Deep Network Pharmacology: Targeting Glutamate Systems as Integrative Treatments for Jump-Starting Neural Networks and Recovery Trajectories.

Significant advances in pharmacological treatments for mental illness and addiction will require abandoning old monoaminergic theories of psychiatric disorders and traditionally narrow approaches to how we conduct treatment research. Reframing our efforts with a view on integrative treatments that target core neural network function and plasticity may provide new approaches for lifting patients out of chronic psychiatric symptom sets and addiction. For example, we discuss new treatments that target brain glutamate systems at key transition points within longitudinal courses of care that integrate several treatment modalities. A reconsideration of what our novel and already available medications are intended to achieve and how and when we deliver them for patients with complex illness trajectories could be the key to unlocking new advances in general and addiction psychiatry.

Polysubstance addiction vulnerability in mental illness: Concurrent alcohol and nicotine self-administration in the neurodevelopmental hippocampal lesion rat model of schizophrenia.

Multiple addictions frequently occur in patients with mental illness. However, basic research on the brain-based linkages between these comorbidities is extremely limited. Toward characterizing the first animal modeling of polysubstance use and addiction vulnerability in schizophrenia, adolescent rats with neonatal ventral hippocampal lesions (NVHLs) and controls had 19 weekdays of 1 hour/day free access to alcohol/sucrose solutions (fading from 10% sucrose to 10% alcohol/2% sucrose on day 10) during postnatal days (PD 35-60). Starting in adulthood (PD 63), rats acquired lever pressing for concurrent oral alcohol (10% with 2% sucrose) and iv nicotine (0.015 mg/kg/injection) across 15 sessions. Subsequently, 10 operant extinction sessions and 3 reinstatement sessions examined drug seeking upon withholding of nicotine, then both nicotine and alcohol, then reintroduction. Adolescent alcohol consumption did not differ between NVHLs and controls. However, in adulthood, NVHLs showed increased lever pressing at alcohol and nicotine levers that progressed more strongly at the nicotine lever, even as most pressing by both groups was at the alcohol lever. In extinction, both groups showed expected declines in effort as drugs were withheld, but NVHLs persisted with greater pressing at both alcohol and nicotine levers. In reinstatement, alcohol reaccess increased pressing, with NVHLs showing greater nicotine lever activity overall. Developmental temporal-limbic abnormalities that produce mental illness can thus generate adult polydrug addiction vulnerability as a mechanism independent from putative cross-sensitization effects between addictive drugs. Further preclinical modeling of third-order (and higher) addiction-mental illness comorbidities may advance our understanding and treatment of these complex, yet common brain illnesses.

On Mourning and Recovery: Integrating Stages of Grief and Change Toward a Neuroscience-Based Model of Attachment Adaptation in Addiction Treatment.

Interpersonal attachment and drug addiction share many attributes across their behavioral and neurobiological domains. Understanding the overlapping brain circuitry of attachment formation and addiction illuminates a deeper understanding of the pathogenesis of trauma-related mental illnesses and comorbid substance use disorders, and the extent to which ending an addiction is complicated by being a sort of mourning process. Attention to the process of addiction recovery-as a form of grieving-in which Kubler-Ross's stages of grief and Prochaska's stages of change are ultimately describing complementary viewpoints on a general process of neural network and attachment remodeling, could lead to more effective and integrative psychotherapy and medication strategies.

Prescription drug monitoring program data tracking of opioid addiction treatment outcomes in integrated dual diagnosis care involving injectable naltrexone.

BACKGROUND AND OBJECTIVES: Fourfold increases in opioid prescribing and dispensations over 2 decades in the U.S. has paralleled increases in opioid addictions and overdoses, requiring new preventative, diagnostic, and treatment strategies. This study examines Prescription Drug Monitoring Program (PDMP) tracking as a novel measure of opioid addiction treatment outcomes in a university-affiliated integrated mental health-addiction treatment clinic. METHODS: Repeated measure parametrics examined PDMP and urine drug screening (UDS) data before and after first injection for all patients (N = 68) who received at least one long-acting naltrexone injection (380 mg/IM) according to diagnostic groupings of having either (i) alcohol (control); (ii) opioid; or (iii) combined alcohol and opioid use disorders. RESULTS: There were no group differences post-injection in treatment days, injections delivered, or treatment service encounters. UDS and PDMP measures of opioid exposures were greater in opioid compared to alcohol-only patients. Post-first injection, UDS's positive for opioids declined (p < .05) along with PDMP measures of opioid prescriptions (p < .001), doses (p < .01), types (p < .001), numbers of dispensing prescribers (p < .001) and pharmacies (p < .001). Opioid patients without alcohol disorders showed the best outcomes with 50% to 80% reductions in PDMP-measures of opioids, down to levels of alcohol-only patients. CONCLUSIONS: This study shows PDMP utility for measuring opioid addiction treatment outcomes, supporting the routine use of PDMPs in clinical and research settings. SCIENTIFIC SIGNIFICANCE: These findings demonstrate that opioid addiction in patients with complex addictions and mental illnesses comorbidities can show effective treatment responses as measured by PDMP tracking of decreases in opioid prescriptions to those patients. (Am J Addict 2016;25:557-564).

Toward early estimation and treatment of addiction vulnerability: radial arm maze and N-acetyl cysteine before cocaine sensitization or nicotine self-administration in neonatal ventral hippocampal lesion rats.

RATIONAL: Prefrontal cortical (PFC)-hippocampal-striatal circuits, interconnected via glutamatergic signaling, are dysfunctional in mental illnesses that involve addiction vulnerability. OBJECTIVES: In healthy and neurodevelopmentally altered rats, we examined how Radial Arm Maze (RAM) performance estimates addiction vulnerability, and how starting a glutamatergic modulating agent, N-acetyl cysteine (NAC) in adolescence alters adult mental illness and/or addiction phenotypes. METHODS: Rats with neonatal ventral hippocampal lesions (NVHL) vs. SHAM-operated controls were randomized to NAC vs. saline in adolescence followed by cognitive testing (RAM) in early adulthood and then cocaine behavioral sensitization (experiment 1; n = 80) or nicotine self-administration (experiment 2; n = 12). RESULTS: In experiment 1, NVHL rats showed over-consumption of food (Froot-Loops (FL)) baiting the RAM with poor working memory (low-arm entries to repeat (ETR)), producing an elevated FL to ETR ratio ("FLETR"; p < 0.001). FLETR was the best linear estimator (compared to FL or ETR) of magnitude of long-term cocaine sensitization (R 2 = 0.14, p < 0.001). NAC treatment did not alter FL, ETR, FLETR, or cocaine sensitization. In experiment 2, FLETR also significantly and uniquely correlated with subsequent drug seeking during nicotine-induced reinstatement after extinction of nicotine self-administration (R 2 = 0.47, p < 0.01). NAC did not alter RAM performance, but significantly reversed NVHL-induced increases in nicotine seeking during extinction and reinstatement. CONCLUSIONS: These findings demonstrate the utility of animal models of mental illness with addiction vulnerability for developing novel diagnostic measures of PFC-hippocampal-striatal circuit dysfunction that may reflect addiction risk. Such tests may direct pharmacological treatments prior to adulthood and addictive drug exposure, to prevent or treat adult addictions.

Pseudoaddiction: Fact or Fiction? An Investigation of the Medical Literature.

Tremendous growth in opioid prescribing over two decades in the USA has correlated with proportional increases in diversion, addiction, and overdose deaths. Pseudoaddiction, a concept coined in 1989, has frequently been cited to indicate that under-treatment of pain, rather than addiction, is the more pressing and authentic clinical problem in opioid-seeking patients. This investigative review searched Medline articles containing the term "pseudoaddiction" to determine its footprint in the literature with a focus on how it has been characterized and empirically validated. By 2014, pseudoaddiction was discussed in 224 articles. Only 18 of these articles contributed to or questioned pseudoaddiction from an anecdotal or theoretical standpoint, and none empirically tested or confirmed its existence. Twelve of these articles, including all four that acknowledged pharmaceutical funding, were proponents of pseudoaddiction. These papers described pseudoaddiction as an iatrogenic disease resulting from withholding opioids for pain that can be diagnosed, prevented, and treated with more aggressive opioid treatment. In contrast, six articles, none with pharmaceutical support, questioned pseudoaddiction as a clinical construct. Empirical evidence supporting pseudoaddiction as a diagnosis distinct from addiction has not emerged. Nevertheless, the term has been accepted and proliferated in the literature as a justification for opioid therapy for non-terminal pain in patients who may appear to be addicted but should not, from the perspective of pseudoaddiction, be diagnosed with addiction. Future studies should examine whether acceptance of pseudoaddiction has complicated accurate pain assessment and treatment, and whether it has contributed to or reflected medical-cultural shifts that produced the iatrogenic opioid addiction epidemic.

Nicotine effects in adolescence and adulthood on cognition and α4ß2-nicotinic receptors in the neonatal ventral hippocampal lesion rat model of schizophrenia.

RATIONAL: Nicotine use in schizophrenia has traditionally been explained as "self-medication" of cognitive and/or nicotinic acetylcholinergic receptor (nAChR) abnormalities. OBJECTIVES: We test this hypothesis in a neurodevelopmental rat model of schizophrenia that shows increased addiction behaviors including enhanced nicotine reinforcement and drug-seeking. METHODS: Nicotine transdermal patch (5 mg/kg/day vs. placebo × 10 days in adolescence or adulthood) effects on subsequent radial-arm maze learning (15 sessions) and frontal-cortical-striatal nAChR densities (α4ß2; [3H]-epibatidine binding) were examined in neonatal ventral hippocampal lesion (NVHL) and SHAM-operated rats. RESULTS: NVHL cognitive deficits were not differentially affected by nicotine history compared to SHAMs. Nicotine history produced minimal cognitive effects while increasing food-reward consumption on the maze, compounding with NVHL-induced overconsumption. Acute nicotine (0.5 mg/kg) delivered before the final maze sessions produced modest improvements in maze performance in rats with nicotine patch histories only, but not differentially so in NVHLs. Consistent with in vivo neuroimaging of ß2 nAChR binding in schizophrenia smokers vs. non-smokers and healthy controls, adult NVHLs showed 12% reductions in nAChR binding in MPFC (p < 0.05) but not ventral striatum (<5% changes, p > .40), whereas nicotine history elevated nAChRs across both regions (>30%, p < 0.001) without interacting with NVHLs. Adolescent vs. adult nicotine exposure did not alter nAChRs differentially. CONCLUSIONS: Although replicating nicotine-induced upregulation of nAChRs in human smokers and demonstrating NVHL validity in terms of schizophrenia-associated nAChR density patterns, these findings do not support hypotheses explaining increased nicotine use in schizophrenia as reflecting illness-specific effects of nicotine to therapeutically alter cognition or nAChR densities.

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.

Prescription drug monitoring program inquiry in psychiatric assessment: detection of high rates of opioid prescribing to a dual diagnosis population.

OBJECTIVE: An epidemic of prescription drug abuse is disproportionately impacting the mentally ill. We examined the utility of a state prescription drug monitoring database for assessing recent controlled substance prescribing to patients presenting for dual diagnosis treatment. METHOD: In a community mental health center that provides integrated dual diagnosis care, we queried the Indiana Scheduled Prescription Electronic Collection and Tracking (INSPECT) system for all cases that were open as of August 2, 2011, and had been practitioner-diagnosed (per DSM-IV criteria) by January 2, 2012. INSPECT provided a record of controlled substance dispensations to each patient; diagnostic evaluation was conducted blind from prescription data compilation covering the prior 12 months. Demographic data, insurance status, and DSM-IV diagnoses were compiled from the clinic's electronic medical record. RESULTS: The sample (N = 201) was 51% female, 56% white, and two-thirds uninsured. Over 80% were dually diagnosed with substance use disorders and psychotic, mood, or anxiety disorders. Nicotine and alcohol disorders were identified in most, with about a third diagnosed with cannabis, cocaine, or opioid disorders. A majority of patients (n = 115) had been prescribed opioids in the prior year, with nearly 1 in 5 prescribed an opioid and benzodiazepine simultaneously. Patients were dispensed a mean of 4 opioid prescriptions and 213 opioid pills. More opioid prescriptions correlated with opioid dependence (OR = 1.08; 95% CI, 1.016-1.145), and more prescribers correlated with personality disorder diagnoses (OR = 1.112; 95% CI, 1.001-1.235). Higher rates and riskier patterns of controlled substance prescribing were identified in patients with Medicaid/Medicare insurance compared to uninsured patients. CONCLUSIONS: Prescription drug monitoring is a powerful tool for assessing addictions and high frequencies of patient exposures to prescribed opioids in a dual diagnosis clinic. Improved prevention and treatment strategies for addictions as facilitated by more research and clinical use of prescription drug monitoring in psychiatric care are warranted.

The iatrogenic epidemic of prescription drug abuse: county-level determinants of opioid availability and abuse.

BACKGROUND: Opioid use and abuse in the United States continues to expand at an alarming rate. In this study, we examine the county-level determinants of the availability and abuse of prescription opioids to better understand the socio-ecological context, and in particular the role of the healthcare delivery system, on the prescription drug abuse epidemic. METHODS: We use community-level information, data from Indiana's prescription drug monitoring program in 2011, and geospatial regression methods to identify county-level correlates of the availability and abuse of prescription opioids among Indiana's 92 counties. RESULTS: The findings suggest that access to healthcare generally, and to dentists and pharmacists in particular, increases the availability of prescription opioids in communities, which, in turn, is associated with higher rates of opioid abuse. CONCLUSIONS: The results suggest that the structure of the local healthcare system is a major determinant of community-level access to opioids adding to a growing body of evidence that the problem of prescription opioid abuse is, at least in part, an "iatrogenic epidemic."

Selective effects of D- and L-govadine in preclinical tests of positive, negative, and cognitive symptoms of schizophrenia.

There is a critical need to develop novel pharmacotherapeutics capable of addressing the positive, negative, and cognitive symptoms of schizophrenia. Building on recent studies with a racemic mixture of the synthetic tetrahydroprotoberberine, D,L-Govadine, we isolated the D- and L-stereoisomers and employed a battery of behavioral, neurochemical, and electrophysiological procedures to assess their individual therapeutic potential. Rodent models predictive of antipsychotic efficacy and those that model positive symptoms were employed and we found that L-Govadine, but not D-Govadine, improved these measures. Pretreatment with either stereoisomer during CS pre-exposure prevented the disruption of latent inhibition by amphetamine. Moreover, pretreatment with either stereoisomer also improved deficits in social interaction in the neonatal ventral hippocampal lesioned rat. Improved cognitive performance in two different prefrontal cortex-dependent tasks was observed with D-, but not L-Govadine, which strongly suggests that the D-steroisomer may be an effective cognitive enhancer. Alterations in dopamine efflux were also assessed and L-Govadine increased dopamine efflux in both the prefrontal cortex and nucleus accumbens. However, D-Govadine only increased dopamine efflux in the prefrontal cortex and not in the nucleus accumbens. Electrophysiological studies confirmed that L-Govadine is a DA-D2 antagonist, whereas D-Govadine shows no appreciable physiological effects at this receptor. Collectively these data show that L-Govadine performs well on measures predictive of antipsychotic efficacy and rodent models of positive symptoms through antagonism of DA-D2 receptors, whereas D-Govadine improves impairments in compromised memory function in delayed response tasks possibly through selective increases in DA efflux in the frontal cortex.

Alcohol use and craving among Veterans with mental health disorders and mild traumatic brain injury.

Mental health disorders (MHDs), mild traumatic brain injury (mTBI), and alcohol use disorder (AUD) are endemic among recent Veterans, resulting in a population with heterogeneous, co-occurring conditions. While alcohol craving negatively affects rehabilitation and leads to relapse, no studies have examined alcohol craving among Veterans with co-occurring MHDs and mTBI. The purpose of this preliminary cohort study is to describe alcohol craving in a convenience sample of Iraq and Afghanistan Veterans (n = 48), including those exposed to traumatic events and experiencing active symptoms. Veterans completed weekly telephone interviews that included the Alcohol Use Disorder Identification Test, consumption questions (AUDIT-C) (week 1) and the Penn Alcohol Craving Scale (PACS) (weeks 1-6). Sixty percent of the sample screened positive on the AUDIT-C for probable AUD. Using Rasch analysis, the person separation reliability of the PACS was strong (0.87) among AUDIT-C positive Veterans. Higher PACS scores were reported among AUDIT-C positive versus AUDIT-C negative Veterans (mixed effects analysis, p < 0.001). PACS scores were higher among AUDIT-C positive Veterans with MHDs with and without mTBI versus AUDIT-C positive combat comparison Veterans (pairwise comparison, p < 0.001). Rates of hazardous alcohol use are high among Iraq and Afghanistan conflict Veterans and suggest that alcohol craving is elevated among those with MHDs with and without mTBI.

Nicotine is more addictive, not more cognitively therapeutic in a neurodevelopmental model of schizophrenia produced by neonatal ventral hippocampal lesions.

Nicotine dependence is the leading cause of death in the United States. However, research on high rates of nicotine use in mental illness has primarily explained this co-morbidity as reflecting nicotine's therapeutic benefits, especially for cognitive symptoms, equating smoking with 'self-medication'. We used a leading neurodevelopmental model of mental illness in rats to prospectively test the alternative possibility that nicotine dependence pervades mental illness because nicotine is simply more addictive in mentally ill brains that involve developmental hippocampal dysfunction. Neonatal ventral hippocampal lesions (NVHL) have previously been demonstrated to produce post-adolescent-onset, pharmacological, neurobiological and cognitive-deficit features of schizophrenia. Here, we show that NVHLs increase adult nicotine self-administration, potentiating acquisition-intake, total nicotine consumed and drug seeking. Behavioral sensitization to nicotine in adolescence prior to self-administration is not accentuated by NVHLs in contrast to increased nicotine self-administration and behavioral sensitization documented in adult NVHL rats, suggesting periadolescent neurodevelopmental onset of nicotine addiction vulnerability in the NVHL model. Delivering a nicotine regimen approximating the exposure used in the sensitization and self-administration experiments (i.e. as a treatment) to adult rats did not specifically reverse NVHL-induced cortical-hippocampal-dependent cognitive deficits and actually worsened cognitive efficiency after nicotine treatment stopped, generating deficits that resemble those due to NVHLs. These findings represent the first prospective evidence demonstrating a causal link between disease processes in schizophrenia and nicotine addiction. Developmental cortical-temporal limbic dysfunction in mental illness may thus amplify nicotine's reinforcing effects and addiction risk and severity, even while producing cognitive deficits that are not specifically or substantially reversible with nicotine.

The Addiction Psychiatrist as Dual Diagnosis Physician: A Profession in Great Need and Greatly Needed.

Addiction is the number one cause of premature illness and death in the U.S., especially among people with mental illness. Yet American medicine lacks sufficient workforce capacity, expertise, training, infrastructure, and research to support treatment for people with co-occurring addictions and mental illness. This essay argues that the addiction psychiatrist is essential in dual diagnosis care.

Adult hippocampal neurogenesis in the pathogenesis of addiction and dual diagnosis disorders.

BACKGROUND: As knowledge deepens about how new neurons are born, differentiate, and wire into the adult mammalian brain, growing evidence depicts hippocampal neurogenesis as a special form of neuroplasticity that may be impaired across psychiatric disorders. This review provides an integrated-evidence based framework describing a neurogenic basis for addictions and addiction vulnerability in mental illness. METHODS: Basic studies conducted over the last decade examining the effects of addictive drugs on adult neurogenesis and the impact of neurogenic activity on addictive behavior were compiled and integrated with relevant neurocomputational and human studies. RESULTS: While suppression of hippocampal neurogenic proliferation appears to be a universal property of addictive drugs, the pathophysiology of addictions involves neuroadaptative processes within frontal-cortical-striatal motivation circuits that the neurogenic hippocampus regulates via direct projections. States of suppressed neurogenic activity may simultaneously underlie psychiatric and cognitive symptoms, but also confer or signify hippocampal dysfunction that heightens addiction vulnerability in mental illness as a basis for dual diagnosis disorders. CONCLUSIONS: Research on pharmacological, behavioral and experiential strategies that enhance adaptive regulation of hippocampal neurogenesis holds potential in advancing preventative and integrative treatment strategies for addictions and dual diagnosis disorders.

Auditory steady state responses in a schizophrenia rat model probed by excitatory/inhibitory receptor manipulation.

Alterations in neural synchrony and oscillations may contribute to the pathophysiology of schizophrenia and reflect aberrations in cortical glutamatergic and GABAergic neurotransmission. We tested the effects of a GABA agonist and an NMDA antagonist on auditory steady state responses (ASSRs) in awake rats with neonatal ventral hippocampal lesions (NVHLs) as a neurodevelopmental model of schizophrenia. NVHL vs. SHAM lesioned rats were injected with saline then either ketamine (NMDA antagonist) or muscimol (GABA(A) agonist). Time-frequency analyses examined alterations in phase locking (consistency) across trials and changes in total power (magnitude). ASSRs were compared at five stimulation frequencies (10, 20, 30, 40, and 50 Hz). In SHAM rats, phase locking and power generally increased with stimulation frequency. Both ketamine and muscimol also increased phase locking and power in SHAM rats, but mostly in the 20 to 40 Hz range. NVHL and ketamine altered the frequency dependence of phase locking, while only ketamine changed power frequency dependence. Muscimol affected power, but not phase locking, in the NVHL rats. NVHL and ketamine models of schizophrenia produce similar independent effects on ASSR, potentially representing similar forms of cortical network/glutamatergic dysfunction, albeit the effects of ketamine were more robust. Muscimol produced NVHL-dependent reductions in ASSR measures, suggesting that cortical networks in this model are intolerant to post-synaptic GABAergic stimulation. These findings suggest the utility of combining lesion, pharmacological, and ASSR approaches in understanding neural mechanisms underlying disturbed synchrony in schizophrenia.

Effects of alcohol availability, access to alcohol, and naltrexone on self-reported craving and patterns of drinking in response to an alcohol-cue availability procedure.

OBJECTIVE: Craving has long been cited by patients and providers as a principal construct in alcohol use disorders and an essential target for treatment. The goal of the current study was to examine the effects of alcohol availability (20% vs. 80% availability), access to alcohol ("open" vs. "locked" trials), and medication (oral naltrexone [Revia] vs. placebo) on self-reported craving and two behavioral measures of drinking (latency of attempt to access alcohol, amount of alcohol consumed when access permitted) in response to an alcohol-cue availability procedure. METHOD: Non-treatment-seeking, alcohol-dependent men and women (N = 58) self-referred for an alcohol administration study and were administered a modified alcohol-cue availability procedure under two medication conditions (naltrexone, placebo) using a within-subjects, repeated-measures design. RESULTS: Analyses demonstrated that the experimental manipulations used in this study had differential effects on craving and patterns of drinking. Specifically, reduced availability of alcohol (i.e., when alcohol was available in only 20% as opposed to 80% of trials) resulted in greater amounts of alcohol consumed per open trial; the unanticipated blocking of access to alcohol (i.e., a "locked" trial during the 80% availability condition) triggered more rapid attempts to obtain alcohol on subsequent trials. Naltrexone, relative to placebo, was associated with significant reductions in cravings for alcohol. CONCLUSIONS: Taken together, these findings offer partial support for the cognitive processing model and reinforce the utility of evaluating both self-report and behavioral indicators of motivation to drink in studies designed to identify factors associated with the construct of craving.

Nicotine exposure during adolescence enhances behavioral sensitivity to nicotine during adulthood in Wistar rats.

RATIONALE: Drug use during adolescence is associated with an increased propensity for drug dependency during adulthood. Therefore, the effects of adolescent exposure to nicotine on adult behavioral responsiveness to nicotine are of particular importance. OBJECTIVES: The objective of the current study was to determine if adolescent nicotine exposure would enhance behavioral sensitivity and development of sensitization to nicotine during adulthood. MATERIALS AND METHODS: Male Wistar rats were assigned to one of three groups that received subcutaneous (s.c.) injections of nicotine (0, 0.25, or 0.5mg/kg) in the home cage for 12 consecutive days during adolescence, PD 31-42. Starting on PD 80, distance traveled, rearing, and stereotypy were recorded in locomotor activity chambers each day for 10 days, following s.c. injections of 0, 0.25, or 0.5mg/kg nicotine. One week later, a final challenge session took place during which rats were injected with 0.5mg/kg nicotine. RESULTS: Rats exposed to nicotine during adolescence displayed a greater locomotor response to a novel environment than saline-treated rats. Adolescent nicotine treatment also resulted in context-independent sensitization to the acute locomotor activating properties of nicotine, including distance traveled and stereotypy, as measured on the first day of adulthood nicotine exposure. Adolescent nicotine-treated rats displayed increased sensitivity to repeated nicotine exposures during adulthood, compared to adolescent saline-treated rats, as measured by distance traveled, rearing, and stereotypic behaviors. Finally, rats treated with nicotine only during adolescence were more sensitive to a final nicotine challenge during adulthood than rats treated with nicotine only previously during adulthood. CONCLUSIONS: Overall, the results suggest that adolescent nicotine treatment predisposes adult rats to develop increased behavioral sensitivity to chronic nicotine treatment and to be more sensitive to the initial effects of nicotine.

Alcohol seeking and consumption in the NVHL neurodevelopmental rat model of schizophrenia.

Alcohol abuse in schizophrenia exceeds rates in the general population and worsens illness outcomes. Neonatal ventral hippocampal lesion (NVHL) rats model multiple schizophrenia dimensions including addiction vulnerability. This study compared NVHL vs. SHAM-controls in operant alcohol seeking and consumption. NVHLs enhanced consumption of combined ethanol/sucrose solution but neither ethanol or sucrose only solutions, consistent with increased vulnerability specific to carbohydrate-laden alcohol beverages typically consumed in early stages of human alcoholism.

The Dual Diagnosis Physician-infrastructure Assessment Tool: examining physician attributes and dual diagnosis capacity.

OBJECTIVE: Inadequate physician training and involvement in addictions treatment are barriers to integrating mental health and addiction services in public behavioral health care. The authors designed and implemented the Dual Diagnosis Physician-infrastructure Assessment Tool (DDPAT) to quantify statewide dimensions of this workforce problem. METHODS: The DDPAT examined institutional dual diagnosis capability and physician workforce, training backgrounds, and clinical roles across Indiana's 30 community mental health centers (CMHCs), six psychiatric hospitals, and 13 addiction treatment centers. RESULTS: All treatment centers and 75% of physicians responded. Sixty-nine percent of all treatment centers and 97% of CMHCs reported dual diagnosis capability. However, 29% of physicians treated both mental illness and addictions, and only 8% had certification in an addiction specialty. Overall workforce shortages, particularly of younger psychiatrists, contextualized these findings. CONCLUSIONS: The DDPAT identified multiple deficiencies in the physician workforce with respect to dual diagnosis and addictions care in Indiana. The DDPAT may be useful for characterizing similar trends in other states.