Biofilm exopolysaccharides alter sensory-neuron-mediated sickness during lung infection.

Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses to limit contact with contagious individuals. Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, we compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice. EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1+ sensory neurons. However, inflammation did not account for sickness. Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. Thus, EPS-producing biofilm pathogens evade initiating a lung-brain sensory neuronal response that results in sickness.

Dissociating reward sensitivity and negative urgency effects on impulsivity in the five-choice serial reaction time task.

Negative urgency describes the tendency for rash and impulsive behaviour during negative emotional states and has been linked to a number of psychiatric disorders. However, there has been limited research on negative urgency as an explanatory mechanism for impulsivity in experimental animals. Such research has important implications for elucidating the neurobiology of negative urgency and thereby the development of future therapeutic interventions. In this study, we investigated the effects of negative urgency using a partial reinforcement schedule to increase the frequency of non-rewarded (i.e. frustrative) trials in the five-choice serial reaction time task, a widely used task to assess visual attention and impulsivity. Using a Markov chain model to analyse trial-by-trial outcomes we found that premature (i.e. impulsive) responses in the five-choice serial reaction time task were more likely to occur after a non-rewarded trial, and mostly after a previous premature trial. However, contrary to the frustration hypothesis of negative urgency, increasing the probability of reinforcement (p(R)) from p(R) = 0.5 to p(R) = 1 increased the number of premature responses in each session. Micro and macro levels of analyses revealed that impulsivity in the five-choice serial reaction time task is governed by at least two processes, one dependent on the overall level of reinforcement hypothesised to determine the state of behavioural activation, the second dependent on trial-by-trial outcomes consistent with negative urgency effects. These processes may depend on distinct neurobiological mechanisms and have relevance for neuropsychiatric disorders that implicate impulsive behaviours dependent on positive and negative affective states.

Preconception paternal morphine exposure leads to an impulsive phenotype in male rat progeny.

RATIONALE: Identifying the long-term neurocognitive implications of opioid addiction may further our understanding of the compulsive nature of this brain disorder. The aim of this study was to examine the effects of paternal adolescent opiate exposure on cognitive performance (visual attention, impulsivity, and compulsivity) in the next generation. METHODS: Male Wistar rats received escalating doses of morphine (2.5-25 mg/kg, s.c.) or saline for 10 days during adolescence (P30-39). In adulthood (P70-80), these rats were allowed to mate with drug-naive females. Male offspring from morphine- and saline-exposed sires, once in adulthood, were trained and tested in the 5-choice serial reaction time test (5-CSRTT) to evaluate their cognitive abilities under baseline, drug-free conditions as well as following acute (1, 3, 5 mg/kg morphine) and subchronic morphine (5 mg/kg morphine for 5 days) treatment. Behavioral effects of the opioid receptor antagonist naloxone were also assessed. RESULTS: Morphine-sired offspring exhibited delayed learning when the shortest stimulus duration (1 s) was introduced, i.e., when cognitive load was highest. These subjects also exhibited a reduced ability to exert inhibitory control, as reflected by increased premature and perseverative responding under drug-free baseline conditions in comparison to saline-sired rats. These impairments could not be reversed by administration of naloxone. Moreover, impulsive behavior was further enhanced in morphine-sired rats following acute and subchronic morphine treatment. CONCLUSION: Paternal opiate exposure during adolescence was found to primarily impair inhibitory control in male progeny. These results further our understanding of the long-term costs and risk of opioid abuse, extending across generations.

Prenatal exposure to morphine impairs attention and impulsivity in adult rats.

RATIONALE: An alarming number of neonates born with prenatal exposure to morphine has resulted from the opioid epidemic; however, the long-term effects of prenatal opioid exposure on offspring behavior remain relatively unknown. In this study, we evaluated whether prenatal exposure to the mu opioid receptor agonist, morphine, has enduring effects on cognitive functions in adult life. METHODS: On embryonic days 11-18 (E11-E18), female pregnant rats were injected subcutaneously with either morphine or saline twice daily. Adult male offspring that was prenatally exposed to saline or morphine was trained in the 5-choice serial reaction time test (5-CSRTT) to test their cognitive abilities under baseline conditions. Next, these rats were treated with saline (1 ml/kg), naloxone (1 mg/kg), and acute morphine (1, 3, 5 mg/kg), subcutaneously, once daily and following drug challenges rats were tested in the 5-CSRTT. Meanwhile, behavioral performance on training days between opioid drug challenges were analyzed to monitor possible drug-induced shifts in baseline performance. As a final experiment in order to investigate subchronic exposure to morphine, rats were injected with 5 mg/kg morphine for 5 days and then naloxone in the last day of the experiment (day 6). RESULTS: Firstly, during acquisition of a stable baseline in the training phase, rats prenatally exposed to morphine showed delayed learning of the task demands. Furthermore, under baseline responding the rats prenatally exposed to morphine showed declined inhibitory control demonstrated by increased impulsive and compulsive-like responding compared to rats prenatally exposed to saline. Moreover, acute and subchronic morphine challenges in the rats prenatally exposed to morphine caused a deficit in visuospatial attention in comparison with saline treatment as well as the rats prenatally exposed to saline. These effects were abolished by naloxone. CONCLUSION: The current findings indicate a direct causal effect of prenatal morphine exposure on inhibitory control and task learning later in life, as well as deficits in attention following morphine exposure in adulthood.

Adaptive aspects of impulsivity and interactions with effects of catecholaminergic agents in the 5-choice serial reaction time task: implications for ADHD.

BACKGROUND: Work in humans has shown that impulsivity can be advantageous in certain settings. However, evidence for so-called functional impulsivity is lacking in experimental animals. AIMS: This study investigated the contexts in which high impulsive (HI) rats show an advantage in performance compared with mid- (MI) and low impulsive (LI) rats. We also assessed the effects of dopaminergic and noradrenergic agents to investigate underlying neurotransmitter mechanisms. METHODS: We tested rats on a variable inter-trial interval (ITI) version of the 5-choice serial reaction time task (5CSRTT). Rats received systemic injections of methylphenidate (MPH, 1 mg/kg and 3 mg/kg), atomoxetine (ATO, 0.3 mg/kg and 1 mg/kg), amphetamine (AMPH, 0.2 mg/kg), the alpha-2a adrenoceptor antagonist atipamezole (ATI, 0.3 mg/kg) and the alpha-1 adrenoceptor agonist phenylephrine (PHEN, 1 mg/kg) prior to behavioural testing. RESULTS: Unlike LI rats, HI rats exhibited superior performance, earning more reinforcers, on short ITI trials, when the task required rapid responding. MPH, AMPH and ATI improved performance on short ITI trials and increased impulsivity in long ITI trials, recapitulating the behavioural profile of HI. In contrast, ATO and PHEN impaired performance on short ITI trials and decreased impulsivity, thus mimicking the behavioural profile of LI rats. The effects of ATO were greater on MI rats and LI rats. CONCLUSIONS: These findings indicate that impulsivity can be advantageous when rapid focusing and actions are required, an effect that may depend on increased dopamine neurotransmission. Conversely, activation of the noradrenergic system, with ATO and PHEN, led to a general inhibition of responding.

The locus coeruleus noradrenergic system gates deficits in visual attention induced by chronic pain.

Despite years of research on pain comorbidity with affective disorders and cognitive deficits, it is still unclear how deficit in attention co-occurs with chronic pain. It is likely that altered neuroplasticity and or dysregulated neurotransmitters induced by chronic pain, at which pain and cognitive processing systems overlap, may have a negative effect on cognitive processing such as attention. One of the main common networks involved in attentional and pain processing is the noradrenergic system originating from the locus coeruleus (LC). We hypothesized that heightened noradrenaline release from LC induced by chronic pain could cause a deficit in visual attention. For this purpose, performance on the 5-choice serial reaction time test (5-CSRTT) was tested in animals with and without a chronic constriction injury and a selective depletion of noradrenaline in the LC. In addition, pain sensitivity was measured via mechanical allodynia and thermal hyperalgesia. We found that the increase in pain sensitivity following chronic pain correlates with a decline in executive functions as measured by 5-CSRTT. This was true in conditions of both low and high attentional demand. Interestingly, a selective depletion of noradrenaline in LC improved the attentional deficits caused by chronic pain. We argue that changes to the noradrenergic system originating in LC can improve deficits in visual attention induced by chronic pain. Deficit in attention is a common comorbidity among patients with chronic pain which adversely affects them in their family and work lives. Patients struggle with functional impairment due to pain, and deficite in attention adds to this dysfunction. Our findings identify the NE-LC system as a key mediator between chronic pain and the attentional deficits associated with this. This finding calls for further investigations concerning treatments related to the noradrenergic system to reduce the malicious effects of chronic pain.

Adolescent morphine exposure induces immediate and long-term increases in impulsive behavior.

RATIONALE: Adolescence in humans represents a unique and critical developmental time point associated with increased risk-taking behavior. Converging clinical and epidemiological studies report a peak of drug use during adolescence, leading to the hypothesis that the developing adolescents brain is at risk to lose control over drug intake. Both adolescence and drug abuse are associated with significant cognitive and psychological changes such as lack of impulse control. A simple definition for impulsive behavior is the tendency to act prematurely without foresight. Increase in impulsivity is evident in acute morphine consumption, but to date, little is known with respect to subchronic morphine administration in impulsive behavior, particularly comparing time-dependent effects in adults, young adults, and adolescents. METHODS: To evaluate this, adult, young adult, and adolescent rats were treated with a subchronic regimen of morphine or saline during 5 days (s.c.). Thereafter, we examined impulsive behavioral effects of morphine administration, 24 h and 25 days after administration in rats, while responding under a five-choice serial reaction time task (5-CSRTT). RESULTS: Subchronic morphine administration increased premature responding 24 h after the last injection of morphine in adult, young adult, and adolescent rats without increasing motor activity but a significant change in motivation in adult and young adult rats only. After 25 days of abstinence, premature responses were significantly increased in comparison with baseline in adolescent rats but not in adults and young adults. CONCLUSION: The main conclusion of this study is that morphine exposure in adolescents has a long-term profound effect on motor impulsive behavior later in adulthood. An implication of our findings might be that we should be especially careful about consuming and prescribing opioid drugs in adolescents.

Synergistic effect of spexin and progesterone on pain sensitivity attenuation in ovariectomized rats.

Spexin is a central modulator of nociception. The aim of the present study was to investigate the effect of intra-hippocampal CA3 (IHCA3) injection of spexin and spexin-progesterone co-administration on pain sensitivity in ovariectomized rat. Thirty-five adult female rats were divided into five groups. Sham: the animals received injection of 0.5 µL ACSF by IHCA3. Experiments 1 and 2: the animals received injection of 0.5 µL of spexin bilaterally (10 and 30 nmol/rat respectively). Experiments 3 and 4: the animals received injection of 0.5 µL of spexin bilaterally (10 and 30 nmol/rat respectively) + subcutaneous (s.c.) injection of progesterone (5 mg/kg). Ovariectomy was performed in all groups to eliminate the effects of cyclic changes in the female rats. The formalin test (formalin 2.5%) was performed following the administration of spexin and progesterone. Results showed that bilateral injection of spexin in IHCA3 at both concentrations a significant (P < .05) decrease in the pain sensitivity in the two phases of formalin test. Similarly, the bilateral injection of spexin in IHCA3 at both concentrations following the s.c. injection of progesterone significantly (P < .05) decreases pain sensitivity in two phases of the formalin test. This pain attenuation due to the co-administration of spexin and progesterone was more potent than spexin-induced analgesia. According to the present results, spexin has a modulatory effect on pain sensitivity, which becomes more pronounced by progesterone administration.