Catharine Winstanley

Addiction is an escalating, compulsive, and relapsing psychiatric disease that affects millions worldwide and exacts immense socioeconomic cost. As for potential pharmacotherapeutic targets, the dopamine system is of most interest, but it is unclear as to whether increasing or decreasing dopamine is the best approach. There is consensus that the cues associated with cocaine use and gambling (e.g., a crack pipe or flashing casino lights) are critical in driving disordered behaviour. It is also clear that the responsivity to drug and gambling cues is governed by dopamine and that there is considerable comorbidity between cocaine use and gambling disorder. Biological sex also plays a critical role in addiction but is confounded by the socioeconomic construct of gender in human studies, necessitating animal models. In the following thesis, we preclinically modeled the complex intersection of cocaine use and gambling-like behaviour by combining operant cocaine self-administration with the cued rat gambling task. While female and male rats gambled and took cocaine, we used chemogenetics to bidirectionally modulate the dopaminergic neurons projecting from the ventral tegmental area. We showed that chemogenetic inhibition of dopamine neurons decreased numerous addiction-like behaviours (e.g., risk-taking, impulsivity) in males, but surprisingly increased risk-taking in females. In both sexes, stimulation of the dopamine system had generally deleterious effects. Both inhibition and stimulation caused females and males to take more cocaine, but paradoxically prevented the increased risk-taking that results from cocaine self-administration. Drawing on the reward deficiency and incentive sensitization theories of addiction, this thesis furthermore proposes a biobehavioural framework through which the present findings may be understood.

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Gambling disorder (GD) and other forms of behavioural and substance addictions are characterized by deficits in decision making and impulsivity. Animal models of behaviour allow researchers to study specific components and features of biased decision making and elucidate the neural circuitry that underpins these biases. Our laboratory has developed several animal models which each examine a specific subfacet of decision making thought to contribute to GD. The rat Gambling Task examines risky decision making by posing a choice between small, safe rewards and larger but more risky options. The rat Betting Task examines a specific choice bias termed the “escalation of commitment” bias, in which humans show an increasing aversion to uncertain wagers as the amount at stake goes up. In order to examine the effect of cues on choice behaviour, we developed the Cued rat Gambling Task, which offers the same choice options as those on the rat Gambling Task, but pairs wins on the risky options with salient cues. The presence of salient environmental stimuli can influence choice behaviour, and may make important contributions to the maintenance and severity of GD.As described in this dissertation, work with these tasks has clarified the environmental, pharmacological and regional contributions to GD-like decision making. The development of the Cued rat Gambling Task demonstrated that the addition of salient cues is sufficient to drive a riskier, more disadvantageous choice preference than that demonstrated on the uncued rat Gambling Task. Disrupting orbitofrontal cortex function while the animal is learning the Cued rat Gambling Task promotes the development of a more optimal choice strategy, perhaps due to the region’s roles in cognitive flexibility and subjective valuation. Choice biases on the rat Betting Task are also ameliorated by inactivation of the orbitofrontal cortex, but not inactivation of other prefrontal regions. Furthermore, the nucleus accumbens core, but not shell, may guide the development of a risk-averse choice strategy on the rat Gambling Task. In sum, the work in this dissertation clarifies the motivational role of cues in gambling and other disorders of addiction, and elucidates the neural circuitry that underpins choice biases.

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Choosing adaptively among candidate actions requires a cost-benefit analysis, inwhich potential rewards are considered against the costs required to obtain them.One cost frequently encountered by humans is the cost of cognitive effort, inwhich executive processes spanning attention, working memory, reasoning, andthe like are taxed. This form of effort is in contrast to the physical effort costs thathave generally been the focus of the cost/benefit decision-making literature. Thisthesis reviews the currently available literature investigating the brain regions andneurotransmitter systems guiding these respective forms of decision making, andthen carries out a set of experiments to further characterize the neurobiologyguiding cognitive effort allocation. These experiments utilize an animal model ofdecision making known as the rodent Cognitive Effort Task (rCET), in whichsubjects decide whether to exert more attention in pursuit of larger rewards, or toobtain smaller reward for comparatively less attentional demand. In experiment1, I use chemogenetics to downregulate cholinergic neurons of the basalforebrain as rats perform the rCET, to determine whether this neuronalpopulation is responsible for the previously ascribed role of acetylcholine inregulating decision making with cognitive effort costs. Experiments 2 and 3 usestandard inactivation techniques to investigate striatal and orbitofrontal cortexcontributions to this form of decision making, and Experiment 4 uses adisconnection procedure to assess whether BLA- ACC signaling regulates willingness to apply cognitive effort. Collectively, the current findings complementexisting work in the domain of physical effort allocation, and support the notionthat these two forms of effort-based decision making are mediated by distinct,albeit overlapping circuitries. While this work fundamentally contributes to anunderstanding of how organisms navigate their environment, it also has practicalutility. Indeed, work with the rCET and related cognitive effort paradigms mayhelp identify behavioural or pharmacological therapies that can boost cognitivewillingness. Alternatively, information gained may shed light on the aberrantprocesses underlying a blunted desire to achieve lucrative outcomes, asobserved in disorders like depression, schizophrenia, and Parkinson’s Disease.

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Addiction is a chronic relapsing psychiatric disorder affecting millions worldwide. Despite years of research investigating the etiology and phenomenology of substance abuse, there is no cure. Determining factors which promote the addictive phenotype may help to discover new therapeutics. Several clinical studies have shown addicts demonstrate poor cost/benefit decision making as measured by validated tasks such as the Iowa Gambling Task (IGT), a cognitive deficit maintained during periods of abstinence and associated with relapse risk. However, it is unclear whether disadvantageous choice precedes or is the consequence of drug abuse. Furthermore, dopaminergic signalling, actively recruited by drugs of abuse, has also been implicated in decision-making biases, and may contribute to choice deficits after drug exposure. The experiments here explored the role of disadvantageous choice in addiction susceptibility using rodent analogues of the IGT, the rat gambling task (rGT) and cued rat gambling task (crGT). These paradigms require the animal to choose between four different nose poke options which are associated with sugar wins, probabilities of winning, and timeouts. The crGT also includes salient reward-paired cues to enhance risky decision making. The first two experiments assessed whether baseline risk-preference on the rGT and crGT affected drug seeking as measured by cocaine self-administration, and whether drug exposure affected task performance. The third study examined the influence of task experience on the locomotor response to cocaine and responding for conditioned reinforcement, two dopamine-dependent behavioural assays associated with addiction risk. Basal and cocaine-induced nucleus accumbens dopamine release was also assessed using microdialysis after task training. The final study used chemogenetics to reduce nucleus accumbens dopamine to investigate the role of dopaminergic tone in choice biases. Our results show poor decision making precedes drug exposure, and is uniquely susceptible to drug-induced cognitive deficits. crGT rats showed greater drug seeking and sensitivity to cocaine-induced choice impairments, a phenotype linked to basal accumbal dopamine efflux. Finally, by reducing accumbens dopamine, animals showed marked reductions in risky choice. These data support the conclusion that poor decision making may serve as a cognitive endophenotype for addiction via aberrant dopaminergic signaling within the mesostriatal network.

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Neurobiological changes in Parkinson’s Disease (PD) involve dramatic loss of dopamine neurons in the substantia nigra (SNc) and terminals in the dorsal striatum. L-DOPA, first line treatment for PD, can produce debilitating side-effects like dyskinesia over time. Preferential dopamine D2/3 agonists like ropinirole, are used to treat PD, but these newer drugs can lead to impulse control disorders (ICDs) and gambling disorder in a significant minority of patients. The mechanism mitigating dopamine replacement therapy (DRT)-induced ICDs, or whether premorbid behavioural tendencies are a risk factor are unknown. We show that chronic ropinirole increases preference for uncertainty on the rodent Betting task (rBT), regardless of animals’ baseline preference for the safe or uncertain option. Comparatively, ropinirole had subtle effects on choice of a cued version of the rat Gambling task (rGT), while increasing impulsivity, suggesting different neural mechanisms in performance of these tasks. GSK3ß has been involved in disorders of impulsivity suggesting a potential intracellular mechanism for DRT-ICDs. However, chronic administration of SB 216763, a GSK3ß inhibitor, did not attenuate gambling-like behaviours following ropinirole, but also did not reliably decrease GSK3ß levels, such that we were unable to unequivocally determine its role in ropinirole-induced preference for uncertainty. The “overdose” hypothesis, in which DRTs would replenish dopamine stores in the deteriorated dorsal striatum and improve movement, but overwhelm the mostly spared mesolimbic reward system, was suggested to explain DRT-ICDs in PD. However, newer studies suggest a potential involvement for the nigrostriatal, rather than mesolimbic, pathway in gambling disorders. We therefore manipulated the nigrostriatal pathway using designer receptors exclusively activated by designer drugs (DREADDs). Activation of dopamine neurons in the SNc increased preference for uncertainty on the rBT in wager-sensitive rats, partially mimicking the effect of ropinirole, while inhibition of these neurons had no effect on the increase in preference for uncertainty caused by ropinirole. These studies suggest a potential role for activation of the nigrostriatal pathway in DRT-ICDs. They also suggest that ICDs result from DRT alone, rather than from an interaction between medication and basal risk preference, or change in dopamine function caused by the diseases for which they are prescribed.

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Gambling is an enjoyable and innocuous past-time for many, but for some it can become a maladaptive compulsion akin to drug or alcohol addiction. Despite increasing recognition that the phenomenological process underlying both substance and behavioural addictions may be similar, treatment options for problem gambling remain limited, and of questionable efficacy. Animal models offer an invaluable opportunity to not only study the underlying neurobiology of disorders such as gambling, but may also facilitate the development of novel pharmacotherapies. To that end we have developed a rodent slot machine task (rSMT) that suggests rats share key behavioural features with human gamblers. The dopamine D₂-like receptor family is critically involved in modulating animals’ performance on the rSMT. Specifically, the D₄ receptor appears to contribute to animals’ attributions of salience to game-related stimuli. D₄ receptors are principally located within prefrontal cortical regions and consequently represent an intriguing target for modulating higher order cognitive processes. In addition to systemic pharmacology, we have demonstrated that disruption of neural regions that are relatively rich in D₄ receptors, such as the anterior cingulate and insular cortex, impact animals’ ability to accurately respond to reward-related stimuli on the rSMT; further emphasising a role for these receptors in gambling-related decision making.Additionally, we have used the rSMT to try and model iatrogenic gambling observed in patients with Parkinson’s disease (PD). This form of compulsive gambling arises de-novo in a small but significant sub-set of patients following adjunctive therapy with D₂-like agonists. Chronic administration of a D₂/₃ receptor agonist galvanized performance on the rSMT, a finding that could be considered translationally analogous to the compulsive play exhibited by some PD patients. These alterations in performance were accompanied by an increase in the transcription factor pCREB in the nucleus accumbens. Administration of the β-adrenoreceptor blocker propranolol, which putatively attenuates this increase in pCREB, ameliorates the compulsive-like task engagement. Ultimately, gambling is a heterogeneous disorder that is unlikely to have a single underlying aetiology. However, these data indicate that aberrant dopaminergic signalling within the D2-like receptor family may underlie at least some of the cognitive perturbations observed in problem gambling.

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Amotivational states and insufficient recruitment of mental effort have been observed in a variety of clinical populations, including depression, traumatic brain injury, post-traumatic stress disorder, and attention-deficit/hyperactivity disorder. Previous animal models of effort-based decision making have utilized physical costs whereas human studies of effort have been primarily cognitive in nature, and it is unclear whether the two types of effortful decision making are underpinned by the same neurobiological processes. We therefore validated a novel rat Cognitive Effort Task (rCET) based on the five-choice serial reaction-time task, a well-established measure of attention and impulsivity. Within each rCET trial, rats were given the choice between an easy or hard visuospatial discrimination, and successful hard trials were rewarded with double the number of sugar pellets. Similar to previous human studies, stable individual variation in choice behaviour was observed, with “workers” choosing hard trials significantly more than their “slacker” counterparts. We used a variety of pharmacological agents as well as temporary inactivation of select brain regions, and showed that the effects of these manipulations often interacted with animals’ baseline preferences. Amphetamine and caffeine caused workers to “slack off”, whereas slackers “worked harder” under amphetamine but not caffeine. Dopamine antagonism had no discernible effects on animals’ choice, contrary to the physical-effort literature. The cholinergic drug nicotine decreased slackers’ willingness to expend effort, whereas scopolamine more substantially decreased workers’ choice of the high-effort option. Temporary inactivation of the basolateral amygdala caused workers to slack off and slackers to work harder, whereas anterior cingulate and medial prefrontal cortex inactivations caused all animals to slack off. In sum, we have shown for the first time that rats are differentially sensitive to cognitive effort when making decisions, independent of other processes such as impulsivity, and these baseline differences appear to be reflected by differences in underlying neurobiology. Further, we demonstrate that mental and physical effort are in part dissociable, both behaviourally and in terms of neurochemistry and neural circuitry. Such findings could inform our understanding of the neurobiological basis of decision making as well as impairments in effort-based decision making, and may contribute to novel therapeutic interventions.

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The Iowa Gambling Task (IGT) is a commonly used clinical test of decision-making. During the IGT, subjects choose between options associated with gains and losses. We have developed a novel rat gambling task (rGT), during which subjects are required to maximize their earnings within a 30 min session. Animals choose between four options, each associated with a different number of sucrose pellets, probability of receiving reward, and the magnitude and possibility of experiencing a punishing time-out period during which reward cannot be earned. Persistent choice of the larger reward options results in greater loss—as these options are associated with more frequent and longer time-out periods—resulting in less reward earned per unit time. Therefore, similar to the IGT, subjects are required to choose from the smaller reward options to maximize long-term gains. Results from Experiment 1 demonstrated that rats learn to choose most often from the best option by incorporating multiple factors into making their decisions. Therefore, the rGT may be a useful tool to study the biological basis of decision-making. Following pharmacological challenges with amphetamine and receptor-specific serotonergic and dopaminergic agents, data from Experiments 1 and 2 demonstrated that both neurotransmitters play important roles in modulating decision-making preferences. Furthermore, results from Experiment 2 suggested that amphetamine’s ability to alter decision-making may not be caused by increased dopamine release. Additionally, animals reared in an enriched environment or in isolation were slower to learn the optimal strategy, but only isolation-reared rats chose more often from the disadvantageous options. Experiment 3 determined that lesions of either orbitofrontal cortex (OFC) or basolateral amygdala (BLA) impaired acquisition of the rGT. However, if these lesions occurred after training on the rGT, only rats with BLA lesions chose disadvantageously. These results indicated that the BLA—but not the OFC—is involved in maintaining an optimal strategy on the rGT, yet both regions are required during task acquisition. Experiment 4 used a contralateral disconnection lesion procedure to determine that the connectivity between the OFC and BLA was important in learning the optimal strategy, as well as updating decision-making preferences following reward devaluation.

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