Our Research


Establishing the underlying mechanisms of methamphetamine-induced deficits in recognition memory

Methamphetamine (meth) addiction is a chronic relapsing disorder unique from other drugs due to pronounced cognitive deficits that occur during abstinence. Memory is one cognitive domain that is particularly impaired in both human and animal models. My laboratory has demonstrated that extended access to methamphetamine self-administration causes reliable deficits in object recognition and object/place recognition memory in male and female rats. These tasks engage a unique and specific circuitry encompassing the hippocampus, prefrontal and perirhinal cortices, with the perirhinal cortex mediating recognition of novelty. We have determined that chronic self-administered meth dysregulates glutamate neurotransmission in the perirhinal cortex, and that recognition memory can be restored with glutamatergic prodrugs. Recently, we demonstrated that chemogenetic activation of the perirhinal cortex reverses meth induced impairments in recognition memory and prevents relapse in the presence of novel cues. We continue to pursue these issues by studying the underlying physiology, circuitry, and neurobiology of meth-induced deficits in recognition memory and salience for novel cues. Currently we are using an AAVretro-Cre approach that employs the retrograde-traveling AAVrg-Cre virus and a Cre-dependent AAV-DIO-hM3Dq or hM4Di to activate or inhibit, respectively, our circuits of interest.

Neurobiology of methamphetamine addiction

Worldwide methamphetamine use is increasing at a rapid rate. Understanding the underlying neurobiology specific to meth addiction will enhance efforts to break the chronic relapsing cycle of addiction. The nucleus accumbens is a well-characterized focal point for drug-induced changes in both dopaminergic and glutamatergic signaling mechanisms. However, since meth has a potent dopamine release mechanism, less attention is devoted to changes in glutamatergic neurotransmission following prolonged meth. Glutamatergic projections from the prefrontal cortex to the nucleus accumbens are critical for reinstatement of drug seeking across several drugs and expression of reinstated meth seeking relies on this excitatory neurocircuitry. Repeated activation of this neurocircuit by drugs of abuse, like meth, induces lasting maladaptive changes. My laboratory and others have reported that 6-hr access to contingent meth results in an escalation of drug intake and impaired cognitive sequelae typically associated with changes within the corticostriatal circuitry. Further, we have found postsynaptic adaptations in ionotropic glutamate receptor distribution and function, expressed as a decrease in AMPA/NMDA ratio in the prefrontal cortex. This change was driven by an increase in NMDA receptor currents and an increase in GluN2B surface expression. In the nucleus accumbens, meth decreased the paired-pulse ratio and increased the frequency of spontaneous excitatory postsynaptic currents with no indication of postsynaptic changes. We also report that Prelimbic (PL) and Infralimbic (IL) cortical projections to the NA core and shell, respectively, both inhibit reinstated meth seeking. Thus, the neural circuitry mediating cued reinstatement of meth seeking is similar to what has been observed in models of cocaine seeking in the dorsal, but not ventral, mPFC-NA circuit. We also demonstrated that sex differences exist in post-synaptic glutamate transmission in the prefrontal cortex that are potentially related to elevated baseline differences in synaptic function. Further, in the NA we report meth decreased synaptic contact of perisynaptic astroglial processes from the synapse but does not impact the astroglial glutamate transporter GLT-1 or general structural characteristics of the astrocyte, yet like cocaine, DREADD-based activation of NAcore astroglia suppressed cue-induced meth seeking. Our current projects focus on synaptic function following meth through measures of matrix metalloproteinase activation in response to meth associated cues and determining divergent roles of dopamine D1 and D2 receptor subtypes in cued meth seeking.

Oxytocin, relapse to drug seeking, and empathy.

In recent years, oxytocin has become a prime candidate for the treatment of several neuropsychiatric disorders, including addiction. I have shown that systemic and nucleus accumbens micro infusions of oxytocin consistently decrease drug seeking in male and female rats that have self-administered heroin, cocaine and methamphetamine. Surprisingly, little is known about the underlying neurobiology by which oxytocin exerts its effects. Receptors are wide-spread in brain and expressed on regionally specific cell-types. We have shown that oxytocin normalized cue-induced fos expression within the addiction circuit. A current line of research in my lab is devoted to identifying cell-type specific effects of oxytocin within the addiction circuitry through genetic knockdown of the oxytocin receptor in a region and cell-type specific manner. Further, oxytocin mediates social interaction and empathic processes. My laboratory has developed a novel behavioral task to study empathic processes in rodents, we have characterized this behavior and currently have unpublished data demonstrating activation of oxytocin neurons are related to performance of this empathy task.

Impact of conditioned stressors on anxiety, heroin seeking, and synaptic function

Stress responses are an adaptive part of physiological and behavioral function. However, it is possible for this normal function to become dysregulated in response to extreme environmental or personal traumatic events that dysregulate this system. We have shown that a neutral stimulus paired with a traumatic experience acquires associative value such that presentation of this stress conditioned stimulus can elevate cortisol levels, increase burying behavior, reinstate extinguished drug seeking, and increase synaptic adaptions in the nucleus accumbens core following heroin seeking.

Sex differences in motivated behavior

There are marked sex differences in the etiology of drug addiction that can be emulated in animal models of motivated drug taking. For example, women take more drug, transition faster into addiction, and report more difficulty maintaining abstinence relative to men. These differences are believed to result from a complex interplay between biology, environment, sociocultural, and development. My laboratory seeks to identify biological mechanisms that contribute to differences/similarities in addiction. We have found that male and female rats escalate drug intake faster and reinstate extinguished lever pressing to a priming injection of drug to a greater degree than males. However, we also find similar reinstatement to methamphetamine, cocaine, and heroin conditioned cues (depending on rat strain) in both males and females. This is interesting because it is generally believed that females respond more to drug conditioned cues. We believe that the neural underpinnings of the behavior are mediated by different mechanisms in males and females, resulting in convergent sex differences. That is, both sexes exert the same response but the neurobiology mediating the behavior is different. This topic is currently under investigation in my laboratory.