The behavioural and neural effects of cannabinoids: Studies using Lewis and Wistar strain rats

Cannabis (known in its common forms as Cannabis sativa or Cannabis indica) is the most widely used illicit drug in the world and has been used for thousands of years for medicinal, religious and hedonistic purposes. In the last half of the 20th century the therapeutic uses of cannabis were largely ignored as most Western governments prohibited the use of the drug. Prohibition has come about largely as a result of the view that cannabis is a dangerous drug that poses major risks to both mental and physical health. However, this view is being increasingly challenged in recent years with a major popular movement towards decriminalization of cannabis occurring in some Western countries and a resurgence of interest in the medicinal properties of cannabis. Since Mechoulam and colleagues first isolated delta 9-tetrahydrocannabinol (delta 9-THC) as the main psychoactive constituent of cannabis, considerable advances have been made in the pharmacology of cannabis and cannabis-like drugs (cannabinoids). Central and peripheral cannabinoid receptors have been isolated and two endogenous ligands have been discovered. In addition, two cannabinoid receptor antagonists have been developed. However, our knowledge of the behavioural, neural and emotional effects of cannabis and the cannabinoids has often lagged behind our understanding of basic cannabinoid pharmacology. The present thesis attempts to further the understanding of the behavioural, neural and emotional effects of cannabinoids, using laboratory rats as subjects. A synthetic analogue of delta 9-THC (CP 55,940), is used as the primary pharmacological tool. The thesis offers a broad perspective with three major areas of investigation. These are: 1) the effects of CP 55,940 on anxiety-related behaviour (Chapters 2 and 3); 2) the effects of CP 55,940 on patterns of brain activation as indicated by c-fos expression (Chapter 4) and; 3) the addictive potential of CP 55,940 and its capacity to produce sensitization to the effects of other drugs such as cocaine (Chapters 5 and 6). A recurring theme throughout the thesis is that genetic factors may partially determine the behavioural, neural and emotional response to cannabinoids. To this end, the thesis compares Lewis and Wistar trains of rat in a wide variety of assays. Previous research has isolated Lewis rats as an "addiction-prone" and a "cannabinoid-preferring" strain, as they are more sensitive to the rewarding effects of various drugs of abuse including cannabinoids. Conversely, cannabinoids appear to have aversive effects in Wistar rats. A long-standing puzzle in cannabinoid research has been the question of why rats do not self-administer cannabis or cannabinoids. One likely reason is that cannabinoids have predominately aversive effects in rats. It is proposed here that these aversive effects arise because cannabinoids are anxiogenic agents in most rat strains. However some evidence indicates that the Lewis strain of rat are the only strain to find cannabinoids rewarding. It is hypothesised that Lewis rats may be more susceptible to the rewarding effects of cannabinoids because they are less susceptible to the anxiogenic effects of these compounds. In Chapters 2 and 3 the anxiogenic effects of the synthetic cannabinoid agonist CP 55,940 were compared in Lewis and Wistar rats in several different animal models of anxiety. In Chapter 2, the predatory odour avoidance, open area avoidance and conditioned ultrasonic vocalization (USV) models were utilised. In the predatory odour avoidance model, rats were exposed to cat odour in a rectangular arena and given the opportunity to hide in a small box. Both Lewis and Wistar rats displayed high levels of hiding during odour exposure. In Wistar but not Lewis rats, 50 �g/kg of CP 55,940 (i.p.) enhanced this avoidance response. Unfortunately, Lewis rats showed exceptionally high avoidance of the cat odour making it difficult to discern the effects of CP 55,940. To avoid this problem a second experiment was conducted, where rats were tested in the same arena as in the first experiment but with no cat odour present. Again in Wistar, but not Lewis rats, 25 and 50 �g/kg of CP 55,940 (i.p.) increased the avoidance of the open space. In the third experiment, Lewis and Wistar rats were placed in a chamber in which they had previously received footshock. Wistar but not Lewis rats re-exposed under the influence of 10, 25 or 50 �g/kg CP 55,940 (i.p.) emitted significantly more USVs than vehicle-treated rats. Thus, CP 55,940 clearly increased anxiety-related behaviour in Wistar rats but not Lewis rats, supporting the notion of a genetic predisposition towards cannabinoid-induced anxiety. In Chapter 3 the generality of the findings made in Chapter 2 were tested by utilising two further animal models of anxiety, the social interaction and light-dark emergence tests. From the results of Chapter 2, it could be claimed that Lewis rats were merely subsensitive to the effects of CP 55,940. Therefore a higher dose range (0, 25, 50 and 75 �g/kg i.p.) of CP 55,940 was employed in Chapter 3. In addition, the rotarod test was used to assess whether CP 55,940 has ataxic effects at these doses. In the first experiment, two unfamiliar rats were placed in a large arena and the time the rats spent socially interacting was recorded. CP 55,940 significantly reduced the total time rats spent socially interacting in Lewis (25 and 75 �g/kg) and Wistar rats (50 and 75 �g/kg). However, CP 55,940 has a significantly greater effect in Wistar rats compared to Lewis rats. In the second experiment, rats were placed in a small box within a large open arena and the latency to emerge from this box was measured. CP 55,940 increased emergence latency (at 75 �g/kg) and mean time per entry into the box (at 25 and 75 �g/kg) in Wistar but not Lewis rats. Furthermore, CP 55,940 caused a greater decrease in time spent in the open arena (at 25 and 75 �g/kg) and frequency of emergence (at 75 �g/kg) in Wistar rats in comparison to Lewis rats. In the third experiment, CP 55,940 (at 25, 50 and 75 �g/kg) caused mild incoordination only in Lewis rats as measured by the rotarod test. This finding argues against the assertion that the CP 55,940-induced anxiety-like behaviours in Wistar rats are merely a result of motoric impairment. Furthermore, it illustrates that Lewis rats are not generally subsensitive to the effects of CP 55,940. That is, when compared to other rat strains, Lewis rats may be more or less sensitive to the effects of CP 55,940 depending on what behaviour is being assessed. From the results of Chapters 2 and 3 it can be seen that Lewis rats are less sensitive to the anxiogenic effects of CP 55,940 than Wistar rats. In Chapter 4 it was hypothesised that in Lewis rats the effects of CP 55,940 on neural substrates of reward far outweigh the effects the compound has on neural substrates mediating anxiety. To examine this issue, the effects of CP 55,940 at a moderate (50 �g/kg i.p.) and high (250 �g/kg i.p.) dose were observed on c-fos expression (a measure of neural activation) and behaviour in Lewis and Wistar rats. CP 55,940 dose-dependently inhibited locomotor activity and reduced body temperature with Lewis rats being significantly less affected than Wistar rats. The 250 �g/kg dose caused significant catalepsy in both strains with a significantly greater effect in Wistar rats. These strain differences in the effects of CP 55,940 on body temperature and motor behaviour clearly correlated with c-fos expression in various regions and subregions. In general, Lewis rats showed significantly less Fos-labeled cells in comparison to Wistar rats. These strain differences in the effects of CP 55,940 on c-fos expression appeared unique to cannabinoids, as cocaine (15 mg/kg i.p.) had equivalent effects on c-fos expression in Lewis and Wistar rats. CP 55,940 promoted c-fos expression in areas not previously assessed, such as the median preoptic nucleus (MnPO), medial preoptic nucleus (MPO), anterior hypothalamic area (AH), islands of Calleja (ICjM), periaqueductal gray (PAG) and the pedunculopontine tegmental nucleus (PPTg). The strain differences uncovered in Chapters 2 and 3 correlated well with strain differences in the effects of CP 55,940 on c-fos expression in areas implicated in cannabinoid-induced anxiety, such as the central nucleus of the amygdala, bed nucleus of the stria terminalis, paraventricular nucleus of the hypothalamus and PAG. However, the effects of CP 55,940 on c-fos expression in a neural circuit which may underlie reward, which includes the shell of the nucleus accumbens (NAS) and PPTg, were also less in Lewis rats in comparison to Wistar rats. Future investigations must address whether the reduced effects of CP 55,940 on the Lewis rat are due to pharmacokinetics or pharmacodynamics. In addition, future studies must reconcile the pattern of c-fos expression observed here with prior reports of the Lewis rat being a unique "cannabinoid-preferring" strain. In Chapter 4, CP 55,940 administration promoted c-fos expression in areas of the brain thought to play a critical role in behavioural sensitization such as the ventral tegmental area and NAS. This is interesting because it is possible that c-fos is involved in promoting neuroadaptations that underlie drug addiction. To examine this idea, Chapter 5 investigated a behavioural assay of the long-term neural adaptations that may occur with the chronic administration of cannabis, namely, behavioural sensitization. This chapter also examined an animal model of the "gateway hypothesis", that is, the hypothesis that prior exposure to cannabis increases an individuals vulnerability to using other drugs. This animal model is known as cross-sensitization. First it was shown that Lewis, but not Wistar rats, given cocaine (15 mg/kg i.p.) every second day over a two week period displayed a progressively greater locomotor response to the drug over days indicating behavioural sensitization. When CP 55,940 (0, 10, 25 or 50 �g/kg i.p.) was administered under a similar regime, no such sensitization was observed in either strain. Rather, the two highest doses of CP 55,940 (25 and 50 �g/kg) caused locomotor suppression that lasted throughout administration. When Lewis or Wistar rats pre-exposed ten times to CP 55,940 were challenged with cocaine (15 mg/kg), no exaggerated locomotor response to cocaine was evident relative to non pre-exposed rats. When these rats were subsequently re-tested with CP 55,940, it continued to produce a dose-dependent suppression of locomotor activity. Finally, when CP 55,940 (50 �g/kg) was co-administered with cocaine in Lewis rats, it significantly reduced the locomotor hyperactivity produced by the drug but did not block the development of behavioural sensitization to cocaine. These results show that CP 55,940 does not sensitize locomotor activity with repeated administration in the same way as cocaine, and that pre-exposure or concurrent exposure to CP 55,940 does not enhance sensitivity to the subsequent behavioural effects of cocaine. Therefore, unlike Chapters 2, 3 and 4 where strain differences were observed in CP 55,940?induced anxiety, hypothermia, catalepsy, c-fos expression and ataxia, there were no strain differences with respect to behavioural sensitization. Landmark studies by Gardner and colleagues showed that Lewis rats are particularly susceptible, in comparison to other rat strains, to the rewarding effects of delta 9-THC on: 1) medial forebrain bundle (MFB) self-stimulation behaviour and; 2) dopamine (DA) efflux in the NAS. However, in Chapter 4 Lewis rats were less susceptible than Wistar rats to CP 55,940-induced c-fos expression in the NAS. Further, Lewis rats showed no behavioural sensitization to the chronic administration of CP 55,940. In light of these findings, Chapter 6 assessed whether CP 55,940 does have a rewarding effect on MFB self-stimulation behaviour in Lewis rats. Lewis rats were trained to self-stimulate the MFB using a rate?frequency paradigm and then administered CP 55,940 (0, 10, 25 and 50 �g/kg i.p.). CP 55,940 had no effect on MFB self-stimulation behaviour as assessed by the M50, the stimulation frequency at which half-maximal response rates were obtained. This result calls into question previous assertions that Lewis rats are a "cannabis-preferring" strain of rat. Previous studies utilising the cannabinoid CB1 receptor antagonist, SR 141716, have shown that the endogenous cannabinoid system may have some involvement in the rewarding effects of cocaine, morphine, sucrose and alcohol. Thus, Chapter 6 also assessed the effects of SR 141716 (0, 1, 3, 10 and 20 mg/kg i.p.) on MFB stimulation in Lewis rats. The role of DA in MFB stimulation reward has already been established, so for comparison purposes the effects of the DA D1 receptor antagonist SCH 23390 (0.06 mg/kg i.p.) was also assessed. Only a very high dose of SR 141716 (20 mg/kg) caused a significant inhibition of the rewarding efficacy of the stimulation with all other doses (1, 3, and 10 mg/kg) being ineffective in modulating the rewarding impact of brain stimulation. This was seen as an increase in M50. By comparison, a relatively low dose (0.06 mg/kg) of SCH 23390 caused a large increase in M50. These results indicate a relatively modest influence of the endogenous cannabinoid system on reward-relevant neurotransmission in the self-stimulation paradigm. Chapter 7 concludes the thesis and discusses the implications of the results obtained. The main findings of the current thesis are: 1) that the suggested "addiction-prone" Lewis strain of rat is less susceptible to cannabinoid-induced anxiety in comparison to Wistar rats; 2) Lewis rats show less cannabinoid-induced c-fos expression in comparison to Wistar rats (including in brain regions implicated in cannabinoid-induced anxiety and reward); 3) cannabinoid-induced c-fos expression exists in a number of brain regions never previously assessed such as the MPO, ICjM and PPTg; 4) behavioural sensitization does not occur with the repeated administration of CP 55,940; 5) cannabinoid pre-exposure or co-administration does not increase the sensitivity of the locomotor-activating effects of cocaine; 6) the endogenous cannabinoid system, at most, only has a minor influence on the neural substrate of brain stimulation reward and; 7) that there are previously unreported strain differences in cannabinoid-induced hypothermia, catalepsy and ataxia. These results add to our understanding of the effects of the behavioural, emotional and neural effects of cannabinoids and the endogenous cannabinoid system

The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of canabinoids

Cannabis increases the risk of schizophrenia in genetically vulnerable individuals. In this study we aim to show that the schizophrenia susceptibility gene neuregulin 1 (Nrg1) modulates the development of tolerance to cannabinoids in mice. Nrg1 heterozygous (HET) and wild-type (WT) mice were treated daily for 15 d with the synthetic analogue of D9-tetrahydrocannabinol, CP55,940 (0.4 mg/kg). We measured the impact of this exposure on locomotor activity, anxiety, prepulse inhibition (PPI), body temperature and FosB/DFosB immunohistochemistry. Tolerance to CP55,940-induced hypothermia and locomotor suppression developed more rapidly in Nrg1 HET mice than WT mice. Conversely in the light-dark test, while tolerance to the anxiogenic effect of CP55,940 developed in WT mice over days of testing, Nrg1 hypomorphs maintained marked anxiety even after 15 d of treatment. Repeated cannabinoid exposure selectively increased FosB/DFosB expression in the lateral septum, ventral part (LSV) of Nrg1 HET but not WT mice. On day 1 of exposure opposite effects of CP55,940 treatment were observed on PPI, i.e. it was facilitated in Nrg1 hypomorphs and impaired in WT mice, despite the drug significantly impairing the acoustic startle reflex equally in both genotypes. These effects of CP55,940 on PPI were not maintained as both genotypes became tolerant to cannabinoid action with repeated exposure. Our results highlight that Nrg1 modulates the development of cannabinoid tolerance dependent on the parameter being measured. Furthermore, these data reinforce the notion that the VLS is an important brain region involved in Nrg1–cannabinoid interactions

Adolescent Oxytocin Exposure Causes Persistent Reductions in Anxiety and Alcohol Consumption and Enhances Sociability in Rats

Previous studies have suggested that administration of oxytocin (OT) can have modulatory effects on social and anxiety-like behavior in mammals that may endure beyond the time of acute OT administration. The current study examined whether repeated administration of OT to male Wistar rats (n = 48) during a key developmental epoch (early adolescence) altered their physiology and behavior in later-life. Group housed rats were given intraperitoneal injections of either 1 mg/kg OT or vehicle during early adolescence (post natal-days [PND] 33–42). OT treatment caused a transient inhibition of body weight gain that recovered quickly after the cessation of treatment. At PND 50, the rats pre-treated with OT displayed less anxiety-like behavior on the emergence test, while at PND 55 they showed greater levels of social interaction. A subgroup of OT pre-treated rats examined at PND 63 showed a strong trend towards increased plasma OT levels, and also displayed significantly increased OT receptor mRNA in the hypothalamus. Rats pre-treated with OT and their controls showed similar induction of beer intake in daily 70 min test sessions (PND 63 onwards) in which the alcohol concentration of beer was gradually increased across days from 0.44% to 4.44%. However, when given ad libitum access to beer in their home cages from PND 72 onwards (early adulthood), consumption of beer but not water was significantly less in the OT pre-treated rats. A “booster” shot of OT (1 mg/kg) given after 25 days of ad libitum access to beer had a strong acute inhibitory effect on beer intake without affecting water intake. Overall these results suggest that exogenous OT administered during adolescence can have subtle yet enduring effects on anxiety, sociability and the motivation to consume alcohol. Such effects may reflect the inherent neuroplasticity of brain OT systems and a feed-forward effect whereby exogenous OT upregulates endogenous OT systems

Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, D9-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT2A receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/ kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABAA receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT2A binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes

Wet Paint: Visual Culture in a Changing Britain – A Round Table Debate

Political decisions and debates regarding the interregional and interna- tional partnerships that constitute Great Britain, including those over Scottish Independence, EVEL (English Votes for English Laws) and proposed legislation on an ‘in/out’ referendum on British membership of the European Union, have contributed to, and intensified, the examination of Britain’s institutions, as well as its national emblems and arche- types. In light of such a dynamic situation, Visual Culture in Britain has asked representatives of British universities, the museum sector and research centres to respond to the idea of a changing Britain through the prism of British art and visual culture, using cogent examples wherever possible, and to outline their observations, understandings and positions within this rapidly developing context

Novel molecular changes induced by Nrg1 hypomorphism and Nrg1-cannabinoid interaction in adolescence : a hippocampal proteomic study in mice

Neuregulin 1 (NRG1) is linked to an increased risk of developing schizophrenia and cannabis dependence. Mice that are hypomorphic for Nrg1 (Nrg1 HET mice) display schizophrenia relevant behavioural phenotypes and aberrant expression of serotonin and glutamate receptors. Nrg1 HET mice also display idiosyncratic responses to the main psychoactive constituent of cannabis, Δ9 -tetrahydrocannabinol (THC). To gain traction on the molecular pathways disrupted by Nrg1 hypomorphism and Nrg1-cannabinoid interactions we conducted a proteomic study. Adolescent wildtype (WT) and Nrg1 HET mice were exposed to repeated injections of vehicle or THC and their hippocampi were submitted to 2D gel proteomics. Comparison of WT and Nrg1 HET mice identified proteins linked to molecular changes in schizophrenia that have not been previously associated with Nrg1. These proteins are involved in vesicular release of neurotransmitters such as SNARE proteins; enzymes impacting serotonergic neurotransmission, and; proteins affecting growth factor expression. Nrg1 HET mice treated with THC expressed a distinct protein expression signature compared to WT mice. Replicating prior findings, THC caused proteomic changes in WT mice suggestive of greater oxidative stress and neurodegeneration. We have previously observed that THC selectively increased hippocampal NMDA receptor binding of adolescent Nrg1 HET mice. Here we observed outcomes consistent with heightened NMDA-mediated glutamatergic neurotransmission. This included differential expression of proteins involved in NMDA receptor trafficking to the synaptic membrane; lipid raft stabilization of synaptic NMDA receptors; and homeostatic responses to dampen excitotoxicity. These findings uncover for the first time novel proteins altered in response to Nrg1 hypomorphism and Nrg1-cannabinoid interactions that improves our molecular understanding of Nrg1 signaling and Nrg1-mediated genetic vulnerability to the neurobehavioural effects of cannabinoids

Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy

Background and Purpose: Cannabis has been used to treat epilepsy for millennia, with such use validated by regulatory approval of cannabidiol (CBD) for Dravet syndrome. Unregulated artisanal cannabis-based products used to treat children with intractable epilepsies often contain relatively low doses of CBD but are enriched in other phytocannabinoids. This raises the possibility that other cannabis constituents might have anticonvulsant properties. Experimental Approach: We used the Scn1a+/− mouse model of Dravet syndrome to investigate the cannabis plant for phytocannabinoids with anticonvulsant effects against hyperthermia-induced seizures. The most promising, cannabigerolic acid (CBGA), was further examined against spontaneous seizures and survival in Scn1a+/− mice and in electroshock seizure models. Pharmacological effects of CBGA were surveyed across multiple drug targets. Key Results: The initial screen identified three phytocannabinoids with novel anticonvulsant properties: CBGA, cannabidivarinic acid (CBDVA) and cannabigerovarinic acid (CBGVA). CBGA was most potent and potentiated the anticonvulsant effects of clobazam against hyperthermia-induced and spontaneous seizures, and was anticonvulsant in the MES threshold test. However, CBGA was proconvulsant in the 6-Hz threshold test and a high dose increased spontaneous seizure frequency in Scn1a+/− mice. CBGA was found to interact with numerous epilepsy-relevant targets including GPR55, TRPV1 channels and GABAA receptors. Conclusion and Implications: These results suggest that CBGA, CBDVA and CBGVA may contribute to the effects of cannabis-based products in childhood epilepsy. Although these phytocannabinoids have anticonvulsant potential and could be lead compounds for drug development programmes, several liabilities would need to be overcome before CBD is superseded by another in this class

When rats rescue robots

Robots are increasingly being used to monitor and even participate in social interactions with animals in their own environments. Robotic animals enable social behaviors to be observed in natural environments, or specifically elicited under the control of an experimenter. It is an open question to what extent animals will form positive social connections with such robots. To test this, we familiarized rats to two rat-sized robots, one exhibiting “social” behaviors, including helping, while the other was also mobile but not helpful. When given an opportunity to release the robots from restrainers, as they do for conspecifics, we found that rats did release the robots, and moreover, were significantly more likely to release the helpful than the unhelpful robot. These findings indicate that robots can elicit helpful behavior from rats, and that rats will even discriminate between robots on the basis of their behaviors

Navigating infection risk during oviposition and cannibalistic foraging in a holometabolous insect

Deciding where to eat and raise offspring carries important fitness consequences for all animals, especially if foraging, feeding and reproduction increase pathogen exposure. In insects with complete metamorphosis, foraging mainly occurs during the larval stage, while oviposition decisions are made by adult females. Selection for infection avoidance behaviours may therefore be developmentally uncoupled. Using a combination of experimental infections and behavioral choice assays, we tested if Drosophila melanogaster fruit flies avoid infectious environments at distinct developmental stages. When given conspecific fly carcasses as a food source, larvae did not discriminate between carcasses that were clean or infected with the pathogenic Drosophila C Virus (DCV), even though cannibalism was a viable route of DCV transmission. When laying eggs, DCV-infected females did not discriminate between infectious and non-infectious carcasses. Healthy mothers however, laid more eggs near a clean rather than an infectious carcass. Avoidance during oviposition changed over time: after an initial oviposition period, healthy mothers stopped avoiding infectious carcasses. We attribute this to a trade-off between infection risk and reproduction. Laying eggs near potentially infectious carcasses was always preferred to sites containing only fly food. Our findings suggest infection avoidance contributes to how mothers provision their offspring and underline the need to consider infection avoidance behaviors at multiple life-stages

Adaptation to ER Stress Is Mediated by Differential Stabilities of Pro-Survival and Pro-Apoptotic mRNAs and Proteins

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates a signaling cascade known as the unfolded protein response (UPR). Although activation of the UPR is well described, there is little sense of how the response, which initiates both apoptotic and adaptive pathways, can selectively allow for adaptation. Here we describe the reconstitution of an adaptive ER stress response in a cell culture system. Monitoring the activation and maintenance of representative UPR gene expression pathways that facilitate either adaptation or apoptosis, we demonstrate that mild ER stress activates all UPR sensors. However, survival is favored during mild stress as a consequence of the intrinsic instabilities of mRNAs and proteins that promote apoptosis compared to those that facilitate protein folding and adaptation. As a consequence, the expression of apoptotic proteins is short-lived as cells adapt to stress. We provide evidence that the selective persistence of ER chaperone expression is also applicable to at least one instance of genetic ER stress. This work provides new insight into how a stress response pathway can be structured to allow cells to avert death as they adapt. It underscores the contribution of posttranscriptional and posttranslational mechanisms in influencing this outcome