RESEARCH INTERESTS

Drug addiction is a chronic disease characterized by an inability to regulate drug-seeking behavior. In order to develop effective behavioral and pharmacological therapies for addiction, it is necessary to have an understanding of the neurochemical and molecular changes that occur following the learned response of drug self-administration. Thus, the goal of my research program is to determine biological factors contributing to the long-term behavioral adaptations produced by operant cocaine and alcohol self-administration in rodents. To that end, our lab uses a multidisciplinary approach to investigate neurochemical and molecular adaptations occurring following chronic drug self-administration. Secondary to this goal is exploring methods of counteracting these pathological neuroadaptations to reverse the pathologies of learning and memory which drive relapse to drug-seeking.

We use the operant drug self-administration – reinstatement paradigm to model relapse in rats. This paradigm involves training animals to self-administer drug in an operant chamber until behavior becomes stable. The drug-seeking response can then be extinguished and “reinstated” with one of the stimuli known to cause relapse in humans, namely stress, cues associated with drug delivery, or the drug itself. An alternate paradigm does not use extinction training but instead puts animals into “forced abstinence” in the home cage. Both paradigms allow for the assessment of persistent drug-seeking which occurs after a drug-free period of two to three weeks.

Present Research

The lab currently four lines of research which all share the overarching hypothesis that both stress and drug use produce persistent alterations in the glutamate neurotransmitter system.

1. Glutamate Transporters and Cocaine Seeking  

Following cocaine self-administration and extinction training, a reduction in basal extracellular glutamate levels has been observed in the nucleus accumbens core. Furthermore, an increase in synaptically-released glutamate along the prefrontal cortical-nucleus accumbens pathway has been shown to be required for animals to reinstate cocaine-seeking. Together, these observations led to the hypothesis that glutamate homeostasis is disrupted in the nucleus accumbens following cocaine self-administration. Glutamate homeostasis refers to the balance between glutamate release (both synaptic and non-synaptic) and uptake. Cocaine produces a down-regulation of system x_c– which exchanges intracellular glutamate for extracellular cysteine and thereby maintains basal glutamate levels in the nucleus accumbens core. Our work has shown that the the expression and function of GLT-1, the glial glutamate transporter that is responsible for 90% of glutamate uptake, is decreased in the nucleus accumbens following cocaine self-administration and 3 weeks of extinction training. It follows that increasing the expression of GLT-1 could be protective against relapse to cocaine-seeking. We have found that the beta-lactam ceftriaxone rescues GLT-1 expression in the nucleus accumbens, thereby restoring glutamate homeostasis following cocaine self-administration and preventing relapse. We have found that ceftriaxone increases the expression of both GLT-1 and xCT, the catalytic subunit of system x_c– following cocaine self-administration and extinction training. We have also demonstrated that ceftriaxone significantly inhibits the relapse of cocaine-seeking, an effect that persists weeks following the last ceftriaxone injection. We are currently exploring the ability of ceftriaxone to alter excitability of neurons projecting to the nucleus accumbens core.

2. Simultaneous alcohol and cocaine self-administration: effects on glutamate homeostasis.  

Cocaine and alcohol have opposite effects on glutamate levels in the nucleus accumbens during abstinence. As the majority (60-90%) of cocaine users consume alcohol with their cocaine, it is important to assess changes in glutamate homeostasis following consumption of both drugs. To that end we have developed a rat model to study the consequences of sequential self-administration of cocaine and alcohol on accumbens glutamate homeostasis, finding that the drug combination produces neuroadaptations which differ from those arising from self-administration of either drug alone. This model involves the self-administration of intravenous cocaine prior to access to alcohol in the homecage. While this pattern yielded significant changes in glutamate homeostasis, it is not clear whether humans take cocaine prior to or after alcohol consumption. Thus, we formed a collaboration with Dr. Linda Cottler (UF Epidemiology) to assess these patterns in human polysubstance users. We will next backtranslate these patterns into outbred rats to determine if the pattern of intake alters glutamate/dopamine homeostasis.

3. GLT-1 Enhancers as Drug Candidates for Treating Cocaine Addiction   

While our lab’s work and the work of others has consistently demonstrated that ceftriaxone potently inhibits cocaine reinstatement, ceftriaxone is not an ideal candidate for human clinical trials due to its poor brain penetration, antibiotic properties, and inability to survive oral administration. We partnered with Dr. Abou-Gharbia (Temple University), whose group conducts medicinal chemistry research to identify ceftriaxone analogs with better oral bioavailability and brain penetration. Our role in the project will be to test these new compounds for their ability to prevent cocaine reinstatement.

4. Investigating the neurobiology of comorbid PTSD and cocaine/oxycodone use

Substance use disorders (SUDs) and post-traumatic stress disorder (PTSD) are at crisis levels in the United States military. In the general population as well in veterans, there is a high co-occurrence of PTSD and SUD. Patients who display comorbidity for these disorders are more resistant to treatment. An animal model for comorbid PTSD and stimulant addiction is greatly needed in order to screen medications for their ability to reduce symptoms of both disorders. Here we have developed an animal model which can separate stressed rats into those that exhibit long-term symptoms of anxiety and those that are “resilient” to the stressor. Animals that exhibit long-term symptoms of anxiety in our PTSD model also demonstrate enhanced cue-primed reinstatement of cocaine-seeking relative to both unstressed and resilient rats. We are currently investigating the neurobiological substrates of comorbid PTSD and SUD vulnerability with a focus on the hippocampus, PFC and amygdala.