Amy A. Herrold

Using conditioned place preference to identify relapse prevention medications.

Stimuli, including contexts, which predict the availability or onset of a drug effect, can acquire conditioned incentive motivational properties. These conditioned properties endure after withdrawal, and can promote drug-seeking which may result in relapse. Conditioned place preference (CPP) assesses the associations between drugs and the context in which they are experienced. Here, we review the potential utility of CPP procedures in rodents and humans to evaluate medications that target conditioned drug-seeking responses. We discuss the translational potential of the CPP procedure from rodents to humans, and review findings with FDA-approved treatments that support the use of CPP to develop relapse-reduction medications. We also discuss challenges and methodological questions in applying the CPP procedure to this purpose. We argue that an efficient and valid CPP procedure in humans may reduce the burden of full clinical trials with drug-abusing patients that are currently required for testing promising treatments.

Mirtazapine treatment after conditioning with methamphetamine alters subsequent expression of place preference

Methamphetamine (MP) is a widely abused psychostimulant. There are currently no FDA approved pharmacotherapies for the MP addict. The antidepressant, mirtazapine (Mirt) is a high affinity antagonist at several monoaminergic receptors that are affected by MP. This study evaluated the potential of Mirt as a therapeutic agent for MP addiction and described associated changes in neuronal signaling. A single pairing conditioned place preference (CPP) paradigm was utilized as a behavioral measure of MP-induced effects. Rats learned to associate unique environmental cues with the effects of 1.0 mg/kg (i.p.) MP (day 1) or saline (day 2). Mirt (5.0 mg/kg i.p.) was given in the home cage on day 3 and CPP was assessed on day 4. To evaluate signaling events that correlate with this behavior, brain tissue of these rats were dissected for immunoblot assays of extracellular signal-regulated kinase (ERK) and a transcriptional regulator, cAMP response element-binding protein (CREB) after the CPP test. During the CPP test, rats conditioned with MP spent more time in the environment associated with MP. Importantly, rats given Mirt did not express CPP. MP-induced CPP was associated with a decrease in phosphorylated CREB (pCREB) in the ventral tegmental area, and decreased phosphorylated ERK and pCREB in the nucleus accumbens and treatment with Mirt did not reverse these changes. No changes in signaling proteins were obtained from rats similarly treated with MP and Mirt, without exposure to cues of the conditioning paradigm. Overall, a post-conditioning treatment with Mirt can nullify MP-induced associative learning. However, additional studies are needed to ascertain the molecular events underlying this effect of Mirt.

Baclofen facilitates the extinction of methamphetamine-induced conditioned place preference in rats

The powerful, long-lasting association between the rewarding effects of a drug and contextual cues associated with drug administration can be studied using conditioned place preference (CPP). The GABA(B) receptor agonist baclofen facilitates the extinction of morphine-induced CPP in mice. The current study extended this work by determining if baclofen could enhance the extinction of methamphetamine (Meth) CPP. CPP was established using a six-day conditioning protocol wherein Meth-pairings were alternated with saline-pairings. Rats were subsequently administered baclofen (2 mg/kg i.p. or vehicle) immediately after each daily forced extinction session, which consisted of a saline injection immediately prior to being placed into the previously Meth- or saline-paired chamber. One extinction training cycle, consisted of six once-daily forced extinction sessions, mimicking the alternating procedure established during conditioning, followed by a test for preference (Ext test). CPP persisted for at least four extinction cycles in vehicle-treated rats. In contrast, CPP was inhibited following a single extinction training cycle. These data indicate that Meth-induced CPP was resistant to extinction, but extinction training was rendered effective when the training was combined with baclofen. These findings converge with the prior demonstration of baclofen facilitating the extinction of morphine-induced CPP indicating that GABA(B) receptor actions are independent of the primary (unconditioned) stimulus (i.e., the opiate or the stimulant) and likely reflect mechanisms engaged by extinction learning processes per se. Thus, baclofen administered in conjunction with extinction training may be of value for addiction therapy regardless of the class of drug being abused.

Administration of GABAB receptor positive allosteric modulators inhibit the expression of previously established methamphetamine-induced conditioned place preference

Little is known about the role of GABA(B) receptors (GABA(B)Rs) in the maintenance of memories associated with using abused substances. We have embarked on a series of studies designed to determine if enhancing the efficacy of GABA-occupied GABA(B)Rs with positive allosteric modulators (PAMs) can negate previously established conditioned place preference (CPP) induced by methamphetamine. In the current study, we evaluated the effects of acute administration of GABA(B)R PAMs, GS39783 and CGP7930. We determined that post-conditioning treatments with these PAMs, administered in the home cage, blocked the subsequent expression of methamphetamine-induced CPP. These data indicate that selectively augmenting GABA-occupied GABA(B)R signaling is sufficient to reduce memory maintenance and/or the salience of contextual cues previously associated with methamphetamine.

Cellular distribution of AMPA receptor subunits and mGlu5 following acute and repeated administration of morphine or methamphetamine

Ionotropic AMPA receptors (AMPAR) and metabotropic glutamate group I subtype 5 receptors (mGlu5) mediate neuronal and behavioral effects of abused drugs. mGlu5 stimulation increases expression of striatal‐enriched tyrosine phosphatase isoform 61 (STEP61) which internalizes AMPARs. We determined the rat brain profile of these proteins using two different classes of abused drugs, opiates, and stimulants. STEP61 levels, and cellular distribution/expression of AMPAR subunits (GluA1, GluA2) and mGlu5, were evaluated via a protein cross‐linking assay in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral pallidum (VP) harvested 1 day after acute, or fourteen days after repeated morphine (8 mg/kg) or methamphetamine (1 mg/kg) (treatments producing behavioral sensitization). Acute morphine decreased GluA1 and GluA2 surface expression in mPFC and GluA1 in NAc. Fourteen days after repeated morphine or methamphetamine, mGlu5 surface expression increased in VP. In mPFC, mGlu5 were unaltered; however, after methamphetamine, STEP61 levels decreased and GluA2 surface expression increased. Pre‐treatment with a mGlu5‐selective negative allosteric modulator, blocked methamphetamine‐induced behavioral sensitization and changes in mPFC GluA2 and STEP61. These data reveal (i) region‐specific distinctions in glutamate receptor trafficking between acute and repeated treatments of morphine and methamphetamine, and (ii) that mGlu5 is necessary for methamphetamine‐induced alterations in mPFC GluA2 and STEP61.

Placebo-Controlled Trial of Familiar Auditory Sensory Training for Acute Severe Traumatic Brain Injury: A Preliminary Report

Background. Sensory stimulation is often provided to persons incurring severe traumatic brain injury (TBI), but therapeutic effects are unclear. Objective. This preliminary study investigated neurobehavioral and neurophysiological effects related to sensory stimulation on global neurobehavioral functioning, arousal, and awareness. Methods. A double-blind randomized placebo-controlled trial where 15 participants in states of disordered consciousness (DOC), an average of 70 days after TBI, were provided either the Familiar Auditory Sensory Training (FAST) or Placebo of silence. Global neurobehavioral functioning was measured with the Disorders of Consciousness Scale (DOCS). Arousal and awareness were measured with the Coma-Near-Coma (CNC) scale. Neurophysiological effect was measured using functional magnetic resonance imaging (fMRI). Results. FAST (n = 8) and Placebo (n = 7) groups each showed neurobehavioral improvement. Mean DOCS change (FAST = 13.5, SD = 8.2; Placebo = 18.9, SD = 15.6) was not different, but FAST patients had significantly (P = .049; 95% confidence interval [CI] = −1.51, −.005) more CNC gains (FAST = 1.01, SD = 0.60; Placebo = 0.25, SD = 0.70). Mixed-effects models confirm CNC findings (P = .002). Treatment effect, based on CNC, is large (d = 1.88, 95% CI = 0.77, 3.00). Number needed to treat is 2. FAST patients had more fMRI activation in language regions and whole brain (P values <.05) resembling healthy controls’ activation. Conclusions. For persons with DOC 29 to 170 days after TBI, FAST resulted in CNC gains and increased neural responsivity to vocal stimuli in language regions. Clinicians should consider providing the FAST to support patient engagement in neurorehabilitation.

Brain region-selective cellular redistribution of mGlu5 but not GABAB receptors following methamphetamine-induced associative learning

Alterations in receptor expression and distribution between cell surface and cytoplasm are means by which psychostimulants regulate neurotransmission. Metabotropic glutamate receptor group I, subtype 5 (mGluR5) and GABAB receptors (GABABR) are critically involved in the development and expression of stimulant‐induced behaviors, including conditioned place preference (CPP), an index of drug‐seeking. However, it is not known if psychostimulant‐induced CPP alters the trafficking of these receptors. To fill this gap, this study used methamphetamine (Meth)‐induced CPP in rats to ascertain if receptor changes occur in limbic brain regions that regulate drug‐seeking, the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral pallidum (VP). To do so, ex vivo tissue was assessed for changes in expression and surface vs. intracellular distribution of mGluR5 and GABABRs. There was a decrease in the surface to intracellular ratio of mGluR5 in the mPFC in Meth‐conditioned rats, commensurate with an increase in intracellular levels. mGluR5 levels in the NAc or the VP were unaltered. There were no changes for GABABR in any brain region assayed. This ex vivo snapshot of metabotropic glutamate and GABA receptor cellular distribution following induction of Meth‐induced CPP is the first report to determine if these receptors are differentially altered after Meth‐induced CPP. The results suggest that this Meth treatment paradigm likely induced a compensatory change in mGluR5 surface to intracellular ratio such that the surface remains unaltered while an increase in intracellular protein occurred. Synapse, 2011.

Exploring the Relationship Between Mild Traumatic Brain Injury Exposure and the Presence and Severity of Postconcussive Symptoms Among Veterans Deployed to Iraq and Afghanistan

The aim of this study was to describe the association between mild traumatic brain injury (mTBI) and persisting postconcussive symptoms according to symptom category, number, and severity.

Transcranial magnetic stimulation: potential treatment for co-occurring alcohol, traumatic brain injury and posttraumatic stress disorders.

Alcohol use disorder (AUD), mild traumatic brain injury (mTBI), and posttraumatic stress disorder (PTSD) commonly co-occur (AUD + mTBI + PTSD). These conditions have overlapping symptoms which are, in part, reflective of overlapping neuropathology. These conditions become problematic because their co-occurrence can exacerbate symptoms. Therefore, treatments must be developed that are inclusive to all three conditions. Repetitive transcranial magnetic stimulation (rTMS) is non-invasive and may be an ideal treatment for co-occurring AUD + mTBI + PTSD. There is accumulating evidence on rTMS as a treatment for people with AUD, mTBI, and PTSD each alone. However, there are no published studies to date on rTMS as a treatment for co-occurring AUD + mTBI + PTSD. This review article advances the knowledge base for rTMS as a treatment for AUD + mTBI + PTSD. This review provides background information about these co-occurring conditions as well as rTMS. The existing literature on rTMS as a treatment for people with AUD, TBI, and PTSD each alone is reviewed. Finally, neurobiological findings in support of a theoretical model are discussed to inform TMS as a treatment for co-occurring AUD + mTBI + PTSD. The peer-reviewed literature was identified by targeted literature searches using PubMed and supplemented by cross-referencing the bibliographies of relevant review articles. The existing evidence on rTMS as a treatment for these conditions in isolation, coupled with the overlapping neuropathology and symptomology of these conditions, suggests that rTMS may be well suited for the treatment of these conditions together.

Predicting levels of independence with expressing needs and ideas 1 year after severe brain injury

PURPOSE/OBJECTIVE Severe brain injury (BI) is a catastrophic event often evolving into a complex chronic and severely disabling condition making activity participation possible only with sustained caregiving. One aspect of building sustainable caregiving is early provision of information about expected outcomes germane to patients and their caregivers. An analysis was conducted to determine whether 2 levels of independence with expressing needs and ideas 1-year after severe BI could be predicted using variables available early after injury. METHOD The authors examined a subsample (n = 79) of participants of an outcome study who received repeated neurobehavioral evaluations with the Disorders of Consciousness Scale (DOCS) and who were assessed 1 year after injury with the Functional Independence Measures (FIM). Explanatory variables included DOCS measures, patient characteristics, coexisting conditions, and interventions. The outcome is measured with the FIM Expression item. Optimal data analysis was used to construct multivariate classification tree models. RESULTS The 2nd (p = .004) DOCS visual measure and seizure (p = .004) entered the final model providing 79% accuracy in classifying more or less independence with expressing needs and ideas at 1 year. The model will correctly identify 78% of future severe BI survivors who will have more independence and 82% of persons who will have less independence. CONCLUSIONS For persons incurring severe BI, it is possible to predict, early after injury, more and less independence with expressing needs and ideas 1-year after injury. This evidence is 1 contribution to a larger body of evidence needed to enable early caregiver education about recovery expectations in terms of patient functioning relative to caregiving needs, which in turn will help build sustainable caregiving for this population.