Terry E. Robinson's research while affiliated with University of Michigan and other places
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Publications (218)
Human unilateral renal agenesis is a congenital urinary tract malformation. Affected individuals have only one kidney, which is often an asymptomatic developmental defect. A total of 5,585 male and female HS rats were assessed for unilateral renal agenesis and genotyped for 3’513,321 markers. The R package SAIGEgds was used for the association anal...
A vexing observation in genome-wide association studies (GWASs) is that parallel analyses in different species may not identify orthologous genes. Here, we demonstrate that cross-species translation of GWASs can be greatly improved by an analysis of co-localization within molecular networks. Using body mass index (BMI) as an example, we show that t...
Background
The development and persistence of addiction is mediated in part by drug-induced alterations in nucleus accumbens (NAc) function. AMPA-type glutamate receptors (AMPARs) provide the main source of excitatory drive to the NAc and enhancements in transmission of calcium-permeable AMPARs (CP-AMPARs) mediate increased cue-triggered drug-seeki...
Power analyses are often used to determine the number of animals required for a genome wide association analysis (GWAS). These analyses are typically intended to estimate the sample size needed for at least one locus to exceed a genome-wide significance threshold. A related question that is less commonly considered is the number of significant loci...
Power analyses are often used to determine the number of animals required for a genome wide association analysis (GWAS). These analyses are typically intended to estimate the sample size needed for at least one locus to exceed a genome-wide significance threshold. A related question that is less commonly considered is the number of significant loci...
Sprague Dawley (SD) rats are among the most widely used outbred laboratory rat populations. Despite this, the genetic characteristics of SD rats have not been clearly described, and SD rats are rarely used for experiments aimed at exploring genotype-phenotype relationships. In order to use SD rats to perform a genome-wide association study (GWAS),...
Repeated drug use can change dopamine (DA) function in ways that promote the development and persistence of addiction, but in what direction? By one view, drug use blunts DA neurotransmission, producing a hypodopaminergic state that fosters further drug use to overcome a DA deficiency. Another view is that drug use enhances DA neurotransmission, pr...
Sensitivity to cocaine and its associated stimuli (“cues”) are important factors in the development and maintenance of addiction. Rodent studies suggest that this sensitivity is related, in part, to the propensity to attribute incentive salience to food cues, which, in turn, contributes to the maintenance of cocaine self-administration, and cue-ind...
Drugs of abuse can change dopamine (DA) function during the development of addiction. But in what direction? By one view, drug use blunts DA neurotransmission, producing a hypodopaminergic state, and drug use is motivated to overcome DA deficiency. Another view is that drug use enhances DA neurotransmission, producing a sensitized, hyperdopaminergi...
Objective
Obesity is influenced by genetic and environmental factors. Despite the success of human genome‐wide association studies, the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify the genetic loci underlying obesity and related morphometric and metabolic traits.
Methods...
D-amphetamine maintenance therapy shows promise as a treatment for people with cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaine’s effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administra...
RationaleWith repeated administration, the psychomotor activating effects of drugs such as cocaine or amphetamine can change in very different ways—showing sensitization or tolerance—depending on whether they are administered more or less intermittently. This behavioral plasticity is thought to reflect, at least in part, changes in dopamine (DA) ne...
Sensitivity to cocaine and its associated stimuli (cues) are important factors in the development and maintenance of addiction. Rodent studies suggest that this sensitivity is related, in part, to the propensity to attribute incentive salience to food cues, which, in turn, contributes to the maintenance of cocaine self-administration, and cue-induc...
BACKGROUND: D-amphetamine maintenance therapy shows promise as a treatment for cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaine's effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administra...
The psychomotor activating effects of drugs such as cocaine or amphetamine can change in very different ways – showing sensitization or tolerance – depending on whether they are administered more or less intermittently. This behavioral plasticity is thought to reflect, at least in part, changes in dopamine (DA) neurotransmission, and therefore, may...
A key question in addiction research concerns how, in some individuals, initial recreational or casual patterns of drug use may change brain and psychological function in ways that promote a transition to the problematic patterns of use that define substance use disorders (addiction). In preclinical studies, this is modeled using self-administratio...
The temporal pattern of drug use (pharmacokinetics) has a profound effect on the ability of self‐administered cocaine to produce addiction‐like behavior in rodents, and to change the brain. To further address this issue, we compared the effects of Long Access (LgA) cocaine self‐administration, which is widely used to model the transition to addicti...
There are a number of traits that are thought to increase susceptibility to addiction, and some of these are modeled in preclinical studies. For example, “sensation-seeking” is predictive of the initial propensity to take drugs; whereas “novelty-seeking” predicts compulsive drug-seeking behavior. In addition, the propensity to attribute incentive s...
Rationale
Intermittent Access (IntA) cocaine self-administration, which models intermittent patterns of cocaine use in humans during the transition to addiction, is especially effective in producing incentive-sensitization and other addiction-like behavior in male rats. However, female rats show more robust psychomotor sensitization than males, and...
Recent studies suggest that the temporal pattern of drug use (pharmacokinetics) has a profound effect on the ability of self-administered cocaine to produce addiction-like behavior in rodents, and to change the brain. To further address this issue, we compared the effects of Long Access (LgA) cocaine self-administration, which is widely used to mod...
When memories are retrieved they become labile, and subject to alteration by a process known as reconsolidation. Disruption of memory reconsolidation decreases the performance of learned responses, which is often attributed to erasure of the memory; in the case of Pavlovian learning, to a loss of the association between a conditioned stimulus (CS)...
Some rats are especially prone to attribute incentive salience to a cue (conditioned stimulus, CS) paired with food reward (sign-trackers, STs), but the extent they do so varies as a function of the form of the CS. Other rats respond primarily to the predictive value of a cue (goal-trackers, GTs), regardless of its form. Sign-tracking is associated...
Psychoactive drugs have the ability to alter the morphology of neuronal dendrites and spines and to influence later experience-dependent structural plasticity. If rats are given repeated injections of psychomotor stimulants (amphetamine, cocaine, nicotine) prior to being placed in complex environments, the drug experience interferes with the abilit...
Drug self-administration models of addiction typically require animals to make the same response (e.g., a lever-press or nose-poke) over and over to procure and take drugs. By their design, such procedures often produce behavior controlled by stimulus–response (S-R) habits. This has supported the notion of addiction as a “drug habit,” and has led t...
The Office of the Surgeon General recently produced its first Report on the consequences of alcohol and drug abuse on health, making several very laudable policy recommendations. The Report also emphasizes the importance of adequate funding for biomedical research, which is good news for both researchers and patients. However, the Report is marred...
Repeated intermittent exposure to cocaine results in the neurochemical sensitization of dopamine (DA) transmission within the nucleus accumbens (NAc). Indeed, the excitability of DA neurons in the ventral tegmental area (VTA) is enhanced within hours of initial psychostimulant exposure. However, it is not known if this is accompanied by a comparabl...
Rewards are both “liked” and “wanted,” and those 2 words seem almost interchangeable. However, the brain circuitry that mediates the psychological process of “wanting” a particular reward is dissociable from circuitry that mediates the degree to which it is “liked.” Incentive salience or “wanting,” a form of motivation, is generated by large and ro...
The sensory properties of a reward-paired cue (a Conditioned Stimulus; CS) may impact the motivational value attributed to the cue, and in turn influence the form of the conditioned response (CR) that develops. A cue with multiple sensory qualities, such as a moving lever-CS, may activate numerous neural pathways that process auditory and visual in...
Rationale:
Contemporary animal models of cocaine addiction focus on increasing the amount of drug consumption to produce addiction-like behavior. However, another critical factor is the temporal pattern of consumption, which in humans is characterized by intermittency, both within and between bouts of use.
Objective:
To model this, we combined p...
Unlabelled:
There is considerable individual variation in the extent to which reward cues are attributed with incentive salience. For example, a food-predictive conditioned stimulus (CS; an illuminated lever) becomes attractive, eliciting approach toward it only in some rats ("sign trackers," STs), whereas others ("goal trackers," GTs) approach th...
A discrete cue associated with intravenous injections of cocaine acquires greater control over motivated behavior in some rats ('sign-trackers', STs) than others ('goal-trackers', GTs). It is not known, however, if such variation generalizes to cues associated with other drugs. We asked, therefore, whether a discrete cue (a light) associated with t...
Some rats [sign-trackers (STs)] are especially prone to attribute incentive salience to reward cues, relative to others [goal-trackers (GTs)]. Thus, reward cues are more likely to promote maladaptive reward-seeking behavior in STs than GTs. Here, we asked whether STs and GTs differ on another trait that can contribute to poor restraint over behavio...
Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.
Rationale:
Cues associated with rewards bias attention towards them and can motivate drug-seeking and drug-taking behavior. There is, however, considerable individual variation in the extent to which cues associated with rewards acquire motivational properties. For example, only in some rats does a localizable food cue become attractive, eliciting...
The role of dopamine in reward is a topic of debate. For example, some have argued that phasic dopamine signaling provides a prediction-error signal necessary for stimulus-reward learning, whereas others have hypothesized that dopamine is not necessary for learning per se, but for attributing incentive motivational value ('incentive salience') to r...
![Data from Lomanowska et al. [25] were used to compare the effectiveness...](profile/Benjamin-Saunders-2/publication/228116455/figure/fig10/AS:202952812830729@1425399129546/Data-from-Lomanowska-et-al-25-were-used-to-compare-the-effectiveness-of-the-rank-order_Q320.jpg){kind=icon}
If reward-associated cues acquire the properties of incentive stimuli they can come to powerfully control behavior, and potentially promote maladaptive behavior. Pavlovian incentive stimuli are defined as stimuli that have three fundamental properties: they are attractive, they are themselves desired, and they can spur instrumental actions. We have...
The repeated administration of psychostimulant drugs produces a persistent and long-lasting increase ("sensitization") in their psychomotor effects, which is thought to be due to changes in the neural circuitry that mediate these behaviors. One index of neuronal activation used to identify brain regions altered by repeated exposure to drugs involve...
Animals vary considerably in the degree to which they attribute incentive salience to cues predictive of reward. When a discrete cue (conditional stimulus) is repeatedly paired with delivery of a food reward (unconditional stimulus) only some rats ("sign-trackers"; STs) come to find the cue itself an attractive and desirable incentive stimulus. For...
Cues associated with rewards acquire the ability to engage the same brain systems as rewards themselves. However, reward cues have multiple properties. For example, they not only act as predictors of reward capable of evoking conditional responses (CRs), but they may also acquire incentive motivational properties. As incentive stimuli they can evok...
Individuals vary considerably in the extent to which they attribute incentive salience to food-associated cues.
We asked whether individuals prone to attribute incentive salience to a food cue are also prone to attribute incentive properties to a stimulus associated with a drug of abuse-cocaine.
We first identified those rats that attributed incent...
The mechanisms by which childhood abuse and/or neglect become risk factors for the development of drug addiction, problem gambling, and other disorders of behavioral inhibition are unknown. The loss of behavioral inhibition is often triggered by reward-related cues that acquire incentive salience. This study examined whether inadequate early-life s...
The intertwining of addiction and responsibility in personal, philosophical, legal, research, and clinical contexts.
Addictive behavior threatens not just the addict's happiness and health but also the welfare and well-being of others. It represents a loss of self-control and a variety of other cognitive impairments and behavioral deficits. An addi...
This chapter focuses on and provides a general overview of the incentive-sensitization theory of addiction. Through the years, it has been gradually recognized that drugs can cause complex changes in the brains of susceptible individuals, and that these changes contribute to the transition to addiction. Multiple symptoms of addiction are caused by...
Cues in the environment associated with drug use draw the attention of addicts, elicit approach, and motivate drug-seeking and drug-taking behavior, making abstinence difficult. However, preclinical studies have identified large individual differences in the extent to which reward cues acquire these incentive motivational properties. For example, o...
It has been proposed that animals that attribute high levels of incentive salience to reward-related cues may be especially vulnerable to addiction. Individual variation has also been observed in the motivational value attributed to aversive cues, which may confer vulnerability to anxiety disorders such as post-traumatic stress disorder (PTSD). The...
Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. During Pavlovian learning, previously neutral stimuli that predict rewards can acquire motivational properties, becoming attractive and desirable incentive stimuli. However, whether a cue acts solely as a predictor of reward, o...
When drugs enter the brain rapidly, liability for addiction is increased, but why this is the case is not well understood. Here we examined the influence of varying the speed of intravenous cocaine delivery on self-administration behavior in rats given limited or extended opportunity to take drug. The speed of cocaine delivery had no effect on self...
In addicts drug cues attract attention, elicit approach, and motivate drug-seeking and drug-taking behavior, and addicts find it difficult to resist such cues. In preclinical studies we have found, however, that food cues acquire incentive motivational properties only in a subset of individuals. For example, a food cue becomes attractive, eliciting...
Cues associated with food availability and consumption can evoke desire for food, sometimes leading to excessive intake. We have found, however, that food cues acquire incentive motivational properties (the ability to attract and to serve as conditional reinforcers) in some individuals (sign-trackers), but not others (goal-trackers). We asked, ther...
Rats selectively bred based on high or low reactivity to a novel environment were characterized for other behavioral and neurobiological traits thought to be relevant to addiction vulnerability. The two lines of animals, which differ in their propensity to self-administer drugs, also differ in the value they attribute to cues associated with reward...
In recent years significant progress has been made delineating the psychological components of reward and their underlying neural mechanisms. Here we briefly highlight findings on three dissociable psychological components of reward: 'liking' (hedonic impact), 'wanting' (incentive salience), and learning (predictive associations and cognitions). A...
If presentation of a stimulus (conditional stimulus, CS) reliably predicts delivery of a reward, the CS will come to evoke a conditional response (CR) through Pavlovian learning, and the CS may also acquire incentive motivational properties. Thus, CSs can have both predictive and incentive properties. We ask here whether it is possible to dissociat...
It is well known that the subthalamic nucleus (STN) plays an important role in regulating motor function, but recent studies suggest the STN is also involved in regulating motivated behavior. For example, bilateral lesions of the STN increase motivation for both food and cocaine as assessed by 'breakpoint' on a progressive ratio schedule. However,...
Cocaine addicts are reported to have decreased numbers of striatal dopamine D2 receptors. However, in rodents, repeated cocaine administration consistently produces hypersensitivity to the psychomotor activating effects of both indirect dopamine agonists, such as cocaine itself, and importantly, to direct-acting D2 receptor agonists. The current st...
We present a brief overview of the incentive sensitization theory of addiction. This posits that addiction is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems that attribute incentive salience to reward-associated stimuli. If rendered hypersensitive, these systems cause pathological incentive motivation ('wantin...
Drugs of abuse acquire different degrees of control over thoughts and actions based not only on the effects of drugs themselves, but also on predispositions of the individual. Those individuals who become addicted are unable to shift their thoughts and actions away from drugs and drug-associated stimuli. Thus in addicts, exposure to places or thing...
Cocaine addicts have a number of cognitive deficits that persist following prolonged abstinence. These include impairments in executive functions dependent on the prefrontal cortex, as well as deficits on learning and memory tasks sensitive to hippocampal function. Recent preclinical studies using non-human animals have demonstrated that cocaine tr...
We studied the influence of rate of intravenous infusion of cocaine or amphetamine on drug-taking and seeking behavior. First, drug-naive rats were tested for acquisition of self-administration of increasing doses of amphetamine or cocaine infused over 5 or 100 s. Second, self-administration of cocaine or amphetamine infused over 5-100 s was assess...
Drug addicts have deficits in frontocortical function and cognition even long after the discontinuation of drug use. It is not clear, however, whether the cognitive deficits are a consequence of drug use, or are present prior to drug use, and thus are a potential predisposing factor for addiction. To determine if self-administration of cocaine is c...
When a discrete cue (a "sign") is presented repeatedly in anticipation of a food reward the cue can become imbued with incentive salience, leading some animals to approach and engage it, a phenomenon known as "sign-tracking" (the animals are sign-trackers; STs). In contrast, other animals do not approach the cue, but upon cue presentation go to the...
Studies that involve analysis of the psychomotor activating effects of drugs often use locomotor activity as the sole measure of psychomotor activation. At low doses, psychostimulant drugs typically produce primarily locomotor hyperactivity. As dose is increased, behavior, however, changes in complex ways, in part because of a transition to behavio...
It has been proposed that some neuroadaptations that underlie behavioral sensitization may play a role in the development and persistence of addiction. However, whether or not sensitization facilitates the development of symptoms specific to addiction, such as the escalation of drug intake, is not known. We examined, therefore, the effect of pretre...
The way an individual responds to cues associated with rewards may be a key determinant of vulnerability to compulsive behavioral disorders.
We studied individual differences in Pavlovian conditioned approach behavior and examined the expression of neurobiological markers associated with the dopaminergic system, the same neural system implicated in...
Repeated exposure to psychostimulant drugs produces long-lasting changes in dendritic structure, presumably reflecting a reorganization in patterns of synaptic connectivity, in brain regions that mediate the psychomotor activating and incentive motivational effects of these drugs, including the nucleus accumbens and prefrontal cortex. However, repe...
The ability of cocaine to produce lasting neural adaptations in mesocorticolimbic brain regions is thought to promote drug seeking and facilitate addiction in humans. The Ras-controlled Raf-MEK-ERK protein kinase signaling cascade has been implicated in the behavioral and neurobiological actions of cocaine in animals. However, these pharmacological...
Microdialysis sampling was coupled on-line to micellar electrokinetic chromatography (MEKC) to monitor extracellular dopamine concentration in the brains of rats. Microdialysis probes were perfused at 0.3 microL/min and the dialysate mixed on-line with 6 mM naphthalene-2,3-dicarboxaldehye and 10 mM potassium cyanide pumped at 0.12 microL/min each i...
The subthalamic nucleus (STN) is traditionally thought of as part of a system involved in motor control but recent evidence suggests that it may also play a role in other psychological processes. Here we examined the effects of STN lesions on two measures of impulsivity and found that STN lesions increased 'impulsive action' (produced behavioral di...
The effects of implantation of a dialysis probe into the striatum of awake rats on indices of dopamine (DA) and serotonin neurotransmission were assessed, first over 24 h following initial insertion of a probe, and then again following reinsertion of a probe at the same site 1 week later. It was found that the basal concentration of DA in dialysate...
Glutamate and gamma-aminobutyric acid (GABA) release in the amygdala are thought to be crucial for the acquisition and expression of fear memories, but the time course of amino acid changes during conditioning is unknown. We used rapid-sampling microdialysis with 14 s temporal resolution to address this issue. During auditory fear conditioning, lar...
A central premise of a number of theories of addiction is that discrete environmental stimuli repeatedly paired with drugs of abuse acquire incentive salience as a result of Pavlovian learning. There is, however, no unequivocal evidence supporting this assumption. Thus, we employed a Pavlovian conditioning procedure known to imbue non-drug reinforc...
Men and women differ in their response to cocaine, and a woman's response varies with the menstrual cycle. For example, women have greater subjective responses to cocaine in the follicular phase of the menstrual cycle when estradiol is predominant, than they do during the luteal phase when both estradiol and progesterone are elevated. Similarly, fe...
Predator odors elicit fear and defensive behavioral responses in rats, but a wide range of individual responsivity exists. The aim of this study was to examine whether individual differences in behavioral responsivity correlate with differences in amino acid neurotransmission to a predator fox odor, 2,5-dihydro-2,4,5-trimethylthiazoline (TMT). We i...
Rats given extended access to cocaine develop several symptoms of addiction, including a gradual escalation of drug intake, whereas rats given limited access do not. We asked here whether extended access to cocaine also produces drug-induced sensitization, a form of neurobehavioral plasticity implicated in addiction.
Rats were given limited (1 hour...