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Regional expressions of Fos-like immunoreactivity in rat cerebral cortex after stress; restraint and intraperitoneal lipopolysaccharide. Yokoyama C,Sasaki K Brain research To demonstrate regional activation in the rat cerebral cortex related to stress-evoked neuroendocrine response, Fos expression in both the cerebral cortex and hypothalamic paraventricular nucleus (PVN) was immunohistochemically examined in two experimental groups; a lipopolysaccharide (LPS) intraperitoneally injected group for inflammatory stress and a restraint group for emotional stress. The LPS injection (100 microg/100 g b.w.) and restraint (for 30 min) had similar effect on Fos-like immunoreactivity (Fos-LI) in PVN with regard to the number of immunoreactive nuclei and their distribution pattern, while the times to maximize Fos-LI were different. Numerical analysis of cortical Fos-LI in untreated rats showed a distinct region-specific pattern. Statistical analysis revealed no significant increase in Fos-LI density in any cortical regions in the LPS group, but restraint resulted in a dramatic and region-specific increase. A significant increase was detected in the prefrontal cortex (the cingulate, orbital and agranular insular cortex), the frontal area 2, the agranular retrosplenial cortex, the parietal cortex, and the medial and lateral occipital area 2. These results indicate that cortical activation relevant to specific functions may be involved in stress-specific neural circuitry. 10.1016/s0006-8993(98)00927-5
Role of catecholamines in the frontal cortex in the modulation of basal and stress-induced autonomic output in rats. Funk D,Stewart J Brain research Exposure of animals to noxious or stressful stimuli increases heart rate (HR) and blood pressure through activation of the autonomic nervous system (ANS) and elicits the release of the catecholamines noradrenaline (NA) and dopamine (DA) in the frontal cortex. Subregions of the frontal cortex, such as the medial frontal cortex (MFC) and agranular insular cortex (AIC) project directly to brainstem nuclei involved in autonomic control. It may be hypothesized that catecholamines in the frontal cortex could influence autonomic output through actions on these descending pathways. To evaluate this hypothesis, the effects of intracortical microinjections of drugs acting at NAergic and DAergic receptors were assessed on an autonomically mediated response, the increase in HR induced by tail pinch, in rats anesthetized with urethane. Intra-MFC or AIC injections of an antagonist of beta-adrenoceptors reduced the magnitude of the HR response to pinch. Injections of an agonist of beta-adrenoceptors into these regions increased basal HR but did not affect the pinch response. Injections of drugs acting at alpha-adrenoceptors were without effect. When injected alone, drugs acting at DAergic receptors did not effect basal HR or the response to pinch, but intra-AIC injections of a combination of a D2 antagonist and an agonist of beta-adrenoceptors increased the magnitude of the pinch response. These results suggest that catecholamines, especially NA, released in the frontal cortex are important modulators of the basal and stress-induced output of the ANS. 10.1016/s0006-8993(96)00931-6
Repeated forced swim stress enhances CFA-evoked thermal hyperalgesia and affects the expressions of pCREB and c-Fos in the insular cortex. Imbe H,Kimura A,Donishi T,Kaneoke Y Neuroscience Stress affects brain activity and promotes long-term changes in multiple neural systems. Exposure to stressors causes substantial effects on the perception and response to pain. In several animal models, chronic stress produces lasting hyperalgesia. The insular (IC) and anterior cingulate cortices (ACC) are the regions exhibiting most reliable pain-related activity. And the IC and ACC play an important role in pain modulation via the descending pain modulatory system. In the present study we examined the expression of phospho-cAMP response element-binding protein (pCREB) and c-Fos in the IC and ACC after forced swim stress (FS) and complete Freund's adjuvant (CFA) injection to clarify changes in the cerebral cortices that affect the activity of the descending pain modulatory system in the rats with stress-induced hyperalgesia. FS (day 1, 10min; days 2-3, 20min) induced an increase in the expression of pCREB and c-Fos in the anterior IC (AIC). CFA injection into the hindpaw after the FS shows significantly enhanced thermal hyperalgesia and induced a decrease in the expression of c-Fos in the AIC and the posterior IC (PIC). Quantitative image analysis showed that the numbers of c-Fos-immunoreactive neurons in the left AIC and PIC were significantly lower in the FS+CFA group (L AIC, 95.9±6.8; L PIC, 181.9±23.1) than those in the naive group (L AIC, 151.1±19.3, p<0.05; L PIC, 274.2±37.3, p<0.05). These findings suggest a neuroplastic change in the IC after FS, which may be involved in the enhancement of CFA-induced thermal hyperalgesia through dysfunction of the descending pain modulatory system. 10.1016/j.neuroscience.2013.11.045
Differential Involvement of the Agranular vs Granular Insular Cortex in the Acquisition and Performance of Choice Behavior in a Rodent Gambling Task. Pushparaj Abhiram,Kim Aaron S,Musiol Martin,Zangen Abraham,Daskalakis Zafiris J,Zack Martin,Winstanley Catharine A,Le Foll Bernard Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Substance-related and addictive disorders, in particular gambling disorder, are known to be associated with risky decision-making behavior. Several neuroimaging studies have identified the involvement of the insular cortex in decision-making under risk. However, the extent of this involvement remains unclear and the specific contributions of two distinct insular subregions, the rostral agranular (RAIC) and the caudal granular (CGIC), have yet to be examined. Animals were trained to perform a rat gambling task (rGT), in which subjects chose between four options that differed in the magnitude and probability of rewards and penalties. In order to address the roles of the RAIC and CGIC in established choice behavior, pharmacological inactivations of these two subregions via local infusions of GABA receptor agonists were performed following 30 rGT training sessions. The contribution made by the RAIC or CGIC to the acquisition of choice behavior was also determined by lesioning these areas before behavioral training. Inactivation of the RAIC, but not of the CGIC, shifted rats' preference toward options with greater reward frequency and lower punishment. Before rGT acquisition, lesions of the RAIC, but not the CGIC, likewise resulted in a higher preference for options with greater reward frequency and lower punishment, and this persisted throughout the 30 training sessions. Our results provide confirmation of the involvement of the RAIC in rGT choice behavior and suggest that the RAIC may mediate detrimental risky decision-making behavior, such as that associated with addiction and gambling disorder. 10.1038/npp.2015.133
Role of the agranular insular cortex in contextual control over cocaine-seeking behavior in rats. Arguello Amy A,Wang Rong,Lyons Carey M,Higginbotham Jessica A,Hodges Matthew A,Fuchs Rita A Psychopharmacology RATIONALE:Environmental stimulus control over drug relapse requires the retrieval of context-response-cocaine associations, maintained in long-term memory through active reconsolidation processes. Identifying the neural substrates of these phenomena is important from a drug addiction treatment perspective. OBJECTIVES:The present study evaluated whether the agranular insular cortex (AI) plays a role in drug context-induced cocaine-seeking behavior and cocaine memory reconsolidation. METHODS:Rats were trained to lever press for cocaine infusions in a distinctive context, followed by extinction training in a different context. Rats in experiment 1 received bilateral microinfusions of vehicle or a GABA agonist cocktail (baclofen and muscimol (BM)) into the AI or the overlying somatosensory cortex (SSJ, anatomical control region) immediately before a test of drug-seeking behavior (i.e., non-reinforced lever presses) in the previously cocaine-paired context. The effects of these manipulations on locomotor activity were also assessed in a novel context. Rats in experiment 2 received vehicle or BM into the AI after a 15-min reexposure to the cocaine-paired context, intended to reactivate context-response-cocaine memories and initiate their reconsolidation. The effects of these manipulations on drug context-induced cocaine-seeking behavior were assessed 72 h later. RESULTS:BM-induced pharmacological inactivation of the AI, but not the SSJ, attenuated drug context-induced reinstatement of cocaine-seeking behavior without altering locomotor activity. Conversely, AI inactivation after memory reactivation failed to impair subsequent drug-seeking behavior and thus cocaine memory reconsolidation. CONCLUSIONS:These findings suggest that the AI is a critical element of the neural circuitry that mediates contextual control over cocaine-seeking behavior. 10.1007/s00213-017-4632-7
The neural consequences of repeated cocaine exposure revealed by functional MRI in awake rats. Febo Marcelo,Segarra Annabell C,Nair Govind,Schmidt Karl,Duong Timothy Q,Ferris Craig F Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology The use of functional magnetic resonance imaging (fMRI) in animal models of cocaine addiction is an invaluable tool for investigating the neuroadaptations that lead to this psychiatric disorder. We used blood-oxygen-level-dependent (BOLD) MRI in awake rats to identify the neuronal circuits affected by repeated cocaine administration. Rats were given an injection of cocaine (15 mg/kg, i.p.) or its vehicle for 7 days, abstained from injections for 1 week, and challenged with an intracerebroventricular cocaine injection during functional imaging. Acute cocaine produced robust positive BOLD responses across well-known monoamine-enriched brain regions, such as the prefrontal cortex, nucleus accumbens, dorsal striatum, sensory cortex, hippocampus, thalamus, and midbrain areas. However, repeated cocaine administration resulted in lower BOLD responses in the prefrontal cortex, agranular insular cortex, nucleus accumbens, ventral pallidum, and dorsomedial thalamus, among other brain regions. Reductions in BOLD intensity were not associated with variations in cerebrovascular reactivity between drug naive rats and those repeatedly exposed to cocaine. Therefore, the lower metabolic activation in response to cocaine could reflect a reduced neuronal and/or synaptic activity upon repeated administration. 10.1038/sj.npp.1300653
Context-dependent prefrontal cortex regulation of cocaine self-administration and reinstatement behaviors in rats. Di Pietro Nina C,Black Yolanda D,Kantak Kathleen M The European journal of neuroscience Evidence of stimulus attribute-specificity within the prefrontal cortex (PFC) suggests that different prefrontal subregions may contribute to cocaine addiction in functionally distinct ways. Thus, the present study examined the effects of lidocaine-induced inactivation of two distinct PFC subregions, the prelimbic (PL) or dorsal agranular insular (AId) cortices, on drug-seeking and drug-taking behaviors under cocaine maintenance and reinstatement testing conditions in rats trained to self-administer 1 mg/kg cocaine under a second-order schedule of drug delivery. Throughout maintenance and reinstatement phases, rats were exposed to conditioned light cues and contextual odor or sound cues. Results showed that PL inactivation during maintenance test sessions significantly reduced drug-seeking and drug-taking behaviors, and disrupted patterns of responding in rats exposed to light-sound, but not light-odor, cues. Moreover, lidocaine-induced inactivation of the PL significantly attenuated drug-seeking behavior during cue-induced and cocaine prime-induced reinstatement in rats exposed to light-sound cues only. In contrast, AId inactivation significantly attenuated cue-induced reinstatement of drug-seeking behavior in rats exposed to light-odor cues only. Drug-seeking and drug-taking behaviors in these rats were not disrupted during maintenance and cocaine prime-induced reinstatement testing regardless of the type of contextual cues used. Together, these data suggest that PL and AId subregions play separate yet overlapping roles in regulating cocaine addiction in rats in ways that are dependent on the presence or absence of cocaine and on the types of contextual cues present in the cocaine self-administration environment. 10.1111/j.1460-9568.2006.05193.x
Brain regions associated with the acquisition of conditioned place preference for cocaine vs. social interaction. El Rawas Rana,Klement Sabine,Kummer Kai K,Fritz Michael,Dechant Georg,Saria Alois,Zernig Gerald Frontiers in behavioral neuroscience Positive social interaction could play an essential role in switching the preference of the substance dependent individual away from drug related activities. We have previously shown that conditioned place preference (CPP) for cocaine at the dose of 15 mg/kg and CPP for four 15-min episodes of social interaction were equally strong when rats were concurrently conditioned for place preference by pairing cocaine with one compartment and social interaction with the other. The aim of the present study was to investigate the differential activation of brain regions related to the reward circuitry after acquisition/expression of cocaine CPP or social interaction CPP. Our findings indicate that cocaine CPP and social interaction CPP activated almost the same brain regions. However, the granular insular cortex and the dorsal part of the agranular insular cortex were more activated after cocaine CPP, whereas the prelimbic cortex and the core subregion of the nucleus accumbens were more activated after social interaction CPP. These results suggest that the insular cortex appears to be potently activated after drug conditioning learning while activation of the prelimbic cortex-nucleus accumbens core projection seems to be preferentially involved in the conditioning to non-drug stimuli such as social interaction. 10.3389/fnbeh.2012.00063
Short-term memory for food reward magnitude: the role of the prefrontal cortex. DeCoteau W E,Kesner R P,Williams J M Behavioural brain research Memory for magnitude of reinforcement was assessed in rats using a go/no-go short-term memory paradigm. During the task's study phase rats were given a piece of cereal comprised of either 25 or 50% sugar. For all trials, one of the cereal types was designated positive, the other negative. On the ensuing test phase the rat was presented with an object which covered a food well. If a positive food reward was given during the study phase, a second food reward was placed beneath the object. No food reward was placed under the object if the study phase consisted of a negative food reward. Latency to object displacement was used as the measure of performance. Following the establishment of a significant difference between latency to approach the object with reward compared to latency to approach the object without reward, rats were given either agranular insular cortex, anterior cingulate cortex, pre- and infralimbic cortex or control lesions. Agranular insular cortex lesioned animals demonstrated a mild post-surgery impairment. Trials consisting of 10 and 20 s delays between the study and test phases were then introduced. Delays exacerbated the previous deficit of the agranular insular cortex lesion group, but had little effect on the other lesion groups. All animals transferred to a new set of cereals containing 25 and 50% sugar and exhibited taste preferences to sugar solutions of different concentrations. These results indicate that the agranular insular cortex may play an important role in the processing of affect-laden information within a prefrontal cortex short-term or working memory system.
Withdrawal from chronic ethanol exposure increases postsynaptic glutamate function of insular cortex projections to the rat basolateral amygdala. McGinnis Molly M,Parrish Brian C,McCool Brian A Neuropharmacology A key feature of alcohol use disorder (AUD) is negative affect during withdrawal, which often contributes to relapse and is thought to be caused by altered brain function, especially in circuits that are important mediators of emotional behaviors. Both the agranular insular cortex (AIC) and the basolateral amygdala (BLA) regulate emotions and are sensitive to ethanol-induced changes in synaptic plasticity. The AIC and BLA are reciprocally connected; and the effects of chronic ethanol exposure on this circuit have yet to be explored. Here, we use a combination of optogenetics and electrophysiology to examine the pre- and postsynaptic changes that occur to AIC-BLA synapses following withdrawal from 7- or 10-days of chronic intermittent ethanol (CIE) exposure. While CIE/withdrawal did not alter presynaptic glutamate release probability from AIC inputs, withdrawal from 10, but not 7, days of CIE increased AMPA receptor-mediated postsynaptic function at these synapses. Additionally, NMDA receptor-mediated currents evoked by electrical stimulation of the external capsule, which contains AIC afferents, were also increased during withdrawal. Notably, a single subanesthetic dose of ketamine administered at the onset of withdrawal prevented the withdrawal-induced increases in both AMPAR and NMDAR postsynaptic function. Ketamine also prevented the withdrawal-induced increases in anxiety-like behavior measured using the elevated zero maze. Together, these findings suggest that chronic ethanol exposure increases postsynaptic function within the AIC-BLA circuit and that ketamine can prevent ethanol withdrawal-induced alterations in synaptic plasticity and negative affect. 10.1016/j.neuropharm.2020.108129
A role for the insular cortex in long-term memory for context-evoked drug craving in rats. Contreras Marco,Billeke Pablo,Vicencio Sergio,Madrid Carlos,Perdomo Guetón,González Marcela,Torrealba Fernando Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Drug craving critically depends on the function of the interoceptive insular cortex, and may be triggered by contextual cues. However, the role of the insula in the long-term memory linking context with drug craving remains unknown. Such a memory trace probably resides in some neocortical region, much like other declarative memories. Studies in humans and rats suggest that the insula may include such a region. Rats chronically implanted with bilateral injection cannulae into the high-order rostral agranular insular cortex (RAIC) or the primary interoceptive posterior insula (pIC) were conditioned to prefer the initially aversive compartment of a 2-compartment place preference apparatus by repeatedly pairing it to amphetamine. We found a reversible but long-lasting loss (ca. 24 days) of amphetamine-conditioned place preference (CPP) and a decreased expression in the insula of zif268, a crucial protein in memory reconsolidation, when anisomycin (ANI) was microinjected into the RAIC immediately after the reactivation of the conditioned amphetamine/context memory. ANI infusion into the RAIC without reactivation did not change CPP, whereas ANI infusion into pIC plus caused a 15 days loss of CPP. We also found a 24 days loss of CPP when we reversibly inactivated pIC during extinction trials. We interpret these findings as evidence that the insular cortex, including the RAIC, is involved in a context/drug effect association. These results add a drug-related memory function to the insular cortex to the previously found role of the pIC in the perception of craving or malaise. 10.1038/npp.2012.59
Role of insular cortex D₁ and D₂ dopamine receptors in nicotine self-administration in rats. Kutlu Munir G,Burke Dennis,Slade Susan,Hall Brandon J,Rose Jed E,Levin Edward D Behavioural brain research The insular cortex has been associated with the processing of rewarding stimuli and with the neural bases of drug addiction. Ischemic damage to the insula has been associated with decreased desire to smoke cigarettes. Which component of insular function is involved in the neural basis of cigarette smoking is not clear. Dopamine systems are crucial for the reinforcing value of addictive drugs. The DA projection from the ventral tegmental area to the nucleus accumbens (NAc) has been shown to be a vital pathway for the primary reinforcement caused by taking a variety of abused drugs. In the current set of studies, the roles of D₁ and D₂ receptors in the insular cortex in the self-administration of nicotine by rats were assessed. Adult female Sprague-Dawley rats were fitted with jugular catheters and given access to self-administer nicotine. Bilateral local infusion cannulae were implanted into the agranular insular cortex to locally administer D₁ and D₂ antagonists (SCH-23390 and haloperidol). Acute local infusions of the D₁ antagonist SCH-23390 into the insula (1-2 μg/side) significantly decreased nicotine self-administration by more than 50%. Repeated infusions of SCH-23390 into the agranular insula caused continuing decreases in nicotine self-administration without signs of tolerance. In contrast, local infusions of the D₂ antagonist haloperidol 0.5-2 μg/side did not have any discernable effect on nicotine self-administration. These studies show the importance of DA D₁ systems in the insula for nicotine reward. 10.1016/j.bbr.2013.08.005
Organization of endogenous opioids in the rostral agranular insular cortex of the rat. Evans Joshua M,Bey Vincent,Burkey Adam R,Commons Kathryn G The Journal of comparative neurology The rostral agranular insular cortex (RAIC) of rats has opioid receptors and has been implicated in the analgesic and reinforcing effects of opiates. To help in understanding the function of endogenous opioids in this structure, we sought to identify and describe the opioid peptides intrinsic to the RAIC by using immunohistochemical methods. Immunolabeling for proopiomelanocortin (POMC), the precursor to beta-endorphin, and endomorphin 1 and 2 on sectioned rat forebrain revealed limited labeling consisting of individual varicose fibers. Immunolabeling for prodynorphin and enkephalin revealed numerous immunopositive cell bodies and fibers with distribution and morphology unique to each. Prodynorphin-immunopositive cell bodies consisted of two types: large, lightly labeled, pyramidal-shaped cell bodies in lamina V and more intensely labeled, small, ovoid cell bodies scattered in other lamina. Axonal fibers immunolabeled for prodynorphin varied in size and were found in all lamina. Immunolabeling for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) was rarely found in dynorphin-containing cell bodies (6%, 10/167) but was visible within a subpopulation of axons. Enkephalin immunolabeling was detected within a single morphological subpopulation of nonpyramidal neurons located predominantly in lamina II/III, 30% (33/109) of which were also GABA immunopositive. Axons immunolabeled for enkephalin were also abundant in lamina II/III. These results suggest that dynorphin and enkephalin peptides are the predominant endogenous opioids in the RAIC and their distinct distributions suggest divergent functional roles. The localization of prodynorphin immunoreactivity to pyramidal cells suggests the possibility that this neuropeptide may be used in RAIC projection neurons, whereas enkephalin distribution was more characteristic of a role in local networks. 10.1002/cne.21197
Functional Heterogeneity within Rat Orbitofrontal Cortex in Reward Learning and Decision Making. Izquierdo Alicia The Journal of neuroscience : the official journal of the Society for Neuroscience Rat orbitofrontal cortex (OFC) is located in the dorsal bank of the rhinal sulcus, and is divided into the medial orbital area, ventral orbital area, ventrolateral orbital area, lateral orbital area, dorsolateral orbital area, and agranular insular areas. Over the past 20 years, there has been a marked increase in the number of publications focused on the functions of rat OFC. While collectively this extensive body of work has provided great insight into the functions of OFC, leading to theoretical and computational models of its functions, one issue that has emerged relates to what is defined as OFC because targeting of this region can be quite variable between studies of appetitive behavior, even within the same species. Also apparent is that there is an oversampling and undersampling of certain subregions of rat OFC for study, and this will be demonstrated here. The intent of the Viewpoint is to summarize studies in rat OFC, given the diversity of what groups refer to as "OFC," and to integrate these with the findings of recent anatomical studies. The primary aim is to help discern functions in reward learning and decision-making, clearing the course for future empirical work. 10.1523/JNEUROSCI.1678-17.2017
Nicotine-induced dendritic remodeling in the insular cortex. Ehlinger Daniel G,Bergstrom Hadley C,McDonald Craig G,Smith Robert F Neuroscience letters The insular cortex has emerged as a novel target for nicotine addiction research. One unresolved question about the insular cortex is whether its neurons exhibit nicotine-induced dendritic remodeling similar to other brain regions implicated in nicotine addiction. To test this question, Long-Evans rats were administered nicotine via osmotic pump for two weeks. Thirty-seven days following the end of nicotine dosing, rats were sacrificed for Golgi-Cox staining and pyramidal neurons from the rostral agranular insular cortex were digitally reconstructed in three dimensions. Results from morphometric analyses revealed an increased complexity of dendrites in the insular cortex following nicotine. Increases were found for both total dendrite length and number of bifurcations. Sholl analyses revealed these changes depended on the distance from the soma, with the most prominent changes distributed at distal points along the dendritic tree. A follow-up comparison of length and bifurcation measurements from Sholl analyses suggested that new dendritic branches, rather than growth of existing dendrites, most likely contributed to overall changes in complexity. No change in dendrite morphology was found for apical dendrites. Together, these results show the insular cortex is a target for neuroplasticity following nicotine exposure. 10.1016/j.neulet.2012.03.064
Involvement of the serotonergic type 1A (5-HT1A) receptor in the agranular insular cortex in the consolidation of memory for inhibitory avoidance in rats. Mello e Souza T,Rodrigues C,Souza M M,Vinadé E,Coitinho A,Choi H,Izquierdo I Behavioural pharmacology Adult male Wistar rats were bilaterally implanted with indwelling cannulae in the agranular insular cortex of the prefrontal cortex. After recovery, animals were trained in a step-down inhibitory avoidance task (3.0-s, 0.4-mA footshock) and received, immediately after training, a 0.5-microl infusion of the serotonergic type 1A (5-HT1A) receptor agonist dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) or of the 5- HT1A receptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN-190), or of vehicle alone (20% DMSO). Retention testing was carried out 24 h after training. 8-OH-DPAT (1.25 and 6.25 microg but not 0.0125 or 0.125 microg) was amnesic. NAN-190 was not effective at 0.125 or 1.25 microg any dose but reversed amnesia when given at 1.250 microg simultaneously with both effective doses of 8-OH-DPAT. These results show that an overactivation of 5-HT1A receptors in the agranular insular cortex impairs memory consolidation of inhibitory avoidance, in rats, immediately after training. This suggests that these receptors of the insular cortex may modulate memory consolidation. 10.1097/00008877-200109000-00006
Role of dopamine D1 receptors in the prefrontal dorsal agranular insular cortex in mediating cocaine self-administration in rats. Di Pietro Nina C,Mashhoon Yasmin,Heaney Chelcie,Yager Lindsay M,Kantak Kathleen M Psychopharmacology RATIONALE:Orbital/insular areas of the prefrontal cortex (PFC) are implicated in cocaine addiction. However, the role of dopamine D1 receptors in mediating cocaine self-administration in these sub-regions remains unknown. OBJECTIVES:To define the role of the dorsal agranular insular (AId) sub-region of the PFC, we investigated the effects of D1 receptor manipulation on self-administration behavior maintained by cocaine and cocaine-related stimuli. MATERIALS AND METHODS:Rats were trained to lever press for cocaine (1 mg/kg) under a fixed-interval 5-min (fixed-ratio 5:S) second-order schedule of reinforcement in the presence of conditioned light cues and contextual sound cues. Intra-AId infusions of vehicle, the D1-like receptor agonist SKF 81297 (0.1, 0.2, 0.4 microg/side) or the D1-like receptor antagonist SCH 23390 (1.0, 2.0, 4.0 microg/side), were administered prior to 1-h self-administration test sessions. Food-maintained responding under a second-order schedule was examined in separate rats to determine if pretreatment with D1 ligands produced general impairments in responding. RESULTS:Infusion of SKF 81297 (0.2 and 0.4 microg/side) reduced active lever responses during the first 30 min of 1-h test sessions, but did not influence cocaine intake. Infusion of 4.0 microg/side SCH 23390 reduced active lever responses and cocaine intake throughout the 1-h test sessions. Additionally, this dose of SCH 23390 disrupted food-maintained responding and intake. CONCLUSIONS:D1 receptor agonists and antagonists in the AId have diverse consequences and time courses of action. D1 receptor stimulation in the AId may reduce the motivating influence of cocaine-related stimuli on responding whereas D1 receptor blockade in this PFC sub-region produces global disruptions in behavior. 10.1007/s00213-008-1149-0
Differential alterations of insular cortex excitability after adolescent or adult chronic intermittent ethanol administration in male rats. Luo Yi-Xiao,Galaj Ewa,Ma Yao-Ying Journal of neuroscience research Adolescent alcohol drinking, primarily in the form of binge-drinking episodes, is a serious public health concern. Binge drinking in laboratory animals has been modeled by a procedure involving chronic intermittent ethanol (CIE) administration, as compared with chronic intermittent water (CIW). The prolonged effects of adolescent binge alcohol exposure in adults, such as high risk of developing alcohol use disorder, are severe but available treatments in the clinic are limited. One reason is the lack of sufficient understanding about the associated neuronal alterations. The involvement of the insular cortex, particularly the anterior agranular insula (AAI), has emerged as a critical region to explain neuronal mechanisms of substance abuse. This study was designed to evaluate the functional output of the AAI by measuring the intrinsic excitability of pyramidal neurons from male rats 2 or 21 days after adolescent or adult CIE treatment. Decreases in intrinsic excitability in AAI pyramidal neurons were detected 21 days, relative to 2 days, after adolescent CIE. Interestingly, the decreased intrinsic excitability in the AAI pyramidal neurons was observed 2 days after adult CIE, compared to adult CIW, but no difference was found between 2 versus 21 days after adult CIE. These data indicate that, although the AAI is influenced within a limited period after adult but not adolescent CIE, neuronal alterations in AAI are affected during the prolonged period of withdrawal from adolescent but not adult CIE. This may explain the prolonged vulnerability to mental disorders of subjects with an alcohol binge history during their adolescent stage. 10.1002/jnr.24737
The role of the agranular insular cortex in anticipation of reward contrast. Neurobiology of learning and memory Sixteen male Long-Evans rats were tested on a modified version of Flaherty et al.'s [Flaherty, C. F., Turovsky, J., & Krauss, K. L. (1994). Relative hedonic value modulates anticipatory contrast. Physiology and Behavior, 55, 1047-1054.] anticipatory contrast paradigm to assess memory for the anticipation of reward. Prior to testing each rat received either a control or quinolinic acid induced lesion of the agranular insular cortex. In the home cage, each rat was allowed to drink a water solution containing 2% sucrose for 3 min followed by a water solution containing 32% sucrose for 3 min. Across 10 days of testing, the control rats showed significantly increased anticipatory discriminability as a function of days. In contrast, rats with agranular insular cortex lesions failed to show anticipatory discriminability. The results of a preference task revealed that both groups could perceptually discriminate between a 2% and a 32% sucrose solution. The data suggest that the agranular insular cortex may be involved in the anticipation of reward. 10.1016/j.nlm.2007.02.002
A biopsychological review of gambling disorder. Quintero Gabriel C Neuropsychiatric disease and treatment The present review is an overview of previous experimental work on biopsychological aspects of gambling disorder. It includes the topics 1) gambling disorder from the neuroimaging and electroencephalography (EEG) perspective, 2) cognitive, executive functioning, and neuropsychological aspects of gambling disorder, and 3) rodent models of gambling disorder. Penalties and losses in gambling can differ in terms of brain activity. Also, specific patterns of brain activity, brain anatomical traits, EEG responses, and cognitive and executive performance can discriminate pathological gamblers from nonpathological gamblers. Also, pathological gamblers can display dysfunction in such brain areas as the insula, frontal lobe, and orbitofrontal cortex. Pathological gambling is a heterogeneous disorder that can vary depending on the severity of cognition, the style of gambling (strategic or not), the prospect of recovery, proneness to relapse, and proneness to treatment withdrawal. Finally, based on rodent models of gambling, the appropriateness of gambling decision is influenced by the presence of cues, the activity of dopamine receptors, and the activity of some brain areas (infralimbic, prelimbic, or rostral agranular insular cortex). Pathological gamblers differed in terms of frontoparietal brain activation compared to nonpathological gamblers (if winning or losing a game). Pathological gamblers had dysfunctional EEG activity. The severity of gambling was linked to the magnification and content of cognitive distortions. The insula was fundamental in the distortion of cognitions linked to result analysis during gambling activity. 10.2147/NDT.S118818
Antinociceptive tolerance to NSAIDs in the agranular insular cortex is mediated by opioid mechanism. Pirkulashvili Natia,Tsiklauri Nana,Nebieridze Marina,Tsagareli Merab G Journal of pain research Several lines of investigations have shown that in some brain areas, in particular, in the midbrain periaqueductal gray matter, rostral ventromedial medulla, central nucleus of amygdala, nucleus raphe magnus, and dorsal hippocampus, microinjections of nonsteroidal anti-inflammatory drugs (NSAIDs) induce antinociception with distinct development of tolerance. The agranular insular cortex (AIC) is a small region of the cerebral cortex located on the lateral area of the rat's cerebral hemisphere that is involved in the perception and response to pain. In the present study, we investigated the development of tolerance to the analgesic effects of NSAIDs diclofenac, ketorolac, and xefocam microinjected into the AIC in rats. Male Wistar rats receiving NSAIDs into the AIC were tested for antinociception by tail-flick and hot plate tests. Treatment with each NSAID significantly enhanced the tail-flick and hot plate latencies on the first day, followed by a progressive decrease in the analgesic effect over a 4-day period, ie, they developed tolerance. Pretreatment with an opioid antagonist naloxone completely prevented, and posttreatment naloxone abolished, the analgesic effects of the three NSAIDs in both behavioral assays. These findings support the notion that the development of tolerance to the antinociceptive effects of NSAIDs is mediated via an endogenous opioid system possibly involving descending pain modulatory systems. 10.2147/JPR.S138360
Effects of inactivating the agranular or granular insular cortex on the acquisition of the morphine-induced conditioned place preference and naloxone-precipitated conditioned place aversion in rats. Li Chun-Lu,Zhu Ning,Meng Xiao-Lu,Li Yong-Hui,Sui Nan Journal of psychopharmacology (Oxford, England) Recent studies have indicated that the insula underlies affective learning. Although affective learning is well-established in the development of opiate addiction, the role of insula in this context remains unclear. To elucidate the organization of opiate-related affective learning within the insular cortex, we reversibly inactivated each of two major subdivisions of the insula in rats and tested the effects of this inactivation on the acquisition of morphine-induced conditioned place preference (CPP) and conditioned place aversion (CPA) induced by naloxone-precipitated acute morphine withdrawal. Results showed that inactivation of the primary interoceptive posterior granular insula (GI), but not that of the high-order anterior agranular insula (AI), disrupted the acquisition of CPP and that both GI and AI inactivation impaired the acquisition of CPA. These data suggest that the insular cortex is involved in positive and negative affective learning related to opiate addiction. In particular, the GI appears to be critical for both forms of affective learning, whereas the AI is crucial for learning associated with negative affects induced by opiate withdrawal. 10.1177/0269881113492028
Involvement of the rostral agranular insular cortex in nicotine self-administration in rats. Pushparaj Abhiram,Kim Aaron S,Musiol Martin,Trigo Jose M,Le Foll Bernard Behavioural brain research Our prior work demonstrated the involvement of the caudal granular subregion of the insular cortex in a rat model of nicotine self-administration. Recent studies in various animal models of addiction for nicotine and other drugs have identified a role for the rostral agranular subregion (RAIC). The current research was undertaken to examine the involvement of the RAIC in a rat model of nicotine self-administration. We investigated the inactivating effects of local infusions of a γ-aminobutyric acid agonist mixture (baclofen/muscimol) into the RAIC on nicotine self-administration under a fixed-ratio 5 (FR-5) schedule and on reinstatement of nicotine seeking induced by nicotine-associated cues in rats. We also evaluated the effects of RAIC inactivation on food self-administration under an FR5 schedule as a control. Inactivation of the RAIC decreased nicotine, but not food, self-administration. RAIC inactivation also prevented the reinstatement, after extinction, of nicotine seeking induced by nicotine-associated cues. Our study indicates that the RAIC is involved in nicotine-taking and nicotine-seeking in rats. Modulating insular cortex function appears to be a promising approach for nicotine dependence treatment. 10.1016/j.bbr.2015.04.039
Postretrieval Microinjection of Baclofen Into the Agranular Insular Cortex Inhibits Morphine-Induced CPP by Disrupting Reconsolidation. Sun Kuisheng,Mu Qingchun,Chang Haigang,Zhang Chun,Wang Yehua,Rong Shikuo,Liu Shenhai,Zuo Di,He Zhenquan,Wan Ding,Yang Hua,Wang Feng,Sun Tao Frontiers in pharmacology Environmental cues associated with drug abuse are powerful mediators of drug craving and relapse in substance-abuse disorders. Consequently, attenuating the strength of cue-drug memories could reduce the number of factors that cause drug craving and relapse. Interestingly, impairing cue-drug memory reconsolidation is a generally accepted strategy aimed at reducing the intensity of cues that trigger drug-seeking and drug-taking behaviors. In addition, the agranular insular cortex (AI) is an important component of the neural circuits underlying drug-related memory reconsolidation. GABA receptors (GABARs) are potential targets for the treatment of addiction, and baclofen (BLF) is the only prototypical GABA agonist available for application in clinical addiction treatment. Furthermore, ΔFosB is considered a biomarker for the evaluation of potential therapeutic interventions for addiction. Here, we used the morphine-induced conditioned place preference (CPP) paradigm to investigate whether postretrieval microinjections of BLF into the AI could affect reconsolidation of drug-reward memory, reinstatement of CPP, and the level of ΔFosB in mice. Our results showed that BLF infused into the AI immediately following morphine CPP memory retrieval, but not 6 h postretrieval or following nonretrieval, could eliminate the expression of a morphine CPP memory. This effect persisted in a morphine-priming-induced reinstatement test, suggesting that BLF in the AI was capable of preventing the reconsolidation of the morphine CPP memory. Our results also showed that the elimination of morphine CPP memory was associated with reduced morphine-associated ΔFosB expression in the longer term. Taken together, the results of our research provide evidence to support that GABARs in the AI have an important role in drug-cue memory reconsolidation and further our understanding of the role of the AI in drug-related learning and memory. 10.3389/fphar.2020.00743