcohol-preferring (P) rats using the standard two-bottle choice method. The compound was also tested on operant alcohol self administration in non-dependent rats and on alcohol-induced ataxia using the rotarod apparatus. In addition, alcohol-induced dopamine release in the nucleus accumbens was tested in freely moving rats.

Results

Subcutaneous administration of the selective H₃ receptor antagonist dose-dependently reduced both alcohol intake and preference in alcohol-preferring rats. JNJ-39220675 also reduced alcohol preference in the same strain of rats following a 3-day alcohol deprivation. The compound significantly and dose-dependently reduced alcohol self-administration without changing saccharin self-administration in alcohol non-dependent rats. Furthermore, the compound did not change the ataxic effects of alcohol, alcohol elimination rate, nor alcohol-induced dopamine release in nucleus accumbens.

Conclusions

These results indicate that blockade of H₃ receptor should be considered as a new attractive mechanism for the treatment of alcoholism.     

Chronic psychosocial stress and citalopram modulate the expression of the glial proteins GFAP and NDRG2 in the hippocampus

Rationale

It has been suggested that there are causal relationships between alterations in brain glia and major depression.

Objectives

To investigate whether a depressive-like state induces changes in brain astrocytes, we used chronic social stress in male rats, an established preclinical model of depression. Expression of two astrocytic proteins, the intermediate filament component glial fibrillary acidic protein (GFAP) and the cytoplasmic protein N-myc downregulated gene 2 (NDRG2), was analyzed in the hippocampus. For comparison, expression of the neuronal protein syntaxin-1A was also determined.

Methods

Adult male rats were subjected to daily social defeat for 5 weeks and were concomitantly treated with citalopram (30 mg/kg/day, via the drinking water) for 4 weeks.

Results

Western blot analysis showed that the chronic stress downregulated GFAP but upregulated NDRG2 protein. Citalopram did not prevent these stress effects, but the antidepressant per se downregulated GFAP and upregulated NDRG2 in nonstressed rats. In contrast, citalopram prevented the stress-induced upregulation of the neuronal protein syntaxin-1A.

Conclusions

These data suggest that chronic stress and citalopram differentially affect expression of astrocytic genes while the antidepressant drug does not prevent the stress effects. The inverse regulation of the cytoskeletal protein GFAP and the cytoplasmic protein NDRG2 indicates that the cells undergo profound metabolic changes during stress and citalopram treatment. Furthermore, the present findings indicate that a 4-week treatment with citalopram does not restore normal glial function in the hippocampus, although the behavior of the animals was normalized within this treatment period, as reported previously.     

Behavioral characterization of escalated aggression induced by GABAB receptor activation in the dorsal raphe nucleus

Rationale

Pharmacological activation of GABA_B receptors in the dorsal raphe nucleus (DRN) can escalate territorial aggression in male mice.

Objectives

We characterized this escalated aggression in terms of its behavioral and environmental determinants.

Methods

Aggressive behavior of resident male (CFW or ICR mouse) was assessed in confrontations with a group-housed intruder. Either baclofen (0.06 nmol/0.2 μl) or vehicle (saline) was microinjected into the DRN 10 min before the confrontation. We examined baclofen-heightened aggression in five situations: aggression in a neutral arena and after social instigation (experiment 1), aggression during the light phase of the cycle (experiment 2), aggression without prior fighting experience (experiment 3), aggression toward a female (experiment 4), and aggression after defeat experiences (experiment 5). In addition, we examined the body targets towards which bites are directed and the duration of aggressive bursts after baclofen treatment.

Results

Regardless of the past social experience, baclofen escalated aggressive behaviors. Even in the neutral arena and after defeat experiences, where aggressive behaviors were inhibited, baclofen significantly increased aggression. Baclofen increased attack bites directed at vulnerable body areas of male intruders but not toward a female and only in the dark. Also, baclofen prolonged the duration of aggressive bursts.

Conclusions

For baclofen to escalate aggression, specific stimulation (male intruder) and tonic level of serotonin (dark cycle) are required. Once aggressive behavior is triggered, intra-DRN baclofen escalates the level of aggression to abnormal levels and renders it difficult to terminate. Also, baclofen counteracts the effects of novelty or past experiences of defeat.     

Candesartan prevents impairment of recall caused by repeated stress in rats

Rationale

Deleterious effects of psychological stress on memory are increasingly important. Overexpression of the AT₁ angiotensin receptors in brain has been found to participate in several negative effects of chronic stress including hypertension and a cognitive impairment.

Objective

In this study, we searched for the protective effects the AT₁ angiotensin receptor blockade with candesartan against the adverse effects of repeated stress on recall of aversively and appetitively motivated behaviours in rats.

Methods

Two groups of male Wistar rats were repeatedly stressed by keeping them daily (2 h/21 days) in tight plastic tubes. The subjects of the group 1 received candesartan (0.1 mg/kg, orally) each day before the stressing procedure. The rats of the group 2 received vehicle. Another two groups of rats (3 and 4) receiving candesartan and vehicle, respectively, were appropriately handled but not stressed. Next day, after ending the repeated stress procedure, all rats were tested in two cognitive paradigms: inhibitory avoidance (IA) and object recognition (OR).

Results

Stressed animals displayed decreased recall of the IA behaviour (p?<?0.01) and decreased OR (p?<?0.05). These effects were not seen in the animals stressed and concomitantly treated with candesartan. The auxiliary tests designed to control for the possible unspecific contribution of motor (open field) and emotional (elevated “plus” maze) effects of the experimental procedures to results of the cognitive tests showed no such contribution.

Conclusion

These data strongly suggest that the AT₁ angiotensin receptor blockade effectively counteracts deleterious effects of stress on recall of aversively and appetitively motivated memories in rats.     

Developmental vitamin D deficiency alters dopamine-mediated behaviors and dopamine transporter function in adult female rats

Rationale

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. DVD deficiency in neonatal rats is associated with alterations in cellular development, dopamine metabolism, and brain morphology. DVD-deficient adult rats show novelty-induced hyperlocomotion and an enhanced locomotor response to MK-801, which can be ameliorated by pretreatment with the antipsychotic drug haloperidol.

Objectives

In this study, we examined locomotor responses of male and female juvenile and adult rats to a dose range of amphetamine. We also measured dopamine receptor and monoamine transporter densities in adult brain.

Results

Female DVD-deficient adult rats displayed an enhanced sensitivity to amphetamine-induced locomotion, an increased dopamine transporter density in the caudate–putamen and increased affinity in the nucleus accumbens compared with control females. By contrast, there were no differences between control and DVD-deficient male rats.

Discussion

Taken together, this suggests an alteration in the development of the dopamine system and on dopamine-mediated behaviors in female DVD-deficient rats, and this may be relevant to the underlying neurobiology of schizophrenia.     

Tobacco smoke exposure induces nicotine dependence in rats

Rationale

Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents.

Objectives

The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats.

Methods

The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central α7 nicotinic acetylcholine receptor (nAChR) and non-α7 nAChR levels (primarily α4β2 nAChRs).

Results

The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke-exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the α7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-α7 nAChR density in the dentate gyrus.

Conclusion

Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus.     

Common influences of non-competitive NMDA receptor antagonists on the consolidation and reconsolidation of cocaine-cue memory

Rationale

Environmental stimuli or contexts previously associated with rewarding drugs contribute importantly to relapse among addicts, and research has focused on neurobiological processes maintaining those memories. Much research shows contributions of cell surface receptors and intracellular signaling pathways in maintaining associations between rewarding drugs (e.g., cocaine) and concurrent cues/contexts; these memories can be degraded at the time of their retrieval through reconsolidation interference. Much less studied is the consolidation of drug-cue memories during their acquisition.

Objective

The present experiments use the cocaine-conditioned place preference (CPP) paradigm in rats to directly compare, in a consistent setting, the effects of N-methyl-d-aspartate (NMDA) glutamate receptor antagonists MK-801 and memantine on the consolidation and reconsolidation of cocaine-cue memories.

Methods

For the consolidation studies, animals were systemically administered MK-801 or memantine immediately following training sessions. To investigate the effects of these NMDA receptor antagonists on the retention of previously established cocaine-cue memories, animals were systemically administered MK-801 or memantine immediately after memory retrieval.

Results

Animals given either NMDA receptor antagonist immediately following training sessions did not establish a preference for the cocaine-paired compartment. Post-retrieval administration of either NMDA receptor antagonist attenuated the animals’ preference for the cocaine-paired compartment. Furthermore, animals given NMDA receptor antagonists post-retrieval showed a blunted response to cocaine-primed reinstatement.

Conclusions

Using two distinct NMDA receptor antagonists in a common setting, these findings demonstrate that NMDA receptor-dependent processes contribute both to the consolidation and reconsolidation of cocaine-cue memories, and they point to the potential utility of treatments that interfere with drug-cue memory reconsolidation.     

Chronic cannabinoid exposure reduces phencyclidine-induced schizophrenia-like positive symptoms in adult rats

Rationale

Chronic cannabis use can induce psychotic states that resemble schizophrenia. Yet, schizophrenic patients often smoke cannabis as a form of self-medication to counter the aversive symptoms of schizophrenia. We recently demonstrated an ameliorating effect of cannabinoid self-administration (SA) on negative and cognitive schizophrenia-like symptoms induced experimentally by the non-competitive N-methyl-d-aspartate receptor antagonist phencyclidine (PCP). Whether cannabinoid SA alleviates or exacerbates schizophrenia-like positive symptoms is still unclear.

Objectives

This follow-up study aimed to evaluate the effect of self-administered cannabinoid on PCP-induced schizotypic positive symptoms in adult rats.

Methods

Male rats were trained to self-administer either the cannabinoid CB1 receptor agonist WIN 55,212-2 (WIN; 12.5 μg/kg/infusion) or its vehicle (Veh) intravenously. The effects of acute and chronic intermittent intraperitoneal administration of PCP (2.5 mg/kg) on motor parameters were then tested in Veh-SA and WIN-SA.

Results

Cannabinoid SA significantly attenuated the psychotomimetic effects of PCP exposure observed in control rats. Following acute PCP administration, WIN-SA animals displayed more frequent rearing and lower anxiety-like profile than Veh-SA rats. WIN-SA rats also exhibited lower behavioural sensitisation to chronic PCP treatment as demonstrated by reduced hyperlocomotion in response to an acute PCP challenge. In addition, parallel experiments performed in experimenter-administered rats that received WIN at comparable SA doses confirmed the ameliorating effects of cannabinoid exposure on PCP-induced schizotypic behaviours, indicating that motivational effects were not responsible for the ameliorative effects of cannabinoids.

Conclusions

Our results indicate that cannabis may exert protective effects on positive schizotypic symptoms in adult animals such as hypermotility and anxiety state.     

Social play behavior,ultrasonic vocalizations and their modulation by morphine and amphetamine in Wistar and Sprague-Dawley rats

Rationale

Social play behavior is the most characteristic social behavior in young mammals. It is highly rewarding and crucial for proper neurobehavioral development. Despite the importance of genetic factors in normal and pathological social behaviors, little information is available about strain influences on social play.

Objective and methods

The aim of this study was to investigate differences in social play behavior, 50-kHz ultrasonic vocalizations (USVs) and their modulation by acute morphine and amphetamine administration in two rat strains widely used in behavioral pharmacology studies, i.e., Wistar and Sprague–Dawley rats.

Results

Sprague–Dawley rats showed higher levels of social play than Wistar rats. In both strains, no correlation was found between the performance of social behaviors and the emission of 50-kHz USVs. In Wistar and Sprague–Dawley rats, morphine increased and amphetamine decreased social play. The effects of morphine, however, were more pronounced in Wistar than Sprague–Dawley animals. In both strains, morphine did not affect USV emission, while amphetamine increased it during cage exploration. In Sprague–Dawley rats only, amphetamine decreased USVs during social interaction.

Conclusions

Wistar and Sprague–Dawley rats differ in their absolute levels of social play behavior and 50-kHz USVs, and quantitative differences exist in their response to pharmacological manipulations of social play. The emission of 50-kHz USVs and the behavioral parameters thought to reflect rewarding social interactions in adolescent rats are dissociable.     

Differential effects of antipsychotics on lateral bias and social attention in female rats

Rationale

Prior research has demonstrated that individuals with schizophrenia may exhibit lateral biases in attention and deficits in social behavior. The use of a noninvasive animal model of attentional impairments in schizophrenia and antipsychotic drugs can help elucidate the biological underpinnings of attentional processes and facilitate the study of novel therapeutics.

Objectives

The purpose of this study was to compare the effects of three antipsychotic drugs on measures of lateral bias and social attention in healthy, unoperated female rats.

Materials and methods

Female Long–Evans rats selected for a preexisting lateral bias in attention, a right behavioral orientation preference (BOP), were administered clozapine, haloperidol, sulpiride, or vehicle. Lateral bias in attention was assessed by determining which forelimb rats removed a nuisance stimulus from first. Social attention was examined by comparing the latency to remove nuisance stimuli in the presence of a social (inaccessible female rat) versus non-social (blinking clock) distractor.

Results

All antipsychotic drugs eliminated right lateral bias in attention, while control animals retained their initial bias. Clozapine eliminated right lateral bias more rapidly than the other drugs. Animals receiving clozapine also selectively displayed increased attention to another rat.

Conclusions

The results suggest that the antipsychotic medication clozapine rapidly alters attentional bias and uniquely influences attention to a social stimulus. The right BOP paradigm is a useful animal model for comparing antipsychotic drug effects on lateralized attentional bias and attention to social stimuli.