What are the genetic, environmental and neurobiological factors that contribute to addiction liability?

We are currently using two different animal models to begin to answer this complex question. 1) In an ongoing collaborative project with Dr. Huda Akil, we have been using a unique genetic animal model of individual differences in addiction liability to examine the neurobiological antecedents and consequences of addiction. Dr. Akil’s rat lines have been selectively bred for over 60 generations on the basis of locomotor response to novelty and we have shown that these animals—bred high-responders (bHRs) and bred low-responders (bLRs)—exhibit differences on a constellation of traits relevant to addiction. In addition, these two lines of rats show differences in their dopamine system both under basal conditions and in response to reward cues and drugs of abuse. We are currently using these bred lines to study epigenetic regulation of gene expression associated with addiction-related behaviors. 2) We have recently begun to study heterogeneous stock (HS) rats provided by Dr. Leah Solberg-Woods at the Medical College of Wisconsin. The HS rats were derived from 8 different founder strains and have been maintained as an outbred population for over 65 generations. The heterogeneity of these rats is highly advantageous for genome wide association studies (GWAS). Thus, we are characterizing these rats on a number of addiction-related traits, in hopes of uncovering genetic factors related to the disorder (see www.ratgenes.org).

What are the neurobiological mechanisms underlying stimulus-reward learning?

Our work over the last several years has focused around an animal model of individual differences in stimulus-reward learning. Following Pavlovian conditioning, whereby a neutral cue (in this case a lever, conditioned stimulus, CS) is paired with a food reward (unconditioned stimulus, US), animals will develop a conditioned response (CR). However, the nature of this CR varies between individuals. All animals learn that the CS is predictive, but some animals will also attribute incentive motivational value (i.e. incentive salience) to the reward cue. Thus, for “sign-trackers” the reward cue becomes attractive and irresistible and they will work for it in the absence of food reward. In contrast, “goal-trackers” treat the cue as a mere predictor and upon its presentation go to the location of reward delivery. This model is extremely valuable in that it allows us to parse the neurobiological mechanisms underlying stimulus-reward learning and motivated behavior. Further, this model will help us understand the processes by which cues associated with reward attain incentive motivational value and gain control over behavior – the same processes that go awry in addicts.

How can we alter these behavioral phenotypes?

We are currently using environmental, pharmacological and chemogenetic approaches to determine whether we can “switch” one phenotype to another. For example, does exposure to stress make a goal-tracker become a sign-tracker? Does altering neuronal communication between certain brain regions alter the propensity to sign- or goal-track? Are there region-specific neurotransmitter systems (e.g. dopamine, orexin) that are critical for the acquisition of one behavior, but not the other?

How does the “stress system” interact with the dopamine system to regulate stimulus-reward learning and response to the environment?

We also have ongoing studies investigating individual differences in stress responsiveness (e.g. corticosterone levels) and how these differences are related to stimulus-reward learning and neuronal activity. We are particularly interested in the role of glucocorticoid receptors in stimulus-reward learning and interactions between HPA Axis activity and the dopamine system.

Techniques

Analysis Tools

Behavioral Procedures

  • Locomotor response to novelty
  • Drug self-administration/reinstatement
  • Pavlovian conditioning
  • Impulsive Action (DRL)
  • Impulsive Choice (delayed discounting, probabilistic choice)
  • Psychomotor Sensitization

Gene Expression Profiling

  • Laser capture microdissection combined with gene microarrays

Hormonal Assays

  • Radioimmunoassay

Neurohistochemical Procedures

  • In situ hybridization
  • Immunohistochemistry
  • Retrograde labeling

Neuropharmacology

  • Systemic injections
  • Local injections via stereotaxic surgery

“Remote Control” of Neuronal Signaling

  • Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)