ASU Scholarship Showcase

Illicit psychostimulant addiction remains a significant problem worldwide, despite decades of research into the neural underpinnings and various treatment approaches. The purpose of this review is to provide a succinct overview of the neurocircuitry involved in drug addiction, as well as the acute and chronic effects of cocaine and amphetamines within this circuitry in humans. Investigational pharmacological treatments for illicit psychostimulant addiction are also reviewed. Our current knowledge base clearly demonstrates that illicit psychostimulants produce lasting adaptive neural and behavioral changes that contribute to the progression and maintenance of addiction. However, attempts at generating pharmacological treatments for psychostimulant addiction have historically focused on intervening at the level of the acute effects of these drugs. The lack of approved pharmacological treatments for psychostimulant addiction highlights the need for new treatment strategies, especially those that prevent or ameliorate the adaptive neural, cognitive, and behavioral changes caused by chronic use of this class of illicit drugs.

Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF) in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders. In recent years, a small collection of preclinical animal studies has also shown that AMPA PAMs may have potential as pharmacotherapeutic adjuncts to extinction-based or cue-exposure therapies for the treatment of drug addiction. The present paper will review this preclinical literature, discuss novel data collected in our laboratory, and recommend future research directions for the possible development of AMPA PAMs as anti-addiction medications.

The group I metabotropic glutamate receptors (mGluR1a and mGluR5) are important modulators of neuronal structure and function. Although these receptors share common signaling pathways, they are capable of having distinct effects on cellular plasticity. We investigated the individual effects of mGluR1a or mGluR5 activation on dendritic spine density in medium spiny neurons in the nucleus accumbens (NAc), which has become relevant with the potential use of group I mGluR based therapeutics in the treatment of drug addiction. We found that systemic administration of mGluR subtype-specific positive allosteric modulators had opposite effects on dendritic spine densities. Specifically, mGluR5 positive modulation decreased dendritic spine densities in the NAc shell and core, but was without effect in the dorsal striatum, whereas increased spine densities in the NAc were observed with mGluR1a positive modulation. Additionally, direct activation of mGluR5 via CHPG administration into the NAc also decreased the density of dendritic spines. These data provide insight on the ability of group I mGluRs to induce structural plasticity in the NAc and demonstrate that the group I mGluRs are capable of producing not just distinct, but opposing, effects on dendritic spine density.

Background: Urbanization can strongly impact the physiology, behavior, and fitness of animals. Conditions in cities may also promote the transmission and success of animal parasites and pathogens. However, to date, no studies have examined variation in the prevalence or severity of several distinct pathogens/parasites along a gradient of urbanization in animals or if these infections increase physiological stress in urban populations.

Methodology/Principal Findings: Here, we measured the prevalence and severity of infection with intestinal coccidians (Isospora sp.) and the canarypox virus (Avipoxvirus) along an urban-to-rural gradient in wild male house finches (Haemorhous mexicanus). In addition, we quantified an important stress indicator in animals (oxidative stress) and several axes of urbanization, including human population density and land-use patterns within a 1 km radius of each trapping site. Prevalence of poxvirus infection and severity of coccidial infection were significantly associated with the degree of urbanization, with an increase of infection in more urban areas. The degrees of infection by the two parasites were not correlated along the urban-rural gradient. Finally, levels of oxidative damage in plasma were not associated with infection or with urbanization metrics.

Conclusion/Significance: These results indicate that the physical presence of humans in cities and the associated altered urban landscape characteristics are associated with increased infections with both a virus and a gastrointestinal parasite in this common songbird resident of North American cities. Though we failed to find elevations in urban- or parasite/pathogen-mediated oxidative stress, humans may facilitate infections in these birds via bird feeders (i.e. horizontal disease transmission due to unsanitary surfaces and/or elevations in host population densities) and/or via elevations in other forms of physiological stress (e.g. corticosterone, nutritional).

Background: The coevolution of male traits and female mate preferences has led to the elaboration and diversification of sexually selected traits; however the mechanisms that mediate trait-preference coevolution are largely unknown. Carotenoid acquisition and accumulation are key determinants of the expression of male sexually selected carotenoid-based coloration and a primary mechanism maintaining the honest information content of these signals. Carotenoids also influence female health and reproduction in ways that may alter the costs and benefits of mate choice behaviors and thus provide a potential biochemical link between the expression of male traits and female preferences. To test this hypothesis, we manipulated the dietary carotenoid levels of captive female house finches (Carpodacus mexicanus) and assessed their mate choice behavior in response to color-manipulated male finches.

Results: Females preferred to associate with red males, but carotenoid supplementation did not influence the direction or strength of this preference. Females receiving a low-carotenoid diet were less responsive to males in general, and discrimination among the colorful males was positively linked to female plasma carotenoid levels at the beginning of the study when the diet of all birds was carotenoid-limited.

Conclusions: Although female preference for red males was not influenced by carotenoid intake, changes in mating responsiveness and discrimination linked to female carotenoid status may alter how this preference is translated into choice. The reddest males, with the most carotenoid rich plumage, tend to pair early in the breeding season. If carotenoid-related variations in female choice behavior shift the timing of pairing, then they have the potential to promote assortative mating by carotenoid status and drive the evolution of carotenoid-based male plumage coloration.

Environmental conditions early in life can affect an organism’s phenotype at adulthood, which may be tuned to perform optimally in conditions that mimic those experienced during development (Environmental Matching hypothesis), or may be generally superior when conditions during development were of higher quality (Silver Spoon hypothesis). Here, we tested these hypotheses by examining how diet during development interacted with diet during adulthood to affect adult sexually selected ornamentation and immune function in male mallard ducks (Anas platyrhynchos). Mallards have yellow, carotenoid-pigmented beaks that are used in mate choice, and the degree of beak coloration has been linked to adult immune function. Using a 2×2 factorial experimental design, we reared mallards on diets containing either low or high levels of carotenoids (nutrients that cannot be synthesized de novo) throughout the period of growth, and then provided adults with one of these two diets while simultaneously quantifying beak coloration and response to a variety of immune challenges.

We found that both developmental and adult carotenoid supplementation increased circulating carotenoid levels during dietary treatment, but that birds that received low-carotenoid diets during development maintained relatively higher circulating carotenoid levels during an adult immune challenge. Individuals that received low levels of carotenoids during development had larger phytohemagglutinin (PHA)-induced cutaneous immune responses at adulthood; however, dietary treatment during development and adulthood did not affect antibody response to a novel antigen, nitric oxide production, natural antibody levels, hemolytic capacity of the plasma, or beak coloration. However, beak coloration prior to immune challenges positively predicted PHA response, and strong PHA responses were correlated with losses in carotenoid-pigmented coloration. In sum, we did not find consistent support for either the Environmental Matching or Silver Spoon hypotheses. We then describe a new hypothesis that should be tested in future studies examining developmental plasticity.

Background: For many bird species, vision is the primary sensory modality used to locate and assess food items. The health and spectral sensitivities of the avian visual system are influenced by diet-derived carotenoid pigments that accumulate in the retina. Among wild House Finches (Carpodacus mexicanus), we have found that retinal carotenoid accumulation varies significantly among individuals and is related to dietary carotenoid intake. If diet-induced changes in retinal carotenoid accumulation alter spectral sensitivity, then they have the potential to affect visually mediated foraging performance.

Methodology/Principal Findings: In two experiments, we measured foraging performance of house finches with dietarily manipulated retinal carotenoid levels. We tested each bird's ability to extract visually contrasting food items from a matrix of inedible distracters under high-contrast (full) and dimmer low-contrast (red-filtered) lighting conditions. In experiment one, zeaxanthin-supplemented birds had significantly increased retinal carotenoid levels, but declined in foraging performance in the high-contrast condition relative to astaxanthin-supplemented birds that showed no change in retinal carotenoid accumulation. In experiments one and two combined, we found that retinal carotenoid concentrations predicted relative foraging performance in the low- vs. high-contrast light conditions in a curvilinear pattern. Performance was positively correlated with retinal carotenoid accumulation among birds with low to medium levels of accumulation (∼0.5–1.5 µg/retina), but declined among birds with very high levels (>2.0 µg/retina).

Conclusion/Significance: Our results suggest that carotenoid-mediated spectral filtering enhances color discrimination, but that this improvement is traded off against a reduction in sensitivity that can compromise visual discrimination. Thus, retinal carotenoid levels may be optimized to meet the visual demands of specific behavioral tasks and light environments.

Sexual selection requires both that there is heritable variation in traits related to fitness, and that either some of this variation is linked to traits of the parents, and/or that there are direct benefits of choosing particular individuals as mates. This suggests that if direct benefits are important offspring performance should be predicted by traits of the rearing adults. But if indirect benefits are more significant offspring performance should be predicted by traits of the adults at the nest-of-origin. We conducted cross-fostering experiments in great tits (Parus major) over four years, in two of which we manipulated environmental conditions by providing supplemental food. In a third year, some nestlings were directly supplemented with carotenoids. Nestlings in broods whose rearing adults received supplemental food were heavier and had improved immune responses even when controlling for body mass. Nestling immune function was related to measures of the yellow plumage color of both the rearing male and the putative father. Nestling body mass was influenced by the coloration of both the rearing female and the genetic mother. Our results suggest that features of both their social and putative genetic parents influence nestling health and growth. From this it would appear that females could be gaining both direct and indirect benefits through mate choice of male plumage traits and that it would be possible for males to similarly gain through mate choice of female traits.

Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated thattype 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson’s disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability toenhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.

Male courtship display is common in many animals; in some cases, males engage in courtship indiscriminately, spending significant time and energy courting heterospecifics with whom they have no chance of mating or producing viable offspring. Due to high costs and few if any benefits, we might expect mechanisms to evolve to reduce such misdirected courtship (or ‘reproductive interference’). In Habronattus jumping spiders, males frequently court heterospecifics with whom they do not mate or hybridize; females are larger and are voracious predators, posing a severe risk to males who court indiscriminately. In this study, we examined patterns of misdirected courtship in a natural community of four sympatric Habronattus species (H. clypeatus, H. hallani, H. hirsutus, and H. pyrrithrix).

We used direct field observations to weigh support for two hypotheses (differential microhabitat use and species recognition signaling) to explain how these species reduce the costs associated with misdirected courtship. We show that, while the four species of Habronattus do show some differences in microhabitat use, all four species still overlap substantially, and in three of the four species individuals equally encountered heterospecifics and conspecifics. Males courted females at every opportunity, regardless of species, and in some cases, this led to aggression and predation by the female. These results suggest that, while differences in microhabitat use might reduce misdirected courtship to some extent, co-existence of these four species may be possible due to complex communication (i.e. species-specific elements of a male’s courtship display). This study is the first to examine misdirected courtship in jumping spiders. Studies of misdirected courtship and its consequences in the field are limited and may broaden our understanding of how biodiversity is maintained within a community.