High Responder Rats Research Articles

The influence of heterogeneity on the analysis of sleep-wake architecture in the single-prolonged stress rats

To observe the influence of heterogeneity on sleep-wake architecture in single-prolonged stress (SPS) animal model. SPS rats were subdivided into low responders (LR) and high responders (HR) based on their freezing responses to a novel environment. Sleeping time (ST), awakening numbers (AN), brief awakening numbers (bAN) and frequency distribution of sleep bouts were used as observing indicators, single factor variance analysis combined with Dunnett t test were used to compare the differences between control, exposure, LR and HR groups. We found sleeping time was increased only in HR group. Moreover, awakening numbers and brief awakening number increased in exposure group and HR group during the light phase, but not in LR group. The number of sleep bouts for the ranges of 40-80s increased obviously in HR group, but not in exposure and LR group. In addition, there were significant correlation between sleep-related parameters and freezing in HR group, but not in LR group. Heterogeneity existed in SPS model in view of different sleep-wake architectures of SPS rats. Rats in HR group exactly mimicked the freezing response and sleep disorders of PTSD. So HR rats were more appropriate to be used as PTSD-like models, especially when studying sleep disorder in PTSD.

Early-life exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats

Selective serotonin reuptake inhibitor (SSRI) antidepressants are the mainstay treatment for the 10–20% of pregnant and postpartum women who suffer major depression, but the effects of SSRIs on their children’s developing brain and later emotional health are poorly understood. SSRI use during pregnancy can elicit antidepressant withdrawal in newborns and increase toddlers’ anxiety and social avoidance. In rodents, perinatal SSRI exposure increases adult depression- and anxiety-like behavior, although certain individuals are more vulnerable to these effects than others. Our study establishes a rodent model of individual differences in susceptibility to perinatal SSRI exposure, utilizing selectively bred Low Responder (bLR) and High Responder (bHR) rats that were previously bred for high versus low behavioral response to novelty. Pregnant bHR/bLR females were chronically treated with the SSRI paroxetine (10mg/kg/day p.o.) to examine its effects on offspring’s emotional behavior and gene expression in the developing brain. Paroxetine treatment had minimal effect on bHR/bLR dams’ pregnancy outcomes or maternal behavior. We found that bLR offspring, naturally prone to an inhibited/anxious temperament, were susceptible to behavioral abnormalities associated with perinatal SSRI exposure (which exacerbated their Forced Swim Test immobility), while high risk-taking bHR offspring were resistant. Microarray studies revealed robust perinatal SSRI-induced gene expression changes in the developing bLR hippocampus and amygdala (postnatal days 7–21), including transcripts involved in neurogenesis, synaptic vesicle components, and energy metabolism. These results highlight the bLR/bHR model as a useful tool to explore the neurobiology of individual differences in susceptibility to perinatal SSRI exposure.

Individual differences in novelty-seeking behavior in spontaneously hypertensive rats: Enhanced sensitivity to the reinforcing effect of methylphenidate in the high novelty-preferring subpopulation

BackgroundHigh novelty seeking has been assumed to predict vulnerability to use addictive drugs. Notably, it is also a symptom associated with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to identify whether spontaneously hypertensive rats (SHRs), putative animal models of ADHD, display individual differences in novelty-seeking behavior, and whether high novelty-seeking SHRs show enhanced sensitivity to the reinforcing effect of methylphenidate, the most commonly prescribed stimulant ADHD medication. MethodsFirst, we established that SHRs show higher levels of novelty-seeking behavior than their normotensive control strain, Wistar Kyoto (WKY) rats. Novelty seeking was measured in two tests: open field test in a novel test arena, and novel object preference tests. Thereafter, SHRs were classified into high responders (HR) or low responders (LR), high novelty-preferring (HNP) or low novelty-preferring (LNP) rats, based on individual scores in the two behavioral assays. Methylphenidate self-administration was assessed thereafter. ResultsSHRs showed higher levels of novelty-seeking behavior than WKY rats. HR/LR and HNP/LNP subgroups were identified. HR and LR rats showed comparable rates of methylphenidate self-administration. However, HNP SHRs worked more for methylphenidate infusions than their LNP counterparts. ConclusionsWe showed some evidence on inter-individual variations in novelty seeking in SHRs. Importantly, we demonstrated enhanced sensitivity of HNP SHRs to the reinforcing effect of methylphenidate, indicating a “drug-vulnerable” SHR subpopulation. These findings are important as they may provide basis for a potential screening tool to identify a subset of ADHD patients (i.e. high novelty seekers) who may be at risk for misusing/abusing methylphenidate.

Interaction between cholecystokinin and the fibroblast growth factor system in the ventral tegmental area of selectively bred high- and low-responder rats

Individual differences in the locomotor response to novelty have been linked to basal differences in dopaminergic neurotransmission. Mesolimbic dopaminergic outputs are regulated by cholecystokinin (CCK), a neuropeptide implicated in anxiety. In turn, CCK expression is regulated by fibroblast growth factor-2 (FGF2), which has recently been identified as an endogenous regulator of anxiety. FGF2 binds to the high-affinity fibroblast growth factor receptor-1 (FGF-R1) to regulate the development and maintenance of dopamine neurons in the ventral tegmental area (VTA). However, the relationship between the FGF and CCK systems in the VTA is not well understood. Therefore, we utilized the selectively-bred low-responder (bLR; high-anxiety) and high-responder (bHR; low-anxiety) rats to examine the effects of repeated (21-day) FGF2 treatment on CCK and FGF-R1 mRNA in the rostral VTA (VTAr). In vehicle-treated controls, both CCK and FGF-R1 mRNA levels were increased in the VTAr of bLR rats relative to bHR rats. Following FGF2 treatment, however, bHR–bLR differences in CCK and FGF-R1 mRNA expression were eliminated, due to decreased CCK mRNA levels in the VTAr of bLR rats and increased FGF-R1 expression in bHR rats. Differences after FGF2 treatment may denote distinct interactions between the CCK and FGF systems in the VTAr of bHR vs. bLR rats. Indeed, significant correlations between CCK and FGF-R1 mRNA expression were found in bHR, but not bLR rats. Colocalization studies suggest that CCK and FGF-R1 are coexpressed in some VTAr neurons. Taken together, our findings suggest that the FGF system is poised to modulate both CCK and FGF-R1 expression in the VTAr, which may be associated with individual differences in mesolimbic pathways associated with anxiety-like behavior.

Individual Differences in Novelty Seeking Predict Subsequent Vulnerability to Social Defeat through a Differential Epigenetic Regulation of Brain-Derived Neurotrophic Factor Expression

Some personality traits, including novelty seeking, are good predictors of vulnerability to stress-related mood disorders in both humans and rodents. While high-novelty-seeking rats [high responders (HRs)] are vulnerable to the induction of depressive-like symptoms by social defeat stress, low-novelty-seeking rats [low responders (LRs)] are not. Here, we show that such individual differences are critically regulated by hippocampal BDNF. While LR animals exhibited an increase in BDNF levels following social defeat, HR individuals did not. This difference in hippocampal BDNF expression promoted the vulnerability of HR and the resilience of LR rats. Indeed, preventing activation of BDNF signaling by infusing the BDNF scavenger TrkB-Fc into the dentate gyrus of the hippocampus of LR rats led to social defeat-induced social avoidance, whereas its activation in HR rats by the TrkB agonist 7,8-dihydroxyflavone promoted social approach. Along with the changes in BDNF expression following defeat, we report in LR animals a downregulation of the inactive BDNF receptor TrkB.T1, associated with an activation of CREB through Akt-mediated signaling, but not MSK1-mediated signaling. In HR animals, none of these molecules were affected by social defeat. Importantly, the BDNF upregulation involved an epigenetically controlled transcription of bdnf exon VI, associated with a coherent regulation of relevant epigenetic factors. Altogether, our data support the importance of hippocampal BDNF regulation in response to stressful events. Moreover, we identify a specific and adaptive regulation of bdnf exon VI in the hippocampus as a critical regulator of stress resilience, and strengthen the importance of epigenetic factors in mediating stress-induced adaptive and maladaptive responses in different individuals.

Association between locomotor response to novelty and light reinforcement: Sensory reinforcement as a rodent model of sensation seeking

BackgroundThe human personality trait of sensation seeking (SS) indicates an attraction to novel sensations and experiences, and is associated with greater likelihood of drug abuse. In rodents, locomotor activity in a novel environment (Loco) has been found to predict drug self-administration (SA), and has been hypothesized to be a translational model of human SS. Previously, we reported (Gancarz et al., 2011 [12]) that high responder (HR) animals responded more than low responder (LR) animals to produce a response contingent light onset. The primary goal of this paper was a detailed analysis of the association between Loco and light contingent responding in a large sample of rats (n=93). MethodsMale rats were pre-exposed to dark operant test chambers for ten 30min sessions and baseline levels of responding (snout poking) were determined. The pre-exposure phase was followed by 6 sessions during which active responding produced a visual sensory reinforcer (VSR; 5s light onset) according to a variable interval 1min schedule of reinforcement. After completion of the VSR phase, Loco was tested. ResultsThe activating effects (total responding) of light were associated with Loco, but the response guiding effects (proportion of active responding) of the light were not. In addition, HR rats habituated more slowly in both the VSR and Loco tests than LR rats. ConclusionsThese data indicate that VSR measures aspects of the rodent's response to novel sensations and experiences that are not detected by Loco. These data provide some evidence for the use of light reinforcement as an animal model of SS.

High novelty-seeking predicts aggression and gene expression differences within defined serotonergic cell groups

Aggression frequently coincides with specific dimensions of emotionality, such as impulsivity, risk-taking, and drug abuse. Serotonergic (5-HTergic) neurotransmission contributes to the regulation of numerous neurobiological functions, and is thought to play a key role in modulating aggressive responses. The current study uses selectively-bred High (bHR) and Low (bLR) Responder rats that exhibit differences in emotionality and behavioral control, with bHRs exhibiting heightened novelty-induced exploration, impulsivity, and increased sensitivity to drugs of abuse, and with bLRs characterized by exaggerated depressive- and anxiety-like behaviors. Based on this behavioral profile we hypothesized that bHR rats exhibit increased aggression along with changes in testosterone and corticosterone secretion characteristic of aggression, and that these changes are accompanied by alterations in the expression of key genes that regulate 5-HTergic neurotransmission (Tph2 and Sert) as well as in the activation of 5-HTergic cell groups following aggressive encounter. Our data demonstrate that when compared to bLR rats, bHRs express increased baseline Tph2 and Sert in select brainstem nuclei, and when tested on the resident–intruder test they exhibited: 1) increased aggressive behavior; 2) potentiated corticosterone and testosterone secretion; and 3) diminished intrusion-induced c-fos expression in select 5-HTergic brainstem cell groups. The most prominent gene expression differences occurred in the B9 cell group, pontomesencephalic reticular formation, median raphe, and the gigantocellular nucleus pars α. These data are consistent with the notion that altered 5-HT neurotransmission contributes to bHRs' heightened aggression. Furthermore, they indicate that a specific subset of brainstem 5-HTergic cell groups contributes to the regulation of intrusion-elicited behavioral responses.

Inborn differences in environmental reactivity predict divergent diurnal behavioral, endocrine, and gene expression rhythms

Circadian dysfunction has long been implicated in the etiology of mood disorders. The gene Clock and related molecules (e.g. Per1, Per2) represent key regulators of circadian rhythmicity, and their targeted disruption in mutant mice produces potentiated reward drive, novelty-seeking, impulsivity, disrupted sleep, reduced depression and anxiety - a behavioral profile highly reminiscent of our selectively bred high responder (bHR) rats compared to bred low responders (bLRs). The current study evaluated potential diurnal bHR-bLR differences in behavior, gene expression, and neuroendocrinology. Relative to bHRs, bLRs showed diminished homecage locomotion during the dark (but not light) phase and a delayed corticosterone peak. In situ hybridizations in hypothalamus, amygdala, and hippocampus at Zeitgeber Time (ZT)2 and ZT14 revealed distinct bHR-bLR day-night gene expression fluctuations. bHRs exhibited altered day-night patterns of corticotrophin releasing hormone (CRH) and arginine vasopression (AVP) mRNA in the hypothalamus, and perturbed hippocampal MR:GR ratios relative to bLR rats. bHR-bLR rats showed disparate day-night Clock expression in the suprachiasmatic nucleus, a master circadian oscillator, with bHRs showing higher levels at ZT14 versus ZT2 and bLRs showing the opposite pattern. Clock, Per1 and Per2 were assessed in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) since disruption of these genes induces "bHR-like" behavior in mutant mice. Clock and Per1 did not differ between strains, but there were robust Per2 differences, with bHRs having reduced Per2 in VTA and SNc. These findings resonate with earlier work demonstrating that perturbation of Clock and related molecules contributes to disturbances of emotional and addictive behaviors.

Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals

Individuals with mood disorders exhibit alterations in the fibroblast growth factor system, including reduced hippocampal fibroblast growth factor-2 (FGF2). It is difficult, however, to pinpoint whether these alterations are a cause or consequence of the disorder. The present study asks whether FGF2 administered the day after birth has long-lasting effects on hippocampal development and emotionality. We show that early-life FGF2 shifts the pace of neurogenesis, with an early acceleration around weaning followed by a deceleration in adulthood. This, in turn, results in a denser dentate gyrus with more neurons. To assess the impact of early-life FGF2 on emotionality, we use rats selectively bred for differences in locomotor response to novelty. Selectively bred low-responder (bLR) rats show low levels of novelty-induced locomotion and exhibit high levels of anxiety- and depression-like behavior compared with their selectively bred high-responder counterparts. Early-life FGF2 decreased anxiety-like behavior in highly anxious bLRs without altering other behaviors and without affecting high-responder rats. Laser capture microscopy of the dentate gyrus followed by microarray analysis revealed genes that were differentially expressed in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of the differentially expressed genes that have been positively associated with anxiety were down-regulated, whereas genes that promote cell survival were up-regulated. Overall, these results show a key role for FGF2 in the developmental trajectory of the hippocampus as well as the modulation of anxiety-like behavior in adulthood, and they point to potential downstream targets for the treatment of anxiety disorders.

Novelty-seeking behavior predicts vulnerability in a rodent model of depression

The onset of major depressive disorder is likely precipitated by a combination of heredity and life stress. The present study tested the hypothesis that rats selectively bred on a trait related to emotional reactivity would show differential susceptibility or resilience to the development of depression-like signs in response to chronic mild variable intermittent stress (CMS). Male Sprague-Dawley rats that were bred based on the trait of either high or low locomotor activity in response to a novel environment were exposed to 4 weeks of CMS or control conditions. Changes in hedonic behavior were assessed using weekly sucrose preference tests and anxiety-like behavior was evaluated using the novelty-suppressed feeding test. During 4 weeks of CMS, bred low responder (bLR) rats became anhedonic at a faster rate and to a larger degree than bred high responder (bHR) rats, based on weekly sucrose preference tests. Measures of anxiety-like behavior in the novelty-suppressed feeding test were also significantly increased in the CMS-exposed bLR rats, though no differences were observed between CMS-exposed bHR rats and their unstressed controls. These findings present further evidence that increased emotional reactivity is an important factor in stress susceptibility and the etiology of mood disorders, and that bHR and bLR rats provide a model of resistance or vulnerability to stress-induced depression. Furthermore, exposing bHR and bLR rats to CMS provides an excellent way to study the interaction of genetic and environmental factors in the development of depression-like behavior.

Locomotor activity in a novel environment predicts both responding for a visual stimulus and self-administration of a low dose of methamphetamine in rats

There is evidence that visual stimuli used to signal drug delivery in self-administration procedures have primary reinforcing properties, and that drugs of abuse enhance the reinforcing properties of such stimuli. Here, we explored the relationships between locomotor activity, responding for a visual stimulus, and self-administration of methamphetamine (METH). Rats were classified as high or low responders based on activity levels in a novel locomotor chamber and were subsequently tested for responding to produce a visual stimulus followed by self-administration of a low dose of METH (0.025 mg/kg/infusion) paired with the visual stimulus. High responder rats responded more for the visual stimulus than low responder rats indicating that the visual stimulus was reinforcing and that operant responding for a visual stimulus has commonalities with locomotor activity in a novel environment. Similarly, high responder rats responded more for METH paired with a visual stimulus than low responder rats. Because of the reinforcing properties of the visual stimulus, it was not possible to determine if the rats were responding to produce the visual stimulus, METH or the combination. We speculate that responding to produce sensory reinforcers may be a measure of sensation seeking. These results indicate that visual stimuli have unconditioned reinforcing effects which may have a significant role in acquisition of drug self-administration, a role that is not yet well understood.

High-Novelty-Preference Rats are Predisposed to Compulsive Cocaine Self-administration

Sensation/novelty-seeking is amongst the best markers of cocaine addiction in humans. However, its implication in the vulnerability to cocaine addiction is still a matter of debate, as it is unclear whether this trait precedes or follows the development of addiction. Sensation/novelty-seeking trait has been identified in rats on the basis of either novelty-induced locomotor activity (high-responder (HR) trait) or novelty-induced place preference (high-novelty-preference trait (HNP)). HR and HNP traits have been associated with differential sensitivity to psychostimulants. However, it has recently been demonstrated that HR rats do not develop compulsive cocaine self-administration (SA) after protracted exposure to the drug, thereby suggesting that at least one dimension of sensation/novelty seeking in the rat is dissociable from the vulnerability to switch from controlled to compulsive cocaine SA. We therefore investigated whether HNP, as measured as the propensity to choose a new environment in a free choice procedure, as opposed to novelty-induced locomotor activity, predicts the vulnerability to, and the severity of, addiction-like behavior for cocaine. For this, we identified HR/LR rats and HNP/LNP rats before any exposure to cocaine. After 60 days of cocaine SA, each rat was given an addiction score based on three addiction-like behaviors (persistence of responding when the drug is signaled as not available, high breakpoint under progressive ratio schedule and resistance to punishment) that resemble the clinical features of drug addiction, namely inability to refrain from drug seeking, high motivation for the drug and compulsive drug use despite adverse consequences. We show that, as opposed to HR rats, HNP rats represent a sub-population predisposed to compulsive cocaine intake, displaying higher addiction scores than LNP rats. This study thereby provides new insights into the factors predisposing to cocaine addiction, supporting the hypothesis that addiction is sustained by two vulnerable phenotypes: a 'drug use prone' phenotype such as HR which brings an individual to develop drug use and an 'addiction prone' phenotype, such as HNP, which facilitates the shift from sustained to compulsive drug intake and addiction.

Impact of baseline prepulse inhibition on nicotine-induced locomotor sensitization in rats

The rats having high locomotor reactivity to a novel environment (LRNE) are known to be more vulnerable to develop locomotor sensitization, which reflects the initial neuroplastic changes in brain systems related to addictive behaviours. The present study aimed to investigate whether sensorimotor gating level, measured by prepulse inhibition (PPI) of acoustic startle reflex, also reflects vulnerability for nicotine sensitization. A batch of rats was assigned into three groups according to their baseline PPI values. The highest 1/3 and the lowest 1/3 proportions were selected and defined as high-inhibitory (HI) and low-inhibitory (LI) groups. LRNE was measured in the rats, then they were treated with nicotine (1 mg/kg, tartrate salt, subcutaneously) or saline and locomotor activity (LMA) was immediately recorded for 15 min. This procedure was performed daily for 5 successive days. After a 3-day drug-free period, all rats were challenged with nicotine (1 mg/kg) on 9th day and with saline on 12th day. Same sensitization protocol was applied in another batch of rats, except assigning them into the high-responder (HR) and low-responder (LR) groups according to LRNE levels. There was no significant difference between HI and LI rats in LRNE. Although the acute effect of nicotine on LMA was higher in HI rats, a locomotor sensitization developed and expressed only in LI rats. In the following experiments, nicotine stimulated LMA both in HR and LR rats, but induced and expressed locomotor sensitization only in HR rats. The present study shows that acute locomotor stimulant effect and locomotor sensitization developing effects of nicotine are associated with the baseline PPI and LRNE levels. But these two factors are independent from each other.

Individual differences in the effects of cannabinoids on motor activity, dopaminergic activity and DARPP-32 phosphorylation in distinct regions of the brain

This study explored the behavioural, neurochemical and molecular effects of Delta9-tetrahydrocannabinol (Delta9-THC) and WIN55,212-2, in two rat phenotypes, distinguished on the basis of their vertical activity upon exposure to a novel environment, as high responders (HR) and low responders (LR). Motor effects were assessed under habituated vs. non-habituated conditions. Dopaminergic activity and DARPP-32 phosphorylation were measured in the dorsal striatum, nucleus accumbens, prefrontal cortex and amygdala. These cannabinoids influenced motor activity in a biphasic manner, i.e. low doses stimulated, whereas high doses suppressed motor activity. Dopamine (DA) biosynthesis was increased in most brain regions studied following Delta9-THC administration mainly in HR rats, and low-dose WIN55,212-2 increased DA biosynthesis in HR rats only. Both high and low doses of Delta9-THC increased DARPP-32 phosphorylation in most brain regions studied in both phenotypes, an effect that was also observed following high-dose WIN55,212-2 administration only in the striatum. The present results provide further support for a key role of cannabinoids in the regulation of motoric responses and elements of dopaminergic neurotransmission and reveal their complex differential effects in distinct rat phenotypes, as seen with other drugs of abuse.

An Animal Model of Genetic Vulnerability to Behavioral Disinhibition and Responsiveness to Reward-Related Cues: Implications for Addiction

Rats selectively bred based on high or low reactivity to a novel environment were characterized for other behavioral and neurobiological traits thought to be relevant to addiction vulnerability. The two lines of animals, which differ in their propensity to self-administer drugs, also differ in the value they attribute to cues associated with reward, in impulsive behavior, and in their dopamine system. When a cue was paired with food or cocaine reward bred high-responder rats (bHRs) learned to approach the cue, whereas bred low-responder rats (bLRs) learned to approach the location of food delivery, suggesting that bHRs but not bLRs attributed incentive value to the cue. Moreover, although less impulsive on a measure of 'impulsive choice', bHRs were more impulsive on a measure of 'impulsive action'- ie, they had difficulty withholding an action to receive a reward, indicative of 'behavioral disinhibition'. The dopamine agonist quinpirole caused greater psychomotor activation in bHRs relative to bLRs, suggesting dopamine supersensitivity. Indeed, relative to bLRs, bHRs also had a greater proportion of dopamine D2(high) receptors, the functionally active form of the receptor, in the striatum, in spite of lower D2 mRNA levels and comparable total D2 binding. In addition, fast-scan cyclic voltammetry revealed that bHRs had more spontaneous dopamine 'release events' in the core of the nucleus accumbens than bLRs. Thus, bHRs exhibit parallels to 'externalizing disorders' in humans, representing a genetic animal model of addiction vulnerability associated with a propensity to attribute incentive salience to reward-related cues, behavioral disinhibition, and increased dopaminergic 'tone.'

The expression of c-Fos and colocalisation of c-Fos and glucocorticoid receptors in brain structures of low and high anxiety rats subjected to extinction trials and re-learning of a conditioned fear response

We designed an animal model to examine the mechanisms of differences in individual responses to aversive stimuli. We used the rat freezing response in the context fear test as a discriminating variable: low responders (LR) were defined as rats with a duration of freezing response one standard error or more below the mean value, and high responders (HR) were defined as rats with a duration of freezing response one standard error or more above the mean value. We sought to determine the colocalisation of c-Fos and glucocorticoid receptors-immunoreactivity (GR-ir) in HR and LR rats subjected to conditioned fear training, two extinction sessions and re-learning of a conditioned fear. We found that HR animals showed a marked decrease in conditioned fear in the course of two extinction sessions (16 days) in comparison with the control and LR groups. The LR group exhibited higher activity in the cortical M2 and prelimbic areas (c-Fos) and had an increased number of cells co-expressing c-Fos and GR-ir in the M2 and medial orbital cortex after re-learning a contextual fear. HR rats showed increased expression of c-Fos, GR-ir and c-Fos/GR-ir colocalised neurons in the basolateral amygdala and enhanced c-Fos and GR-ir in the dentate gyrus (DG) in comparison with LR animals. Our data indicate that recovery of a context-related behaviour upon re-learning of contextual fear is accompanied in HR animals by a selective increase in c-Fos expression and GRs-ir in the DG area of the hippocampus.

Individual differences in response to novelty and the conditioned locomotor effects of nicotine

Rats' locomotor reactivity to an inescapable novel environment has been shown to be correlated with the psychomotor response to many stimulant drugs. However, the effects of nicotine on rats categorized as high responder (HR) or low responder (LR) has yielded inconclusive results. This study examined the effects of nicotine ditartrate in HR and LR rats using both a high (0.8 mg/kg; freebase) and a low dose (0.2 mg/kg; freebase). Male Sprague-Dawley rats were trained for the acquisition of nicotine-induced conditioned hyperactivity. After conditioned-hyperactivity testing, rats underwent extinction training to decrease hyperactivity by administering saline as a substitution for nicotine. Hyperactivity was then reinstated with a nicotine challenge (0.8 or 0.2 mg/kg). Pretreatment with nicotine during acquisition training significantly increased locomotor activity. Similarly, rats that had nicotine repeatedly paired with a distinct environment displayed significant conditioned hyperactivity and reinstatement of nicotine-induced hyperactivity. However, nicotine treatment was not found to differentially affect HR and LR rats. These data suggest that individual differences in response to an inescapable novel environment do not predict nicotine-induced locomotor sensitivity or sensitivity to nicotine-associated drug cues.

Individual differences in the sensitivity to serotonergic drugs: a pharmacobehavioural approach using rats selected on the basis of their response to novelty

RationaleThe mechanisms underlying individual differences in the response to serotonergic drugs are poorly understood. Rat studies may contribute to our knowledge of the neuronal substrates that underlie these individual differences.ObjectivesA pharmacobehavioural study was performed to assess individual differences in the sensitivity to serotonergic drugs in rats that were selected based on their response to a novel environment.MethodsLow responders (LR) and high responders (HR) to novelty rats were tested on the elevated T-maze following systemic injections of increasing doses of various serotonergic agents. The duration of avoidance of the open arms was scored for five trials.ResultsThe duration of avoidance behaviour was larger in saline-treated LR rats compared to saline-treated HR rats. The 5-HT1A agonist 8-OH-DPAT and the 5-HT2 agonists mCPP and DOI decreased the duration of avoidance behaviour in LR rats, but increased it in HR rats. The 5-HT3 agonist SR57227A and the 5-HT releaser/reuptake inhibitor d-fenfluramine increased the duration of avoidance behaviour in both types of rat. However, higher doses of SR57227A were required to alter avoidance behaviour in HR than in LR rats. The onset of the effects of SR57227A, d-fenfluramine and WAY100635 was faster in LR than in HR rats. The described effects were receptor specific. A model explaining the data is presented.ConclusionsThese data demonstrate that LR and HR rats differ in their sensitivity to serotonergic drugs that act at 5-HT3, 5-HT2 and 5-HT1A receptors. The implications of these individual differences for individual-specific treatment of substance abuse are briefly discussed.

The contribution of the central nucleus of the amygdala to individual differences in amphetamine-induced hyperactivity

Rats classified as high responders (HR) based on their response to an inescapable novel environment self-administer more amphetamine and have greater amphetamine-induced sensitization than rats classified as low responders (LR). Recent research suggests that the central nucleus of the amygdala (ACe) contributes to the elevated self-administration in HR rats. Therefore, the current study examined the role of the ACe in the expression of both amphetamine-induced sensitization and conditioned hyperactivity in HR and LR rats. Male Sprague–Dawley rats were screened for their response to inescapable novelty and classified as HR or LR rats. Rats were implanted with bilateral cannulae into the ACe and received amphetamine (1.0 mg/kg, s.c.) or saline injections immediately prior to 1-h locomotor sessions. Following five training sessions, all rats received an infusion of muscimol (0.5 μg/0.5 μl) or phosphate buffered saline (PBS) followed by a saline injection to measure conditioned hyperactivity. HR rats displayed conditioned hyperactivity, while LR rats did not, suggesting that HR and LR rats differ in the expression of conditioned hyperactivity. While ACe inactivation attenuated the expression of conditioned hyperactivity, it did not differentially affect HR and LR rats. Following additional training and a 10-day rest period, all rats were then tested for amphetamine-induced sensitization (1.0 mg/kg) following an infusion of muscimol or PBS. Inactivation of the ACe attenuated the expression of sensitization only in HR rats. These results suggest the ACe contributes to the greater amphetamine sensitization in HR rats.

Colocalisation of c-Fos and glucocorticoid receptor as well as of 5-HT 1A and glucocorticoid receptor immunoreactivity-expressing cells in the brain structures of low and high anxiety rats

We sought to determine the colocalisation of c-Fos (a marker of neuronal activation) and glucocorticoid receptors (GRs) as well as of 5-HT 1A and glucocorticoid receptor immunoreactivity-expressing cells (ir) in the dorsomedial prefrontal cortex (M2), dentate gyrus of the hippocampus (DG), and basolateral nucleus of the amygdala (BLA) in low and high anxiety rats (i.e., rats with duration of a freezing response in the conditioned fear test one standard error or more below or above the mean value: low responders (LR) and high responders (HR), respectively). It was found that 1.5 h after a testing session of the conditioned fear test, the LR animals had a higher activity of the cortical M2 area and DG (c-Fos), a higher expression of GRs-ir, as well as an increased number of cells co-expressing c-Fos and GRs-ir in the same brain areas. In the case of HR rats, they had similar expression of c-Fos in the BLA, but a significantly higher concentration of GRs-ir and c-Fos/GR colocalised neurons in the same amygdala nucleus. The pattern of distribution of 5-HT 1A and GR receptor-ir in LR and HR animals was similar to the c-Fos and GRs-ir expression. LR animals showed a higher density of 5-HT 1A and GRs-ir in the cortical M2 area and DG as well as an increased number of cells co-expressing 5-HT 1A and GR-ir in the same brain areas. HR rats had a significantly higher concentration of 5-HT 1A and GR-ir as well as a greater number of c-Fos/GR protein colocalised neurons in the BLA. The present data add to the arguments for the neurobiological background of differences in individual responses to aversive conditioned stimuli.