Value-based decisions optimize behavioral outcomes. Because delayed rewards are discounted, an increased tendency to choose smaller, immediate rewards can lead to suboptimal choice. Steep discounting of delayed rewards (impulsivity) characterizes subjects with frontal lobe damage and behavioral disorders including substance abuse. Correspondingly, animal studies and indirect evidence in humans suggest that lower dopamine in the frontal cortex contributes to steeper discounting by impairing corticostriatal function. To test this hypothesis directly, we performed a randomized, double-blind, counterbalanced, placebo-controlled study in which we administered the brain penetrant catechol-O-methyltransferase inhibitor tolcapone or placebo to healthy subjects performing a delay discounting task. Tolcapone significantly increased choice of delayed monetary rewards, and this tolcapone-induced increase covaried with increased BOLD activity in the left ventral putamen and anterior insula. Tolcapone also changed corticostriatal connectivity: specifically, by inducing a decrease in the coherence between ventral putamen and pregenual cingulate cortex. These results indicate that raising cortical dopamine levels attenuates impulsive choice by changing corticostriatal function.
Trained monkeys performed a two-choice perceptual decision-making task in which they reported the perceived orientation of a dynamic Glass pattern, before and after unilateral, reversible, inactivation of a brainstem area involved in preparing eye movements, the superior colliculus (SC). Surprisingly, we found that unilateral SC inactivation produced significant decision biases and changes in reaction times consistent with a causal role for the primate SC in perceptual decision-making. Fitting signal detection theory and sequential sampling models to the data revealed that SC inactivation produced a decrease in the relative evidence for contralateral decisions, as if adding a constant offset to a time-varying evidence signal for the ipsilateral choice. The results provide causal evidence for an embodied cognition model of perceptual decision-making and provide compelling evidence that the SC of primates, a brainstem structure, plays a causal role in how evidence is computed for decisions, a process usually attributed to the forebrain.
Attentional set-shifting ability is an executive function underling cognitive flexibility in humans and animals. In humans, this function is typically observed during a single experimental session where dimensions of playing cards are used to measure flexibility in the face of changing rules for reinforcement (i.e., the Wisconsin Card Sorting Test (WCST)). In laboratory animals, particularly non-human primates, variants of the WCST involve extensive training and testing on a series of dimensional discriminations, usually in social isolation. In the present study, a novel experimental approach was used to assess attentional set-shifting simultaneously in 12 rhesus monkeys. Specifically, monkeys living in individual cages but in the same room were trained at the same time each day in a set-shifting task in the same housing environment. As opposed to the previous studies, each daily session began with a simple single-dimension discrimination regardless of the animal’s performance on the previous session. A total of eight increasingly difficult, discriminations (sets) were possible in each daily 45 min session. Correct responses were reinforced under a second-order schedule of flavored food pellet delivery, and criteria for completing a set was 12 correct trials out of a running total of 15 trials. Monkeys progressed through the sets at their own pace and abilities. The results demonstrate that all 12 monkeys acquired the simple discrimination (the first set), but individual differences in the ability to progress through all eight sets were apparent. A performance index (PI) that encompassed progression through the sets, errors and session duration was calculated and used to rank each monkey’s performance in relation to each other. Overall, this version of a set-shifting task results in an efficient assessment of reliable differences in cognitive flexibility in a group of monkeys.
These data indicate that the therapeutic potential of DOR agonists for alcohol abuse is through a selective action at the DOR-1 form of the receptor.
RATIONALE Abstinence-based approaches to treating alcohol use disorder (AUD) are highly prevalent, but abstinence from chronic drinking may exacerbate subsequent levels of alcohol intake in relapse. OBJECTIVE Use a non-human primate model that encompasses a range of chronic voluntary ethanol drinking to isolate biological responses to repeated cycles of imposed abstinence as a function of baseline voluntary alcohol drinking levels. METHODS Over a 26-month protocol, young adult male rhesus macaques were first induced to drink alcohol and then given continuous access to 4% (w/v) ethanol (n=8) or water (n=4) for approximately 14 months, followed by three 28–35 day abstinence phases, with 3 months of ethanol access in between. Ethanol intake and BEC were the primary dependent variables. Observational signs of physical dependence and circulating ACTH and cortisol were monitored. RESULTS Prior to abstinence, stable, categorical, individual differences in voluntary ethanol intake under chronic access conditions were found. Following abstinence, categorical “non-heavy” drinking subjects increased drinking transiently (increased between 0.7–1.4 g/kg/day in first month after abstinence), but returned to baseline after three months. Categorical “heavy” drinkers, however maintained drinking 1.0–2.6 g/kg above baseline for over 3 months following abstinence. Signs of physical dependence were rare, although huddling and social withdrawal increased in ethanol and control subjects. The most prominent effect on hormonal measures was heightened cortisol during abstinence that increased to a greater extent in ethanol subjects. CONCLUSION Involuntary abstinence increases drinking in the absence of overt physical withdrawal symptoms, and heavy drinkers are more robustly affected compared to non-heavy drinkers.
Nicotinic acetylcholine receptors (nAChRs) are highly conserved between humans and non-human primates. Conservation exists at the level of genomic structure, protein structure and epigenetics. Overall homology of nAChRs at the protein level is 98% in macaques versus 89% in mice, which is highly relevant for evaluating subtype-specific ligands that have different affinities in humans versus rodents. In addition to conservation at the protein level, there is high conservation of genomic structure in terms of intron and exon size and placement of CpG sites that play a key role in epigenetic regulation. Analysis of single nucleotide polymorphisms (SNPs) shows that while the majority of SNPs are not conserved between humans and macaques, some functional polymorphisms are. Most significantly, cynomolgus monkeys express a similar α5 nAChR Asp398Asn polymorphism to the human α5 Asp398Asn polymorphism that has been linked to greater nicotine addiction and smoking related disease. Monkeys can be trained to readily self-administer nicotine, and in an initial study we have demonstrated that cynomolgus monkeys bearing the α5 D398N polymorphism show a reduced behavioral sensitivity to oral nicotine and tend to consume it in a different pattern when compared to wild-type monkeys. Thus the combination of highly homologous nAChR, higher cortical functions and capacity for complex training makes non-human primates a unique model to study in vivo functions of nicotinic receptors. In particular, primate studies on nicotine addiction and evaluation of therapies to prevent or overcome nicotine addiction are likely to be highly predictive of treatment outcomes in humans.
Translating chemogenetic techniques from nonhuman primates to potential clinical applications has been complicated in part due to in vivo conversion of the chemogenetic actuator, clozapine N-oxide (CNO), to its pharmacologically active parent compound, clozapine, a ligand with known side effects, including five boxed warnings from the Food and Drug Administration. Additionally, the limited solubility of CNO requires high concentrations of potentially toxic detergents such as dimethylsulfoxide (DMSO). To address these concerns, pharmacokinetic profiling of commercially available CNO in DMSO (CNO-DMSO, 10% v/v DMSO in saline) and a watersoluble salt preparation (CNO-HCl, saline) was conducted in rhesus macaques. A time course of blood plasma and cerebrospinal fluid (CSF) concentrations of CNO and clozapine was conducted (30-240 minutes post-administration) following a range of doses (3-10 mg/kg, i.m. and/or i.v.) of CNO-DMSO or CNO-HCl. CNO-HCl resulted in 6-to 7-fold higher plasma concentrations of CNO compared to CNO-DMSO, and relatively less clozapine (3%-5% clozapine/CNO in the CNO-DMSO group and 0.5%-1.5% clozapine/CNO in the CNO-HCl group). Both groups had large between-subjects variability, pointing to the necessity of performing individual CNO pharmacokinetic studies prior to further experimentation. The ratio of CNO measured in the CSF was between 2% and 6% of that measured in the plasma and did not differ across drug preparation, indicating that CSF concentrations may be approximated from plasma samples. In conclusion, CNO-HCl demonstrated improved bioavailability compared with CNO-DMSO with less conversion to clozapine. Further investigation is needed to determine if brain concentrations of clozapine following CNO-HCl administration are pharmacologically active at off-target monoaminergic receptor systems in the primate brain.
The progress on understanding the pharmacological basis of ethanol’s discriminative stimulus effects has been substantial, but appears to have plateaued in the past decade. Further, the cross-species translational efforts are clear in laboratory animals, but have been minimal in human subject studies. Research findings clearly demonstrate that ethanol produces a compound stimulus with primary activity through GABA and glutamate receptor systems, particularly ionotropic receptors, with additional contribution from serotonergic mechanisms. Further progress should capitalize on chemogenetic and optogenetic techniques in laboratory animals to identify the neural circuitry involved in mediating the discriminative stimulus effects of ethanol. These infrahuman studies can be guided by in vivo imaging of human brain circuitry mediating ethanol’s subjective effects. Ultimately, identifying receptors systems, as well as where they are located within brain circuitry, will transform the use of drug discrimination procedures to help identify possible treatment or prevention strategies for alcohol use disorder.
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