Indiana University-Purdue University Indianapolis (IUPUI) / Adolescent alcohol abuse is a global problem that initiates lifelong addiction. Alcohol use during adolescence is associated with subsequent Meth dependence in humans. Specifically, female adolescents are particularly vulnerable to serial alcohol and Meth use. However, it is unknown if prior voluntary alcohol drinking impacts subsequent Meth-taking in female adolescent rats. Both alcohol and Meth increase the prostaglandin synthesis enzyme cyclooxygenase-2 (COX-2) in the brain but the effect of serial exposure to alcohol and Meth on COX-2 has not been determined. The first study uses a novel method of serial voluntary alcohol drinking and Meth self-administration in female adolescent rats to model human patterns of co-abuse. Prior alcohol drinking did not affect subsequent Meth self-administration, but it reduced the cue-primed reinstatement of Methseeking after abstinence from Meth. Rats with a history of adolescent alcohol drinking also had increased COX-2 in the dorsal striatum, regardless of subsequent Meth selfadministration. These findings demonstrate that a history of adolescent alcohol drinking does not alter Meth self-administration but persistently reduces cue-primed Meth seeking and increases COX-2 after prolonged abstinence from alcohol. To further examine the role of COX-2 in alcohol drinking, the second study found that adolescent alcohol drinking not only increased COX-2 after four weeks of alcohol abstinence, but also increased endothelin-1 (ET-1) and prostaglandin E2 (PGE2) in the dorsal striatum. Furthermore, adolescent alcohol drinking increased alcohol drinking after abstinence, and this increase was attenuated by treatment with the COX-2 inhibitor nimesulide during abstinence. Antagonism of the interaction between PGE2 and its receptor 1 (EP1) also attenuated the increase in relapse drinking and restored alcohol drinking to the rate of alcohol naïve rats. Overall, these experiments identified a prostaglandin-mediated mechanism that is a putative target for the treatment of alcohol relapse following abstinence in individuals with a history of adolescent alcohol abuse.

Thesis (LLM. (Labour Law)) -- University of Limpopo, 2013 / Reinstatement is one of the remedies for unfair dismissals. Dismissed employees have a recourse to approach the Commission for Conciliation, Mediation and Arbitration1 or labour courts to seek reinstatement. The arbitrator or the courts have a discretion to order reinstatement based on the facts of the case, sometimes retrospectively. Retrospectivity is a discretionary matter in the hands of the courts and therefore the courts of law have been inundated with cases where the employers wanted to limit the retrospectivity of the application of reinstatement as a remedy for unfair dismissals. On the other hand, the dismissed employees would want the court to extend the application. In other circumstances the court would award compensation instead of retrospective reinstatement like where reinstating the employee is just practically impossible or the employee himself does not want to be reinstated. The Labour Relations Act2 has limited the power or discretion of the employers to dismiss employees at will. Section 185 of the LRA provides that there should be fair and valid reason for dismissals. The employer would have to prove the reason for dismissal for it to be valid. On the other hand, the case law also has established that where there is unfair dismissal, the arbitrator or the court must give the primary remedy in favour of the employees which is to reinstate them in their work. Such reinstatement would have the effect as if the employee was never dismissed in the first place.

Cadastral reinstatement methods within Queensland involve the use of modern digital surveying techniques in combination with traditional non-digital methods of recording and reporting information. This leads to the need to manually enter and re-enter data into a digital format at different stages of a survey. The requirement to lodge survey information with government organisations in a non-digital survey plan format also forces a break in digital data flow throughout the cadastral surveying system, which can only be updated by changes in the lodgement regulations. The private cadastral organisations are predominantly responsible for carrying out the cadastral surveys and the government agencies are primarily responsible for the examination, verification and administration of the cadastral data. These organisations will have no communication link for digital cadastral data until the introduction of digital data lodgement. The digital system within the private cadastral surveying organisations can therefore be considered to be an independent system with consideration needed to be given to the future introduction of a digital lodgement system at some undefined time in the future. Cadastral surveyors hold large amounts of digital information that is suitable for digital reinstatement systems. This information, if appropriately archived and distributed, has the capacity to meet the needs of reinstatement systems including as an alternative source of digital information that will eventually be obtained from digital lodgement systems. The existing technology and the private organisation structures are capable of supporting continuous digital data flow and automated systems. This research proposes a process of development for private cadastral organisations to advance from traditional systems to continuous digital data flow and automated processes within their cadastral reinstatement systems. The development process is linked to existing legislation and technology taking into consideration likely future directions. The current legislative and technological environments within Queensland allow for development towards automated digital systems that will enhance most current cadastral reinstatement systems.

The tendency of users to relapse severely hinders adequate treatment of addiction. Physical and psychological stressors often contribute to difficulties in maintaining behavior change, and may play a significant role in relapse. We have previously shown that the activation of pituitary adenylate cyclase activating peptide (PACAP) systems in the bed nucleus of the stria terminalis (BNST) mediates many consequences of chronic stressor exposure. Hence, chronic stress substantially increased BNST PACAP levels, intra-BNST PACAP infusions produced the behavioral and endocrine consequences of stressor exposure, and BNST PACAP antagonism blocked many of the consequences of chronic stress. In the present set of studies, we investigated the role of BNST PACAP in stress-induced reinstatement of cocaine seeking. Rats self-administered cocaine (3mg/ml; 0.5mg/ig/infusion, i.v.) for 1hr daily over 10 days, which was followed by extinction training in which lever pressing no longer resulted in cocaine delivery. In the first experiment we showed that intra-BNST PACAP infusion (1 μg; 0.5 μl per side) reinstated previously extinguished cocaine seeking behavior. In the second experiment intra-BNST infusions of the PAC1/VPAC2 antagonist, PACAP 6-38 (1 μg; 0.5 μl per side) blocked stress-induced reinstatement. Hence, stressor exposure (5 sec 2mA footshock) caused significant reinstatement of cocaine seeking behavior, which was blocked by intra-BNST PACAP6-38 infusion. Overall, these data suggest that BNST PACAP systems mediate stress-induced reinstatement to drug seeking. Understanding the neuropharmacology of BNST PACAP in stress-induced reinstatement and the role of PACAP systems may lead to viable targets for relapse prevention.

Thesis advisor: Scott D. Slotnick / Episodic memory is a constructive process in which a system of sensory and control processes works to transport one’s conscious mind through time–in essence, recreating a previous perceptual experience. For instance, sensory-specific activity that was associated with an original encoding experience is reinstated during retrieval–almost as if the sensory regions are processing the stimulus again, albeit this activation is smaller in spatial extent. This process of sensory-specific reinstatement occurs across all sensory modalities (e.g., Gottfried et al., 2004; Nyberg et al., 2001; Vaidya et al., 2002; Wheeler et al., 2000). That is, retrieval of a visually encoded stimulus (e.g., a picture of a dog) reinstates activity in the visual cortex, while retrieval of an aurally encoded stimulus (e.g., a barking dog) reinstates activity in the auditory cortex. In Chapter 1 and Chapter 2, I demonstrate the specificity of such sensory reinstatement during true memory for visual features and investigate the role of such sensory regions during the construction of false memory for visual features. In addition to sensory processes, our conscious experience of memory also relies on control regions. At the center of this memory control network sits a key memory structure, the hippocampus, as well as other important control regions such as the dorsolateral prefrontal cortex and the parietal cortex. Furthermore, the parahippocampal cortex appears to play a critical role in memory; however, the exact role of this region has been debated (Aminoff, Kverga, & Bar, 2013). In Chapter 3, I investigate the functional role of the parahippocampal cortex during true memory and false memory, and provide evidence that the parahippocampal cortex mediates general contextual processing.

abstract: Nicotine self-administration is associated with decreased expression of the glial glutamate transporter 1 (GLT-1) and the cystine-glutamate exchange protein xCT in the nucleus accumbens core (NAcore). N-acetylcysteine (NAC), which is an antioxidant, anti-inflammatory, and glutamatergic agent, restores these proteins associated with increased relapse vulnerability. However, the specific molecular mechanisms driving NAC inhibitory effects on cue-induced nicotine reinstatement are unknown. Thus, the present study assessed NAC’s effects on cue-induced nicotine reinstatement are dependent on NAcore GLT-1 expression. Here, rats were treated with NAC in combination with intra-NAcore vivo-morpholinos to examine the role of GLT-1 in NAC-mediated inhibition of cue-induced nicotine seeking. Subchronic NAC treatment attenuated cue-induced nicotine seeking in male rats and an antisense vivo-morpholino (AS) designed to selectively suppress GLT-1 expression in the NAcore blocked this effect. NAC treatment was also associated with an inhibition of pro-inflammatory tumor necrosis factor alpha (TNFα) expression in the NAcore. As well, GLT-1 AS markedly increased expression of CD40, a known marker of pro-inflammatory M1 activation of microglia and macrophages. To further examine whether NAC-induced decreases in nicotine seeking involve suppression of TNFα, we manipulated a downstream mediator of this pathway, nuclear factor kappa B (NF-kB). Considering the putative role of NF-κB in learning, memory, and synaptic plasticity, separate experiments were performed where rats were treated with herpes simplex virus (HSV) vectors designed to increase (HSV-IKKca) or decrease (HSV-IKKdn) NF-κB signaling through interactions with IκB Kinase (IKK). The goal was to examine the role of NF-κB signaling in mediating nicotine seeking behavior and if NF-κB signaling regulates GLT-1 expression. HSV-IKKdn alone and in combination with NAC inhibited cue-induced nicotine reinstatement, while HSV-IKKca blocked the attenuating effect of NAC on reinstatement. Interestingly, both HSV-IKKdn and HSV-IKKca, regardless of NAC treatment, inhibited GLT-1 expression. Taken together, these results suggest that while GLT-1 may be a conserved neurobiological substrate underlying relapse vulnerability across drugs of abuse, immunomodulatory mechanisms may regulate drug-induced alterations in glutamatergic plasticity that mediate cue-induced drug-seeking behavior through GLT-1-independent mechanisms. / Dissertation/Thesis / Masters Thesis Psychology 2019

Behavioral momentum theory provides a conceptual framework for the study of the recurrence of previously extinguished operant behavior. Commonly referred to as treatment relapse, this is the failure to maintain treatment gains (e.g., reductions in challenging behavior) when there is a change in conditions under which these gains were achieved. One treatment relapse paradigm previously examined in basic and applied research is reinstatement. Reinstatement of challenging behavior has been shown to occur when functional reinforcers are delivered on a fixed-time schedule following extinction of challenging behavior. Although examinations appropriate behavior have applied value, analyses of reinstatement have been conducted almost exclusively with challenging behavior. During the current study, a reinstatement methodology was applied to communicative responses with five children diagnosed with developmental disabilities who exhibited comorbid communication deficits, as well as challenging behavior maintained by positive reinforcement. In the first phase of the reinstatement evaluation, each child received functional communication training (FCT) within a positive reinforcement context within a two-component multiple schedule design with each schedule paired with a distinct communicative response. After achieving steady-state responding in the first phase, in which all participants were independently emitting both communicative responses, all appropriate communication was placed on extinction in the second phase. Extinction continued until rates of appropriate communication were at or near zero. In the third phase, positive reinforcement was delivered and the recurrence of appropriate communication was evaluated. For two of five participants, communicative responding recurred following the fixed-time delivery of the functional reinforcer, indicating a successful demonstration of reinstatement. For three of five participants, communicative responding recurred prior to the delivery of fixed-time reinforcement, indicating that an alternative recurrence phenomenon likely occurred. These results suggest that reinstatement methodologies can be applied to cases in which FCT treatment failures have occurred to efficiently restore clinical gains for some participants. Implications for clinical practice and future directions of this line of research are discussed.

Psychostimulant-induced reinstatement of place preferences have been used to investigate underlying physiological mechanisms mediating drug-seeking behavior in adolescent and adult rodents; however, it is still unclear how psychostimulant exposure during adolescence affects neuronal communication in the mesolimbic dopamine (DA) pathway and whether these changes would elicit enhanced drug-seeking behavior later in adulthood. The aim of the present study was to investigate the effects of intra-ventral tegmental area (VTA) or intra-nucleus accumbens septi (NAcc) DA D2 receptor antagonist infusions on cocaine-induced reinstatement of cocaine place conditioning in high and low responders for cocaine reward. Adolescent rats were exposed to cocaine place conditioning [postnatal day (PND 28-39)] and divided into high and low responders for cocaine reward based on their place preference expression score. Place preferences were extinguished and guide cannula were implanted into either the VTA or NAcc followed by one of the following: 1) intra-VTA or intra-NAcc infusion of the DA D2 receptor antagonist sulpiride (100 µM) during a cocaine-primed reinstatement test (10 mg/kg/ip cocaine) or 2) measurement of NAcc DA levels during intra-VTA or intra-NAcc infusion of sulpiride (100 µM), a cocaine prime (10 mg/kg cocaine) and re-exposure to the cocaine paired chamber. Infusion of sulpiride into the VTA but not the NAcc blocked reinstatement of cocaine place conditioning in rats exposed to cocaine during adolescence. Furthermore, re-exposure to cocaine-associated cues and simultaneous local infusion of sulpiride into either the VTA or NAcc attenuated cocaine-induced increases in accumbal DA levels for rats pretreated with cocaine during adolescence, regardless of phenotype. These data suggest intrinsic compensatory mechanisms in the mesolimbic DA pathway mediate adolescent behavioral responsivity to cocaine prime-induced reinstatement of cocaine place conditioning later on in adulthood.

The neuropeptide, corticotropin-releasing factor (CRF), plays a critical role in the central regulation of various stress-related behaviours, including those unique to subjects with prior cocaine experience. The three series of experiments presented in this dissertation explored the role of two neurochemical systems, the teneurin C-terminal associated peptides (TCAP) and the endocannabinoids (eCBs), in several cocaine- and anxiety-related behaviours induced or mediated by CRF. The first series of experiments examined the effects of TCAP-1 on the reinstatement of cocaine seeking and expression of cocaine-induced behavioural sensitization. Repeated (5-day), but not acute, TCAP-1 treatment blocked the reinstatement of cocaine seeking induced by central injections of CRF. TCAP-1 was, however, without effect on footshock- or cocaine-induced reinstatement. Repeated TCAP-1 further interfered with the expression of behavioural sensitization to a CRF, but not a cocaine, challenge. These findings suggest that TCAP-1 normalizes CRF signaling dysregulated by cocaine exposure to interfere in the subsequent effects of CRF on cocaine-related behaviours. A parallel series of experiments investigated the role of eCB signaling at CB1 receptors in the reinstatement of cocaine seeking and cocaine-sensitized locomotion. Pretreatment with the CB1 receptor antagonist, AM251, selectively interfered with CRF-, but not footshock- or cocaine-induced reinstatement. AM251 further blocked the expression of behavioural sensitization induced by challenge injections of both CRF and cocaine. These findings reveal a mediating role for CB1 receptor transmission in the effects of CRF on cocaine-related behaviours. A final series of experiments examined the role of CB1 receptor transmission in the behavioural anxiety induced by central injections of CRF, and by withdrawal from chronic cocaine exposure. AM251, although itself anxiogenic, reversed anxiety induced by CRF and cocaine withdrawal. Furthermore, AM251 elevated plasma corticosterone levels, indicative of increased HPA axis activity, irrespective of CRF treatment or cocaine withdrawal. These findings suggest that CRF- and cocaine withdrawal-induced anxiety are mediated, at least in part, by CB1 receptor transmission, independent of HPA axis regulation. The collective findings are discussed within a framework of CRF-TCAP-eCB interactions, wherein TCAP-1 and AM251 are proposed to act in parallel to modulate amygdalar CRF transmission, and thus regulate the expression of cocaine- and anxiety-related behaviours.

The neuropeptide, corticotropin-releasing factor (CRF), plays a critical role in the central regulation of various stress-related behaviours, including those unique to subjects with prior cocaine experience. The three series of experiments presented in this dissertation explored the role of two neurochemical systems, the teneurin C-terminal associated peptides (TCAP) and the endocannabinoids (eCBs), in several cocaine- and anxiety-related behaviours induced or mediated by CRF. The first series of experiments examined the effects of TCAP-1 on the reinstatement of cocaine seeking and expression of cocaine-induced behavioural sensitization. Repeated (5-day), but not acute, TCAP-1 treatment blocked the reinstatement of cocaine seeking induced by central injections of CRF. TCAP-1 was, however, without effect on footshock- or cocaine-induced reinstatement. Repeated TCAP-1 further interfered with the expression of behavioural sensitization to a CRF, but not a cocaine, challenge. These findings suggest that TCAP-1 normalizes CRF signaling dysregulated by cocaine exposure to interfere in the subsequent effects of CRF on cocaine-related behaviours. A parallel series of experiments investigated the role of eCB signaling at CB1 receptors in the reinstatement of cocaine seeking and cocaine-sensitized locomotion. Pretreatment with the CB1 receptor antagonist, AM251, selectively interfered with CRF-, but not footshock- or cocaine-induced reinstatement. AM251 further blocked the expression of behavioural sensitization induced by challenge injections of both CRF and cocaine. These findings reveal a mediating role for CB1 receptor transmission in the effects of CRF on cocaine-related behaviours. A final series of experiments examined the role of CB1 receptor transmission in the behavioural anxiety induced by central injections of CRF, and by withdrawal from chronic cocaine exposure. AM251, although itself anxiogenic, reversed anxiety induced by CRF and cocaine withdrawal. Furthermore, AM251 elevated plasma corticosterone levels, indicative of increased HPA axis activity, irrespective of CRF treatment or cocaine withdrawal. These findings suggest that CRF- and cocaine withdrawal-induced anxiety are mediated, at least in part, by CB1 receptor transmission, independent of HPA axis regulation. The collective findings are discussed within a framework of CRF-TCAP-eCB interactions, wherein TCAP-1 and AM251 are proposed to act in parallel to modulate amygdalar CRF transmission, and thus regulate the expression of cocaine- and anxiety-related behaviours.