Human Self-Domestication and the Extended Evolutionary Synthesis of Addiction: How Humans Evolved a Unique Vulnerability

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Human Self-Domestication and the Extended Evolutionary Synthesis of Addiction: How Humans Evolved a Unique Vulnerability

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Tanya Calvey

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School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, South Africa

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Abstract—Humans are more vulnerable to addiction in comparison to all other mammals, including nonhuman primates, yet there is a lack of research addressing this. This paper reviews the field of comparative addiction neuroscience, highlighting the significant inter-species variation in the mesocortical dopaminergic and other neuromodulatory systems involved in addiction. Artificial selection gives rise to significant changes in neuroanatomy, neurophysiology and behaviour as shown in certain rodent strains and other domesticated animals. These changes occur over a few generations, relatively short periods of time in evolutionary terms, and demonstrate how dynamic these neuromodulatory systems are in response to the environment. During the course of human evolution, traits crucial to our survival, expansion and domination (traits such as the ability to innovate, adapt to different environments and thrive in a civilization) have been positively selected for, yet also predispose humans to addiction. This is evident in our unique neurochemistry and receptor-drug activation potencies. Examples of these are provided as possible targets for precision medicine. Ó 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

Key words: the extended evolutionary synthesis; addiction; comparative addiction neuroscience; domestication; epigenetics; dopamine.

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INTRODUCTION

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There is little evidence of non-domesticated mammals becoming addicted to substances in nature (Siegel, 2005). Mammals will use intoxicating substances with an abuse potential yet the use is seasonal and does not affect the animal’s survival or reproduction. There is a lack of research addressing this issue. Domesticated animals are more prone to addiction (Calvey, 2017). Even so, domesticated laboratory animals display substantially lower rates of addiction in comparison to human populations. For example, the capture rate of heroin is 20% in rats whereas in human populations this number is more than double (Siegel, 2005). What are the neurochemical and molecular reasons for this difference in propensity for addiction?

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Abbreviations: ADE, Alcohol deprivation effect; AMPA, a-amino-3-hyd roxy-5-methyl-4-isoxazolepropionic acid; CRH, Corticotropin-releasing hormone; CYP2A6, Cytochrome P450 2A6; DA, Dopamine; DAT, Dopamine transporter; DDC, DOPA decarboxylase; DOM, 2,5-Dime thoxy-4-methylamphetamine; F344, Fisher rat strain; HPA, Hypothalamic-pituitary-adrenal; LEW, Lewis rat strain; MPP+, 1methyl-4-phenylpyridinium; NMDA, N-Methyl-D-aspartate; OCD, Obsessive-compulsive disorder; RHA, Roman High Avoidance rat strain; RLA, Roman Low Avoidance rat strain; SNPs, Single-nucleotide polymorphism; SUDs, Substance use disorders; TH, Tyrosine hydroxylase; TAAR1, Trace amine-associated receptor 1. E-mail address: [email protected]

Animal models are essential to study certain aspects of addiction but considering that more than 80% of potential therapeutics fail when tested on humans (Perrin, 2014), there is an urgent need to evaluate what is different about human neuroscience and behavior in the hopes of discovering more effective treatments for substance use disorders (SUDs), psychiatric disorders and other diseases. This review summarizes the field of comparative addiction research, listing inter-species differences in key neuromodulatory systems and genetics implicated in the propensity for addiction. I provide examples of how artificial selection is able to change neurochemistry in domesticated animals and offer human selfdomestication as one hypothesis which may explain certain human-specific neurochemistry and behavior related to addiction.

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SPECIES DIFFERENCES IN PHARMACODYNAMICS AND DRUG METABOLISM

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Considerable differences exist between different species and how they respond to substances of abuse. These neurobiological and behavioural responses relate to the extensive genetic variation in gene families that code for liver enzymes and neuroreceptors, amongst others.

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https://doi.org/10.1016/j.neuroscience.2019.09.013 0306-4522/Ó 2019 IBRO. Published by Elsevier Ltd. All rights reserved. 1 Please cite this article in press as: Calvey T. Human Self-Domestication and the Extended Evolutionary Synthesis of Addiction: How Humans Evolved a Unique Vulnerability. Neuroscience (2019), https://doi.org/10.1016/j. neuroscience.2019.09.013

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Drug metabolism is related to addiction propensity as found recently in a drug discovery trial to curb nicotine addiction. Drugs targeting liver enzyme Cytochrome P450 2A6 (CYP2A6), which metabolizes nicotine and many narcotics, decrease the desire for nicotine by slowing metabolism and fewer copies of the CYP2A6 gene has been linked to diminished propensity for addiction (Denton et al., 2018). There is extensive interspecies variation in the CYP gene family that is relevant in drug toxicity and metabolism. For example, human variation in CYP2D6 can lead to an inability to metabolize certain drugs. Five to ten percent of Caucasians lack the CYP2D6 gene which is also involved in metabolizing ibogaine (a psychedelic indole alkaloid) and the majority of deaths due to ibogaine occur in Caucasian individuals (Corkery, 2018). For this reason, many ibogaine clinics are incorporating CYP2D6 cytochrome genotyping into screening procedures. Inter-species variation in this gene family could play a role in the differing median lethal dose (LD50) of ibogaine in rodents. The LD50 of ibogaine is 145 mg/kg in rats, 263 mg/kg in mice and 82 mg/kg in guinea pigs (Corkery, 2018). Another interesting example of CYP variation is found in the koala bear, Phascolarctos conereus, as a recent genome sequencing study has uncovered CYP expansions that allow the animal to survive on a diet of eucalypt foliage (Johnson et al., 2018). As further example of inter-species variation in drug toxicity, fly agaric is known to be toxic to humans and results in death which is not the case for wild animals, and baboons enjoy eating Cycadaceae fruit which is known to be poisonous to humans (Siegel, 2005). Research into the inter- and intra-species variation in this and other gene families involved in drug metabolism in relation to addiction propensity could be of tremendous value in the field. Psychedelics are a clear example of inter-species differences in substance use behavior and neuropharmacology. The differences in pharmacokinetics and metabolism of certain psychedelic drugs between rodents and primates may be related to differences in the serotonergic system (Murnane, 2018). For example, when rats and primates were trained to discriminate 2,5-Dimethoxy-4-methylamphetamine (DOM), 5HT2A agonists enhanced the discriminative stimulus effect of DOM in both rodents and primates and 5HT1A attenuated the effect in primates but not in rodents (Li et al., 2010; Murnane, 2018). Further species differences exist in the functioning of the 5HT1A receptor, such as its ability to release noradrenalin from the locus coeruleus to either dilate the pupil in rodents or constrict the pupil in primates, including humans (Prow et al., 1996; Fanciullacci et al., 1995; Yu et al., 2004). The cellular anatomy of the locus coeruleus also differs between rodents and primates, where primates have two divisions of the A6 locus coeruleus nucleus, the diffuse and compact divisions (A6c and A6d), and rodents (and most other mammals) only have the diffuse division (Calvey et al., 2015a). There are significant species differences in ligand/ receptor interactions. The ligand recognition site of the kappa opioid receptor subtypes differ among

mammalian species as found in a study comparing ligand selectivity patterns between humans, rats and guinea pigs (Rothman et al., 1992). Human dopamine transporter (DAT) shows the highest activities for dopamine uptake, uptake of neurotoxin 1-methyl-4phenylpyridinium (MPP+) and cocaine binding when compared to bovine and rat (Lee et al., 1996). Lee et al. (1996) concluded that humans are, therefore, more vulnerable to MPP+ toxicity and cocaine addiction.

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SPECIES VARIATION IN NEUROANATOMY AND RELEVANT NEUROMODULATORY SYSTEMS

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Rodents and primates vary considerably in cortical and prefrontal cortical regions. Although rodents could be considered to have a homologue of the prefrontal cortex if you include orbital and cingulate cortices, rodents do not have a homologue of the dorsolateral prefrontal cortex (Preuss, 1995), the cortical region most implicated in SUDs. Considerable inter-species variation exists between the cytoarchitectonic profile of the functionally distinct cortical regions and the underlying anatomical connectivity (van den Heuvel et al., 2016) and recent evidence highlighting human connectome architecture renders humans more vulnerable to numerous psychiatric diseases (e.g. bipolar disorder and schizophrenia) in comparison to even nonhuman primates (Griffa and Van den Heuvel, 2018). Humans possess a unique dopaminergic system, displaying human-specific modifications in gene expression in the dopaminergic system in anatomical regions involved in working memory, reasoning, exploratory behavior and intelligence (Raghanti et al., 2016, 2018; Sousa et al., 2017). Human-specific up- or down-regulation is predominantly found in the striatum followed by the thalamus, primary visual cortex and dorsolateral prefrontal cortex. Dopamine receptor genes DRD1, DRD2 and DRD3 exhibit human-specific downregulation in the striatum. Tyrosine hydroxylase (TH) and DOPA decarboxylase (DDC) dopamine biosynthesis genes display human-specific up-regulation in the striatum. The human striatum and neocortex are enriched with rare interneurons that express TH and DDC and are significantly more numerous compared to African apes (Raghanti et al., 2016, 2018; Sousa et al., 2017). There are differences in ligand/receptor interactions between rodent and human trace amine-associated receptor 1 (TAAR1) as well as substantial inter-species variation between substances and their ability to activate TAAR1 (de Gregorio et al., 2018; Simmler et al., 2016; Rutigliano et al., 2018). TAAR1 is a G protein-coupled receptor expressed throughout the limbic system that interacts with and modulates additional neurotransmitter systems such as dopamine, serotonin, adrenalin and glutamate (Simmler et al., 2016; Rutigliano et al., 2018). TAAR1 modulates glutamatergic transmission in the prefrontal cortex (Rutigliano et al., 2018). It also plays a role in controlling neuronal firing frequency (Simmler et al., 2016). TAAR1 exerts negative control over dopaminergic tone and inhibits dopaminergic neurotransmission in response to drug use in relevant struc-

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tures such as the nucleus accumbens (Rutigliano et al., 2018). TAAR1 agonists control impulsivity, reduce cocaine self-administration, reinstatement of drug seeking behavior and inhibit cocaine conditioned place preference (Rutigliano et al., 2018). Individuals with sub-functional TAAR1 could be predisposed to addiction and several psychiatric disorders such as psychosis, mood disorders and attention-deficit/hyperactivity disorder (Rutigliano et al., 2018). The species variation in the activation potencies of TAAR1 have important implications for addiction propensity of different animals and the translational validity of certain animal models. Humans demonstrate significantly lower activation potencies for psychoactive substances meaning that substances are less potent at human TAAR1 than at rodent TAAR1. This has implications for translational validity as rodent addiction models may underestimate risk of addiction to psychoactive substances (Simmler et al., 2016). Differences exist in the catecholaminergic and glutamatergic cellular characteristics of the ventral midbrain between rodents and primates. Marmosets and humans display a higher proportion of (TH)-only and dopamine-only cells in contrast to rodents where there is a higher proportion of TH/glutamate and dopamine/ glutamate cells in the ventral midbrain (Kelly and Fudge, 2018). Rodents and primates also vary considerably in stress response partly due to significant variation in levels of expression and distribution of key mediators of stress responses as well as adolescent time courses that drive the development of these responses (Barr, 2011). Rhesus macaques and humans have a promotor region of the corticotropin-releasing hormone (CRH) gene that is under purifying selection, this region is thought to react with environmental stressors to increase stress responding and alcohol consumption in humans (Barr, 2011). The distribution of CRH receptors, CRH1 and CRH2, differ considerably in the rodent and primate regions (pituitary, neocortex, locus coeruleus, cerebellar cortex, thalamus, striatum, certain hypothalamic nuclei and the nucleus of the stria terminalis) suggesting that these receptor subtypes have differing roles in rodents and primates (Sa´nchez et al., 1999).

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COMPARATIVE ADDICTION BEHAVIOUR

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Given the differences in anatomy and physiology of key addiction-related systems, it is not surprising that humans and animals differ in their appetite for drugs. For example, monkeys trained to smoke cannabis in order to obtain food and water will stop smoking when food and water become freely available (Siegel, 2005). In an experiment with monkeys and apes, animals were given a choice of low or high dose cocaine gum and throughout the experiment showed little interest in the higher doses (Siegel, 2005). Psychedelics seem to have very little appeal to nonhuman primates and rodents and are considered to be a false negative of selfadministration procedures even though there is some

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level of recreational abuse of psychedelics in humans (Murnane, 2018; UNODC 2018). Inbred strains of rodents provide valuable information related to propensity for addiction within the order Rodentia and the corresponding differences in molecular biology. This evidence also serves as a lead into the domestication research discussed further on. The following strains will be discussed; C57BL/6N and DBA/2J mice, the Fisher (F344) and Lewis (LEW) rat strains, the Roman High and Roman Low Avoidance rat strains (RHA and RLA respectively), Sprague-Dawley rats, and Wistar rats. Alcohol deprivation effect (ADE) is a robust model for relapse behavior and is dependent on the genetic background of the animal (Vengeliene et al., 2014). There are differences of ADE and alcohol intake among rodent strains. For example, Sprague-Dawley rats have a lower alcohol intake than Wistar rats (Vengeliene et al., 2014). Alcohol consumption varies in different rodent species and strains and has been found to be inconsistent in mice as compared to rats (Vengeliene et al., 2014). C57BL/6N mice voluntarily consume considerable amounts of alcohol and exhibit robust alcohol deprivation effect (ADE), a model for relapse behaviour. After 3 months of voluntary drinking, baseline alcohol intake drops considerably in these mice, a reliable and replicable observation made by Vengeliene et al. (2014). After 15 weeks, average alcohol consumption was as low as 2 g/kg per day. In contrast, Wistar rats maintained relatively stable baseline alcohol consumption levels. This study found that if there is relapse onset in mice, it is very seldom longer than a day which questions transgenic mouse models of addiction and specifically, alcohol relapse (Vengeliene et al., 2014). This study also found that common pharmaceuticals used to treat substance abuse (acamprosate, naltrexone, nalmefene, lamotrigine) have the opposite effect in mice when compared to rats and increased the amount of alcohol consumed during relapse-like drinking. The Fisher rat strain (F344) is addiction resistant and the Lewis rat strain (LEW) is addiction prone. LEW rats display greater behavioural responses to drugs and fail to show biochemical adaptations in the mesolimbic dopamine system after chronic drug exposure in contrast to F344 rats (Kosten et al., 1997). These strains also differ in their behavioural and neurochemical response to novel environments (Flores et al., 1998). Flores et al. (1998) found that the differences in novelty seeking and responses to drugs are in part, due to specific differences in the dopaminergic system. LEW rats have lower DAT levels in the striatum and nucleus accumbens, lower levels of D2 receptors in the striatum and core of the nucleus accumbens and lower levels of dopamine D3 receptors in the nucleus accumbens and the olfactory tubercle compared to F344 rats. Flores et al. (1998) concluded that the differences in behavior may be due to alterations in genetic elements that regulate the dopaminergic system. These strains also differ considerably in their stress response (F344 are more sensitive to stress), opioid gene expression (Oprm, Oprk, Pdyn, Penk) and D1 and D2 receptor binding (Sa´nchez-Cardoso et al., 2007; Valenza et al., 2016). F344 rats have higher levels of

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TH protein, glutamate, DAT, corticosterone, serotonin, opioids and an increased number of mu-opioid receptors in the nucleus accumbens. In contrast, LEW rats have higher baseline levels of TH, dopamine D1 and NMethyl-D-aspartate (NMDA) receptors in the ventral tegmental area as well as increased mu-opioid receptor activity in several brain regions (Ballesteros-Yanez et al., 2008). F344 and LEW rats show significant differences in the structure of pyramidal neurons from prelimbic and motor cortices where LEW rats have a higher density and total number of dendritic spines per neuron in the basal dendritic tree compared to F344 rats (Ballesteros-Yanez et al., 2008). TH gene expression and protein levels were found to be significantly increased in the hippocampus and striatum of F344 compared to LEW (Herrado´n et al., 2006). Differing hippocampal noradrenergic activity could be involved in their differing stress, pain and drug responses (Herrado´n et al., 2006). LEW rats display diminished hippocampal and frontal cortical 5HT1A receptor binding sites and mRNA expression than compared to Sprague-Dawley rats and drug naı¨ ve LEW rats display mesolimbic features similar to drugtreated Sprague-Dawley rats (Brimberg et al., 2007). Genetic factors account for differences in individual vulnerability to heroin addiction as shown between C57BL/6J and DBA/2J mice (Bailey et al., 2010). Heroin induces locomotion and sensitization in C57BL/6J mice but not in DBA/2J mice and the strains prefer different doses of heroin as measured by conditioned place preference. These differences in behavior are due to differences in mu-opioid receptor activation and DAT expression (Bailey et al., 2010). The selective breeding of 100 generations of rats has resulted in two strains (RHA and RLA) that differ in addiction propensity, novelty seeking, sensation seeking and stress response and these differences in behavior are, in part, due to significant differences in the functional properties of the mesolimbic dopaminergic system. These rats were bred from Wistar rats and selected for rapid (RHA) versus poor (RLA) acquisition of active avoidance in a shuttle box (Giorgi et al., 2007) such that the RHA line is now a valid model to investigate the neural basis of novelty seeking. An increase in cortical dopaminergic output is positively correlated to the performance in this task and selective breeding has resulted in two phenotypes that consistently differ in dopaminergic tone. As reviewed by Giorgi et al. (2007), stressors and anxiogenic drugs activate the mesocortical dopaminergic pathway of RHA but not RLA rats, RHA rats have a faster turnover rate of dopamine in the caudate nucleus, RHA rats show more intense stereotypies in response to apomorphine than do RLA rats, the density of dopamine D1 receptors in the nucleus accumbens is higher in RHA rats than in their RLA counterparts. These rats also differ in coping styles where RHA rats display a proactive coping strategy with low intensity hypothalamic-pituitaryadrenal (HPA) axis responses and RLA rats show reactive, fearrelated behaviours (freezing, self-grooming) and elevated HPA axis reactivity (Giorgi et al., 2007). The Roman rat lines differ in their neurochemical and behavioural responses to drugs of abuse. Acute low-dose

morphine, cocaine or amphetamine administration elicits a larger increment in dopamine output in the nucleus accumbens shell of RHA rats in contrast to the RLA rats and this increased responsiveness of the mesolimbic dopaminergic projections is associated with a more robust, drug-induced increase in ambulatory and stationary activities in RHA rats. This suggests that the Roman lines differ in the functional properties of neural circuits of reward. RHA rats also show significantly higher ethanol and cocaine preference relative to RLA rats. In non-selected Sprague-Dawley rats, 9–13% of animals receiving daily cocaine for a week develop behavioural sensitization in contrast to 90% of RHA and 2% of RLA. Giorgi et al. (2007) concluded that genetically determined patterns of mesocortical and mesolimbic dopaminergic functioning and neural circuits encoding brain reward and goal-directed behavior influence individual susceptibility to develop drug addiction.

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DOMESTICATION

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Domestication is a form of selective breeding that leads to significant changes in brain function and behavior over generations (Spocter et al., 2018). There are important differences between wild and domesticated animals and their propensity for substance use and addiction (Calvey, 2017). For example, wild monkeys seem to fear the psilocybin mushroom whereas domesticated monkeys experiment with it (Siegel, 2005). Kukekova et al. (2018) details the findings of the sequencing and assembly of the red fox, Vulpes vulpes, genome in tame and aggressive populations developed through five decades of selection for behaviour, known as the Russian farm-fox experiment. Fox domestication led to genetic differences between the populations selected for aggressive or friendly behavior towards humans in contrast to normally bred foxes which included genetic factors that may be involved in blunting the response of the HPA axis. SorCS1 was identified as a strong candidate gene for tame behavior. SorCS1 encodes the main trafficking protein for a-amino-3-hydro xy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors and neurexins and suggests a role for synaptic plasticity in fox domestication which supports previous findings of genes coding for different types of glutamate receptors being associated with domestication in dogs, cats and rabbits. Other regions identified as likely to have been under selection in foxes include genes implicated in human neurological disorders and mouse behavior: 13 genes associated with autism spectrum disorder, 13 genes associated with bipolar disorder and 6 genes in regions previously associated with aggressive behavior in mice (Kukekova et al., 2018). The changes in physiology and morphology observed over the course of fox domestication is thought to be the result of pleitropy, random fixation or DNA methylation. Another interesting finding of this study was the discovery of a link between aggressive behavior and immunological responsiveness as the same set of interleukin genes were found as in a previous study on the domestication of the dog from the wolf suggesting

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a role of immune genes in both dog and wolf domestication. A comparative genomics study of domesticated animals, modern humans and early Homo, provides evidence that humans have self-domesticated as there is overlap between common genes that have been selected for during animal and human selfdomestication (Theofanopoulou et al., 2017). The term self-domestication indicates that the processes leading to domestication have been due to autonomous seeking of cohabitation. Many of the genetic markers of domestication are involved in neural crest development (FAM172A, BRAF, NRG3, DCC) which supports the neural crest-based hypothesis of domestication (Theofanopoulou et al., 2017) and reinforces the hypothesis that human self-domestication likely emerged with reduced canine size (Raghanti, 2019). Indeed, certain of these genes could play a role in the morphological characteristics of domestication syndrome (e.g., smaller teeth, reduced cranial capacity and feminization): RNPC3 (mutations lead to growth hormone deficiencies and pituitary hypoplasia), ERBB4 (loss of function leads to defects in hindbrain cranial neural crest pathfinding). Feminization, or a reduction in sexual dimorphism, leads to a reduction in androgen levels and a rise in estrogen levels which is also associated with reduced reactivity of the HPA axis, a characteristic feature of domestication syndrome. Other genes play a role in synaptic plasticity and cognition, for example, BRAF, positively selected in modern humans, cats and horses, is involved in the ERK/MAPK signaling pathways which regulates synaptic plasticity, learning and memory (Theofanopoulou et al., 2017). Glutamatergic receptor genes are positively selected for during domestication. As already mentioned, SorCS1 is a candidate gene for tameness in foxes (Kukekova et al., 2018). GRIK3 glutamate receptor is positively selected for in modern humans, dogs and cattle, GRID1 in horses, GRIA1/2 in cats (Theofanopoulou et al., 2017). Polymorphisms in GRIK3 and GRID1 are implicated in schizophrenia and GRIK2 is implicated in obsessive–compulsive disorder (OCD) behavior. Additional domestication mutations can lead to OCD and autisticlike traits, S33OA mutation of SLITRK1 and A429V respectively (Theofanopoulou et al., 2017). These findings clearly suggest that domestication may enhance neurological processing, enhance sensory-motor perceptual and learning pathways but also lead to neurodevelopmental disorders and psychiatric diseases. Selection for prosocial neurochemistry in the striatum of early hominids contributed to the emergence of our species from the last common ancestor we shared with the ancestors of extant African apes. Evidence suggests that increased cooperation and bonding could have been achieved through changes in the neurochemistry of the striatum as the striatum has well established roles in social function (Raghanti et al., 2016; 2018). Organization of the dopaminergic, cholinergic and serotonergic systems in the human striatum are both unique among primates and consistent with our distinctive social behavior (Ba´ez-Mendoza and Schultz, 2013; Raghanti et al.,

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2016, 2018). Humans have increased dopaminergic innervation and functioning in the striatum than do nonhuman primates (Raghanti et al., 2016, 2018; Sousa et al., 2017), and striatal dopamine has a wellestablished role in social reward and conformity in a wide variety of species (Rilling and Sanfey, 2011; Ba´ezMendoza and Schultz, 2013; Stallen and Sanfey, 2015). In summary, artificial selection, such as domestication, leads to changes in animal and human genetic mechanisms that drive rapid changes in neurochemistry, brain function and behavior. Human individuals and groups able to thrive in a community would have a considerable advantage over those unable to. The resulting changes in our neurochemistry may, in part, explain our augmented propensity for addiction as there is an overlap of genes and neuromodulators implicated in human and animal domestication literature (Raghanti et al., 2016; Kukekova et al., 2018; Theofanopoulou et al., 2017) as well as in human addiction research (Calvey, 2017; Uhl et al., 2009; Ozburn et al., 2015).

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Additional evolutionary theories have been proposed to explain our unique neurochemistry and vulnerability to psychiatric disease (reviewed in Calvey, 2017; Saah, 2005). Due to the complex nature of addiction and the multiple neurotransmitter systems involved, it is likely that multiple environmental and social selection pressures influenced the evolution of modern human neurochemistry. Animals are able to adapt their behavior according to their habitat and social environment via changes in the physiology of the various neurotransmitter systems. Dopaminergic functioning seems to be particularly important in these processes as well as in contributing to addiction pathology. All substances of abuse either act directly or indirectly on the dopaminergic system whereby chronic drug use leads to hypofunctioning of the system (Beeler et al., 2014; Benyamina et al., 2016; Calvey, 2017; Diana, 2011; Entler et al., 2016; Fehr et al., 2008; Miller, 2013; Myers et al., 2017; Rademacher et al., 2016; Siegel, 2006; Volkow et al., 2011). The manipulation of dopamine concentration drives behavioral flexibility as dopamine modulates neural network flexibility (Beeler et al., 2014; Sharples et al., 2014). Specifically, the D2 receptors in the prefrontal cortex facilitate adaptive flexibility and cognitive flexibility (Beeler et al., 2014; Durstewitz and Seamans, 2008). The isocortex and striatum of mammals are abundant in dopaminergic end fibers (Calvey et al., 2013, 2015a, 2015b, 2016) which have also been implicated in the ability of nonhuman primates to innovate (Zaidel, 2014). Innovation is also related to the ability of the animal to deal with seasonal change (Zaidel, 2014). Additional evidence of dopamine’s role in behavioural flexibility is provided by Bergey et al. (2016) in extant baboons (Papio anubis and Papio hamadryas). Dopamine receptor-mediated genes (SLC6A3, COMT, and

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PPP1CC) are implicated in the divergent social behaviors (male impulsivity or restraint during mate acquisition) of these closely related, inter-fertile baboon species and several loci within the dopamine receptor-mediated signaling pathway were flagged as focal points of functionally significant species divergence which suggests that modification of dopamine function may be the cause, not a correlate, of the behavioral difference in these baboons (Bergey et al., 2016). As dopamine is the primary neuromodulator involved in reinforcement learning and behavioral flexibility it is possible that, as in the Roman rat lines and hamadryas and anubis baboons, behavior related to social environment, risk avoidance, positive coping strategies, ability to innovate and adapt to changing environments (Calvey, 2017) may have led to changes in the functioning of our dopaminergic system and ultimately, as in the RHA rats (Giorgi et al., 2007), our predisposition to addiction. Delay discounting (a measure of impulsivity and a recognized endophenotype for addictive disorders) is associated with single-nucleotide polymorphism (SNPs) in genes associated with dopamine transmission (MacKillop et al., 2015). Functional changes in human neuromodulatory systems could evolve in 2000–5000 years or less. The Roman rat lines have been bred over 100 generations and the Russian farm-fox experiment started 60 years ago. Given the difference in lifespan between the rat, red fox and Homo, significant changes in neurochemistry could evolve, as a conservative estimate, in 5000 years. Australopithecus emerged around 4 million years ago, the severe climate conditions in the Pleistocene period came to an end around 12 000 years ago, followed by the advent of agriculture in the early Neolithic period. This time period is ample for adaptations leading to functional changes in our neuromodulatory systems to evolve. Neurotransmitter receptors are coded by individual genes with SNPs able to elicit noticeable changes in function (Young, 2003), thus, changes in these neuromodulatory systems are able to evolve and adapt within a few generations. The changes in neurochemistry that increased our propensity for addiction also stimulated our early substance use. Australian aborigines used nicotine 40,000 years ago and beer was brewed by early Neolithic agriculturalists (Saah, 2005). This early substance use accelerated our brain evolution as substance use leads to epigenetic changes that control expression of genes involved in brain plasticity (including DRD2) which further led to stable changes in behavior, neuroanatomy and neurophysiology. Epigenetics is an important aspect of developmental plasticity in the Extended Evolutionary Synthesis as epigenetic changes lead to functional adjustments in parts of an organism during development that lead to rapid adaptation in the absence of genetic mutation (Calvey, 2017; Cortijo et al., 2014; Laland et al., 2015; Zimmer, 2017). In summary, species differ in their propensity for addiction due to substantial variation in genetics, neuroanatomy, ligand/receptor interactions, cortical

cytoarchitecture, brain connectivity and function of key neuromodulatory systems involved in addiction. Selective breeding of mice strains, rat strains, and other domesticated animals can lead to rapid changes in brain function and behaviour that render the animal predisposed to addiction and other psychiatric disorders. These changes coincide with changes to the dopaminergic system and animal and human genetic sequencing research implicates selection of neuromodulatory polymorphisms during domestication. During our evolution, traits ensuring our survival and reproduction have been positively selected for. Traits such as the ability to innovate, thrive in a civilization, adapt to changing environments and diets have altered our brain function, specifically related to the dopaminergic system which may explain why ours is unique. Substance use accelerated this evolution by creating heritable changes to our epigenome that further predisposed us to addiction. Progress in the field requires innovation into new experimental methods to identify the genetic factors underlying addiction propensity in various mammalian species. Genomic research of addiction prevalence in the various human populations may uncover additional targets for future precision therapies.

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FUNDING

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The author’s research is funded by the South African Medical Research Council (SAMRC) and the National Research Foundation (NRF).

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Anton et al. (2014), Ashok et al. (2017), Salvadore et al. (2010), Sherman (2012).

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DECLARATION OF COMPETING INTEREST

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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(Received 25 June 2019, Accepted 11 September 2019) (Available online xxxx)

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