IU Indianapolis ScholarWorks :: Browsing by Subject "Sensitization"

Browsing by Subject "Sensitization"

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Basic symptoms of schizophrenia are related to symptoms of traumatic stress: A pivotal role of sensitization. An observational study
(Wolters Kluwer, 2022-07-15) Pec, Ondrej; Lysaker, Paul H.; Bob, Petr; Psychiatry, School of Medicine
Introduction: Subjective cognitive deficits have been broadly reported in schizophrenia and described by Huber as basic symptoms. It remains unclear however to what extent they may be related to psychosocial stressors including trauma. Methods: We assessed basic symptoms using the Frankfurt Complaint Questionnaire (FCQ) in a sample of 40 patients with schizophrenia. Trauma-related symptoms were assessed concurrently using the Trauma Symptom Checklist-40, symptoms of dissociation using the Dissociative Experiences Scale, and sensitization phenomena using the Complex Partial Seizure-like Symptoms Inventory and Limbic System Checklist-33. Psychotic symptoms were measured by Health of the Nation Outcome Scales. The dosage of antipsychotic medication was assessed in terms of equivalents of chlorpromazine, and antidepressant medication in terms of equivalents of fluoxetine. Spearman correlations were performed to explore the relationship between FCQ and other trauma-related measures. To determine the relative contributions of trauma-related symptoms to basic symptoms a linear regression analysis was performed. Results: The results showed that higher levels of basic symptoms of schizophrenia were associated with greater levels of symptoms of dissociation, traumatic stress, and sensitization or kindling-like processes in schizophrenia. Among the trauma-related variables, sensitization phenomena assessed with Complex Partial Seizure-like Symptoms Inventory were closely associated with basic symptoms. Discussion: These results indicate that basic symptoms measured by FCQ might be related to trauma. The potential of trauma to influence neurodevelopmental hypotheses of schizophrenia is discussed.
The cAMP transduction cascade mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: whole-cell and single-channel studies
(Society for Neuroscience, 1998-08-15) Lopshire, John C.; Nicol, Grant D.; Pharmacology and Toxicology, School of Medicine
Treatment with proinflammatory prostaglandin E2 (PGE2) produced a transient sensitization of whole-cell currents elicited by the vanilloid capsaicin. The intracellular signaling pathways that mediate the initiation of this PGE2-induced sensitization of the capsaicin-elicited current in rat sensory neurons are not well established. Treatment with either forskolin (100 nM to 10 microM) or membrane-permeant analogs of cAMP, 8-bromo-cAMP (8-Br-cAMP) and chlorphenylthio-cAMP (10 microM to 1 mM), transiently sensitized neuronal responses elicited by capsaicin in a manner analogous to that produced by PGE2. The duration of sensitization was lengthened with increasing concentrations of forskolin; however, higher concentrations of 8-Br-cAMP or chlorphenylthio-cAMP led to a shortening of sensitization. The inactive analog of forskolin, dideoxy-forskolin, had no effect on capsaicin responses. Inclusion of the inhibitor of protein kinase A in the recording pipette completely suppressed the sensitization produced by PGE2 or forskolin. In recordings from membrane patches in the cell-attached configuration, the bath application of capsaicin evoked single-channel currents in which the level of channel activity was concentration-dependent and had an EC50 of 1.4 microM. These single-channel currents evoked by capsaicin exhibited an apparent reversal potential of +4 mV and were blocked by the capsaicin antagonist capsazepine. Exposure of the sensory neuron to either PGE2 or forskolin produced a large and transient increase in the mean channel activity (NPo) elicited by capsaicin, although the unitary conductance remained unaltered. Taken together, these observations suggest that modulation of the capsaicin-gated channel by the cAMP-protein kinase A signaling pathway enhanced the gating of these channels and consequently resulted in the sensitization of the whole-cell currents.
Cell-Specific Spinophilin Function Underlying Striatal Motor Adaptations Associated with Amphetamine-Induced Behavioral Sensitization
(2022-07) Watkins, Darryl Shumon; Yamamoto, Bryan K.; Atwood, Brady K.; Baucum, Anthony J. II; Hudmon, Andy; Logrip, Marian L.
Striatal-mediated pathological disease-states such as Obsessive-Compulsive Disorder (OCD), Parkinson’s Disease (PD), and psychostimulant drug addiction/abuse are coupled with distinct motor movement abnormalities. In addition, these disorders are associated with perturbed synaptic transmission. Proper synaptic transmission is critical for maintaining neuronal communication. Furthermore, in many striatal-dependent disease-states, the principle striatal neurons, medium spiny neurons (MSNs), exhibit differential perturbations in downstream signaling. Signal transduction pathways that are localized to the glutamatergic post-synaptic density (PSD) of GABAergic MSNs regulate protein phosphorylation in a tightly controlled manner. Alterations in the control of this phosphorylation in striatal MSNs are observed in myriad striatal pathological diseasestates and can give rise to perturbations in synaptic transmission. While serine/threonine kinases obtain substrate specificity, in part, by phosphorylating specific consensus sites, serine/threonine phosphatases such as protein phosphatase 1 (PP1) are much more promiscuous. To obtain substrate selectivity, PP1 associates with targeting proteins. The major targeting protein for PP1 in the PSD of striatal dendritic spines is spinophilin. Spinophilin not only binds PP1, but also concurrently interacts with myriad synaptic proteins. Interestingly, dopamine depletion, an animal model of PD, modulates spinophilin protein-protein interactions in the striatum. However, spinophilin function on basal striatal-mediated motor behaviors such as the rotarod or under hyperdopaminergic states such as those observed following psychostimulant-induced behavioral sensitization are less well characterized. To elucidate spinophilin function more specifically, we have generated multiple transgenic animals that allow for cell type-specific loss of spinophilin as well as cell-specific interrogation of spinophilin protein interactions. Here, I report the functional role of spinophilin in regulating striatal mediated motor behaviors and functional changes associated with amphetamine-induced locomotor sensitization. In addition, we define changes in spinophilin protein-protein interactions that may mediate these behavioral changes. Furthermore, global loss of spinophilin abrogates amphetamine-induced sensitization and plays a critical role in striatal motor learning and performance. The data suggest that the striatal spinophilin protein interactome is upregulated in MSNs following psychostimulant administration. In addition, loss of spinophilin changes protein expression in myriad psychostimulant-mediated striatal adaptations. Taken together the data suggests that spinophilin’s protein-protein interactions in the striatum are obligate for appropriate striatal mediated motor function.
Developmental differences in hypothermic and behavioral responses to ethanol treatment in Alcohol Preferring and Non-Preferring Rats
(2012-08-30) Myers, Mallory Lynn; Goodlett, Charles R.; Murphy, James M.; Bell, Richard L.
Differences in voluntary consumption of ethanol have been negatively correlated with differences in initial sensitivity and tolerance to ethanol’s pharmacological effects. From this perspective, both adolescent and adult alcohol-nonpreferring (NP) rats would be expected to be initially more sensitive to the sedative and hypothermic effects of ethanol and fail to acquire tolerance to those effects than preferring (P) rats. The first objective of this experiment was to assess alcohol-induced hypothermia and locomotor sedation in adolescent and adult P and NP rats over five consecutive daily administrations (saline, 1.5 g/kg, or 3.0 g/kg ethanol 17%v/v), testing the hypothesis that the P rats would acquire tolerance to the hypothermic response whereas the NP rats would not show changes across days. In addition, it was hypothesized that there would be age-related differences in initial sensitivity to ethanol, evident by adolescent rats displaying less ethanol-induced hypothermia and locomotor sedation than adult rats on Day 1. The second objective was to determine if conditioning was occurring between the administration environment and the hypothermic response and locomotor sedation elicited by ethanol exposure, via a sixth injection of saline. Female rats were surgically implanted with intraperitoneal Mini Mitter telemetry probes on postnatal day 25 or 85 and experimental manipulations began five days later. Data were collected every minute; temperature data were then converted to change from baseline scores and locomotor data were totaled for each session. On Day 1, maximum temperature reduction elicited by the 3.0 g/kg dose was greater in the NP rats than the P rats, regardless of age. That dose also produced greater levels of locomotor sedation in the adult rats compared to the adolescent rats, regardless of line. The 1.5 g/kg dose of ethanol produced a greater hypothermic response in adult rats compared to adolescent rats, locomotor activity was reduced equally across the groups. With repeated administrations, NP adult rats displayed sensitization to the hypothermic response elicited from the 3.0 g/kg dose; in contrast, tolerance to the hypothermic response was found within the 1.5 g/kg dose for the adolescent P, adult P, and the adult NP rats. Repeated saline administrations also resulted in tolerance to the hypothermic response associated with administration in the adult NP and adolescent P rats. On the Day 6 saline administrations, adult rats which had previously been exposed to the 3.0 g/kg dose, maintained their baseline body temperatures better than both of the other exposure groups. Adolescent rats failed to show any signs of conditioning when administered saline on Day 6. Contrary to prediction the P rats failed to acquire tolerance to the 3.0 g/kg dose for either measure; and the line difference in ethanol-induce hypothermia was due to sensitization of the hypothermic response in adult NP rats. These results also provide further support that adolescent rats are less sensitive to the initial aversive effects of ethanol at the 1.5 g/kg dose for ethanol-induced hypothermia and the 3.0 g/kg dose for locomotor activity. The current experiment provides evidence that initial sensitivity as well as the acquisition of tolerance to ethanol-induced hypothermia may be behavioral phenotypes correlated with selection for high and low alcohol drinking preference.
The effect of voluntary binge caffeine and ethanol co-exposure on neurobehavioral sensitivity to cocaine in male C57BL/6J mice
(2016-05) Fritz, Brandon M.; Boehm, Stephen L., II; Czachowski, Cristine Lynn; Kinzig, Kimberly; Engleman, Eric A.; Grahame, Nicholas J.
Recently, the co-consumption of highly caffeinated energy drinks and alcohol has become a public health concern. Consumption of these beverages has been linked to a wide variety negative consequences including alcohol poisoning, driving under the influence, physical harm, and sexual violence. The more protracted consequences of caffeinated alcohol consumption have received very little attention, however. Some evidence suggests that individuals that frequently consume energy drinks mixed with alcohol are more likely to develop an alcohol use disorder. Interestingly, both caffeine and alcohol use alone have been linked to polydrug abuse. It is therefore of interest whether combined caffeine and alcohol consumption may pose an additive risk for substance abuse. Given that both compounds can positively influence dopamine signaling in mesolimbocortical reward circuitry via different mechanisms, this is an important question to address. Psychostimulants, such as cocaine, are of particular interest considering the significant involvement of dopamine in their effects. The current project explored this possibility employing an established mouse model of binge caffeine and alcohol co-consumption. Male C57BL/6J mice underwent 14 days of daily, 2hr limited access to water, alcohol, caffeine, or combined caffeine and alcohol. Water was freely available after these sessions. In Experiment 1, mice underwent an 11-day locomotor sensitization protocol for cocaine initiating on day 15. Locomotor sensitization has been associated with a greater propensity to self-administer psychostimulants in rodents. Mice were subjected to injections of cocaine (5 or 10 mg/kg; i.p.) or saline every other day, with 15 minute activity monitoring until day 25. In Experiment 2, a separate group of mice underwent an identical drinking procedure. A conditioned place preference (CPP) protocol commenced on day 15. CPP assesses the conditioned rewarding effects of cues associated with drugs of abuse. On day 15, mice received saline injections and were immediately placed onto a neutral floor texture (paper) in the place conditioning box for 15 minutes in order to habituate the animals to the apparatus and injection procedure. Starting on day 16, mice received daily alternating systemic injections of cocaine (1 or 5 mg/kg; i.p.) and saline or saline throughout (naïve controls) and were placed onto one of two particular tactile floor cues: a metal floor with holes punched out or a grid floor made of metal rods. Mice were exposed to the other injection/floor pairing on the alternate days. Mice were placed into these activity monitors for 15 minute conditioning sessions. These sessions alternated drug and vehicle over the course of 8 days so that a total of 4 drug and 4 saline injections were given. The first place preference test occurred on day 24 wherein all mice were injected with saline and offered access to both floor textures. On day 25, mice were returned to the conditioning protocol for another 8 days and a second CPP test on day 33. The results of Experiment 1 suggested that prior caffeine consumption, irrespective of the presence of ethanol, enhanced the initial psychomotor stimulating effect of 10 mg/kg cocaine. However, prior fluid consumption history did not influence the capacity to develop locomotor sensitization. The results of Experiment 2 indicate that prior caffeine and/or ethanol consumption had no influence on the development or expression of CPP for 1 mg/kg or 5 mg/kg cocaine. Collectively, these results suggest that a history of caffeine consumption may increase the stimulant response to a moderate dose of cocaine, perhaps indicating cross-sensitization. Although the conditioned rewarding effects of cocaine were not altered by prior caffeine and/or ethanol consumption, an enhanced stimulant response may be indicative of enhanced cocaine abuse potential. This study demonstrates that moderate caffeine consumption may influence an individual’s early interactions with cocaine which may eventually influence the likelihood of later problematic use.
Methamphetamine-induced deficits in social interaction are not observed following abstinence from single or repeated exposures
(Wolters Kluwer, 2015-12) Janetsian, Sarine S.; McCane, Aqilah M.; Linsenbardt, David N.; Lapish, Christopher C.; Department of Psychology, School of Science
The purpose of the current study was to assess social interaction (SI) following acute and repeated methamphetamine (MA) administration. Rats were injected with 5.0 mg/kg of MA and SI was tested 30 minutes or 24 hours later. In another group of animals, MA sensitization was induced using 5.0 mg/kg of MA, and SI was assessed after one day or thirty days of abstinence. SI was reduced in rats injected with MA 30 minutes, but not 24 hours, prior to testing, compared with saline controls. Impaired SI was observed in combination with active avoidance of the conspecific animal. Repeated injections of MA progressively reduced locomotor activity and increased stereotypy, indicating that animals were sensitized. However, no differences in SI were observed 24 hours or 30 days following the induction of sensitization. The absence of detectable differences in SI following MA sensitization may be attributable to the relatively short regimen used to induce sensitization. However, the current series of experiments provides evidence that an acute injection of MA decreases SI and simultaneously increases avoidance behavior, which supports a link between psychostimulant use and impaired social functioning. These data suggest that the acute injection model may provide a useful model to explore the neural basis of impaired social functioning and antisocial behavior.
Sphingosine 1-phosphate enhances the excitability of rat sensory neurons through activation of sphingosine 1-phosphate receptors 1 and/or 3
(Springer (Biomed Central Ltd.), 2015) Li, Chao; Li, Jun-nan; Kays, Joanne; Guerrero, Miguel; Nicol, Grant D.; Department of Pharmacology and Toxicology, IU School of Medicine
BACKGROUND: Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that acts through a family of five G-protein-coupled receptors (S1PR1-5) and plays a key role in regulating the inflammatory response. Our previous studies demonstrated that rat sensory neurons express the mRNAs for all five S1PRs and that S1P increases neuronal excitability primarily, but not exclusively, through S1PR1. This raises the question as to which other S1PRs mediate the enhanced excitability. METHODS: Isolated sensory neurons were treated with either short-interfering RNAs (siRNAs) or a variety of pharmacological agents targeted to S1PR1/R2/R3 to determine the role(s) of these receptors in regulating neuronal excitability. The excitability of isolated sensory neurons was assessed by using whole-cell patch-clamp recording to measure the capacity of these cells to fire action potentials (APs). RESULTS: After siRNA treatment, exposure to S1P failed to augment the excitability. Pooled siRNA targeted to S1PR1 and R3 also blocked the enhanced excitability produced by S1P. Consistent with the siRNA results, pretreatment with W146 and CAY10444, selective antagonists for S1PR1 and S1PR3, respectively, prevented the S1P-induced increase in neuronal excitability. Similarly, S1P failed to augment excitability after pretreatment with either VPC 23019, which is a S1PR1 and R3 antagonist, or VPC 44116, the phosphonate analog of VPC 23019. Acute exposure (10 to 15 min) to either of the well-established functional antagonists, FTY720 or CYM-5442, produced a significant increase in the excitability. Moreover, after a 1-h pretreatment with FTY720 (an agonist for S1PR1/R3/R4/R5), neither SEW2871 (S1PR1 selective agonist) nor S1P augmented the excitability. However, after pretreatment with CYM-5442 (selective for S1PR1), SEW2871 was ineffective, but S1P increased the excitability of some, but not all, sensory neurons. CONCLUSIONS: These results demonstrate that the enhanced excitability produced by S1P is mediated by activation of S1PR1 and/or S1PR3.
Tumor necrosis factor enhances the capsaicin sensitivity of rat sensory neurons
(Society for Neuroscience, 1997-02-01) Nicol, Grant D.; Lopshire, John C.; Pafford, Carl M.; Pharmacology and Toxicology, School of Medicine
The capacity of the proinflammatory cytokines, tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta), to modulate the sensitivity of isolated sensory neurons grown in culture to the excitatory chemical agent capsaicin was examined. Alterations in capsaicin sensitivity were assessed by quantifying the number of neurons labeled with cobalt after exposure to capsaicin and by recording the whole-cell response from a single neuron to the focal application of capsaicin. A 24 hr pretreatment of the neuronal cultures with TNF alpha (10 or 50 ng/ml), but not IL-1 beta (10 or 50 ng/ml), produced a concentration-dependent increase in the number of cobalt-labeled neurons after exposure to 100 nM capsaicin. The peak increase in the number of labeled neurons was attained after a 4 hr treatment with 10 ng/ml TNF alpha. Similarly, pretreatment with TNF alpha (10 ng/ml for 4, 12, and 24 hr) produced a greater than twofold increase in the average peak amplitude of the inward current evoked by 100 nM capsaicin. Both the TNF alpha-induced increase in labeling and current amplitude were blocked by treating the neuronal cultures with indomethacin before the addition of TNF alpha. Enhancement of the capsaicin-evoked current also was blocked by the specific cyclo-oxygenase-2 inhibitor SC-236. These results indicate that TNF alpha can enhance the sensitivity of sensory neurons to the excitation produced by capsaicin and that this enhancement likely is mediated by the neuronal production of prostaglandins. Isolated sensory neurons grown in culture may prove to be a useful model system in which to explore how prolonged exposure to mediators associated with chronic inflammation alter the regulatory pathways that modulate the excitability of the nervous system.
Ventral and dorsal striatal dopamine efflux and behavior in rats with simple vs. co-morbid histories of cocaine sensitization and neonatal ventral hippocampal lesions
(Springer Verlag, 2010-07-15) Chambers, Robert Andrew; Sentir, Alena M.; Engleman, Eric A.; Psychiatry, School of Medicine
xposing animal models of mental illness to addictive drugs provides an approach to understanding the neural etiology of dual diagnosis disorders. Previous studies have shown that neonatal ventral hippocampal lesions (NVHL) in rats produce features of both schizophrenia and addiction vulnerability. Objective This study investigated ventral and dorsal striatal dopamine (DA) efflux in NVHL rats combined with behavioral sensitization to cocaine. Methods Adult NVHL vs. SHAM-operated rats underwent a 5-day injection series of cocaine (15 mg/kg/day) vs. saline. One week later, rats were cannulated in nucleus accumbens SHELL, CORE, or caudate–putamen. Another week later, in vivo microdialysis sampled DA during locomotor testing in which a single cocaine injection (15 mg/kg) was delivered. Results NVHLs and cocaine history significantly increased behavioral activation approximately 2-fold over SHAM-saline history rats. DA efflux curves corresponded time dependently with the cocaine injection and locomotor curves and varied significantly by striatal region: Baseline DA levels increased 5-fold while cocaine-stimulated DA efflux decreased by half across a ventral to dorsal striatal gradient. However, NVHLs, prior cocaine history, and individual differences in behavior were not underpinned by differential DA efflux overall or within any striatal region.Conclusion Differences in ventral/dorsal striatal DA efflux are not present in and are not required for producing differential levels of acute cocaine-induced behavioral activation in NVHLs with and without a behaviorally sensitizing cocaine history. These findings suggest other neurotransmitter systems, and alterations in striatal network function post-synaptic to DA transmission are more important to understanding the interactive effects of addictive drugs and mental illness.

Browsing by Subject "Sensitization"

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