Panel Session Co-Morbid Pain and Addiction: Novel Treatments

2006 Neuropsychopharmacology  
Schizophrenic patients and individuals who go on to develop schizophrenia have high rates of comorbid tobacco smoking, smoke more cigarettes and extract more nicotine from cigarettes than other smokers. Chronic nicotine exposure upregulates nicotinic agonist binding to brain nicotinic acetylcholine receptors (nAChR). Postmortem studies have showed higher nicotinic agonist binding in the frontal cortex and hippocampus in control smokers compared to nonsmokers, but not in schizophrenic smokers
more » ... gesting a dysfunction in nAChR regulation in schizophrenia. The relevance of this upregulation and the failure of it in schizophrenia in relation to clinical symptoms and cognitive deficits is not yet known. Objective: To determine the effects of tobacco smoking on beta2nicotinic acetylcholine receptor (Beta2-nAChR) availability in control and schizophrenic smokers compared to control never smokers using [I-123]5-IA85380 ([I-123]5-IA) SPECT imaging. Methods: Beta2-nAChR were imaged in control never smokers (n =16), control smokers (n =16) and schizophrenic smokers (n=4) using theBeta2 subunit specific nicotinic agonist radiotracer [I-123]5-IA and SPECT. Schizophrenic and control smokers abstained from smoking for approximately 4-9 days (using progressive reinforcement techniques contingent on abstinence which was biochemically verified using cotinine and carbon monoxide levels) to allow sufficient time for residual nicotine to clear from the brain. Schizophrenic smokers were hospitalized to achieve confirmed abstinence. Subjects were studied using SPECT and 5-IA followed by MRI for coregistration of SPECT data. In schizophrenic smokers, cognitive testing (attention, working memory, selective attention and verbal learning and recall) was assessed while smoking as usual, 24hours after quitting, 5 days abstinence and if subjects resume smoking with the goal of correlating cognitive data with regional brain [I-123]5-IA uptake. Preliminary Results: [I-123]5-IA uptake was significantly higher in cortical brain areas (26-36%), striata (27%) and cerebella (25%) of recently abstinent (4-9 days) control smokers compared to control never smokers. Consistent with post mortem data, healthy smokers have 30% higher beta2-nAChR availability compared to never smokers. Further, consistent with post-mortem studies pilot data (n=4) show that relative to control smokers, [I-123]5-IA uptake was significantly lower in the frontal and occipital cortices (p <0.05), and trended towards towards lower [I-123]5-IA uptake in the parietal, anterior cingulate and temporal cortices in schizophrenic smokers. Interestingly, there was no difference in [I-123]5-IA uptake in the caudate, putamen and cerebellum between the schizophrenic and control smokers. Conclusions: These preliminary findings may reflect a failure to upregulate B2-nAChR in a region specific manner in schizophrenic smokers, and may contribute to nicotine addiction vulnerability in schizophrenia. ACNP 2006 Annual Meeting S4 elicits activation of the PFC to Nac BDNF/D3R pathway, which is accompanied by PFC dysfunction and psychotic-like behavioral disturbances, which are corrected by D3R-selective ligands or antipsychotic drugs. These results suggest that activation of the BDNF/D3R pathways may facilitate drug cue-induced drug seeking or craving in addiction, but that the anatomical location of the primary changes, VTA or PFC, may modulate the behavioral outcomes. Chronic exposure to cocaine induces long-lasting neuroadaptations within the mesocorticolimbic and mesocorticostriatal pathways that are thought to underlie the emergence and expression of addictive behaviors. Infusion of brain derived neurotrophic factor (BDNF) within the nucleus accumbens (NAc) or the ventral tegmental area (VTA) has been demonstrated to augment cocaine reinforcement and the reinstatement of cocaine-seeking behavior. However, the dorsal striatum (caudate-putamen) and ventral striatum (NAc) receive most of their BDNF by anterograde transport from corticostriatal, not mesostriatal, pathways. Yet little is known about the role of BDNF in the projections from the pre-frontal cortex (PFC) to the dorsal and ventral striatum that are critical to relapse behaviors. Therefore, in the present study, rats self-administered cocaine (0.2 mg/inf) on an FR1 schedule of reinforcement, with contingent presentation of a light and tone, during 2 hour sessions per day for 10 days. Immediately after the 10th self-administration session, rats received bilateral intra-PFC or intra-VTA infusions of BDNF (0.75µg/0.5µl/side) or vehicle (PBS, 0.5µl). Following 7 days of abstinence in the home cage, rats were re-exposed to the self-administration environment in the response-contingent presence of the conditioned light and tone stimuli during a 2-hour session. Rats that had received intra-PFC infusions of BDNF exhibited significantly less active lever responding during this test relative to vehicle-treated rats. Similarly, rats that received intra-PFC infusions of BDNF exhibited less lever responding following extinction and a conditioned cue (tone and light) test or a cocaine challenge (10 mg/kg, i.p.). This evidence sharply contrasts with animals that received intra-VTA infusions of BDNF in which reinstatement behaviors were augmented or not changed. These data implicate BDNF in the PFC as an important suppressor of relapse to cocaine seeking. Brain-derived nerve growth factor (BDNF) is critical for neuronal survival and differentiation; it also plays pivotal roles in the maintenance and remodeling of neuronal functioning in the adult brain. BDNF was recently found to enhance responding for cues associated with natural rewards, which suggests that BDNF may be involved in mediating long-term cellular and behavioral adaptations associated with drug addiction. Using a rat relapse model, we found that cocaine seeking induced by exposure to cocaine-associated cues progressively increases after withdrawal. This progressive increase is associated with increases in BDNF levels within the mesolimbic dopamine system. Based on these findings, we further studied whether BDNF infusions into the ventral tegmental area (VTA), the cell body region of mesolimbic dopamine neurons, would potentiate cocaine seeking after withdrawal. Rats were trained to self-administer cocaine for 10 d, and cocaine seeking was measured in extinction tests 3, 10, or 30 d after withdrawal. During testing, rats were exposed to contextual cues that had predicted cocaine availability during training, and lever presses resulted in contingent presentations of a discrete tone-light cue that was previously temporally paired with cocaine infusions. ACNP 2006 Annual Meeting S5 BDNF (0-0.75 microg/site) or nerve growth factor (NGF; 0-0.75 microg/site) was infused into the VTA 1-2 hr after the last self-administration session. To examine the role of the mitogen-activated protein kinase (MAPK) pathway in BDNF effects, U0126 (1 microg/site), an MEK inhibitor, was used. We found that a single intra-VTA infusion of BDNF, but not NGF, induced long-lasting enhancement of cocaine seeking for up to 30 d, an effect reversed by U0126. In contrast, neither BDNF infusions into the substantia nigra, nor acute intra-VTA BDNF infusions 2 hr before testing on day 3 of withdrawal, were effective. These data suggest that BDNF-mediated neuroadaptations in mesolimbic areas are involved in the persistent cocaine seeking induced by exposure to drug cues after withdrawal. Mood and Anxiety Disorders are among the most prevalent and serious of all medical disorders. Most of the availible treatments were discovered by serendipity and work via similiar mechanisms of action. Moreover, these treaments have significant limitations in efficacy and tolerability.This presentation will briefly review the history of therapeutic discovery for mood and anxiety disorders. More attention will directed toward developing a strategic plan for accelerating the pace of therapeutic discovery via enhancing research directed toward molecular target identification, molecular drug libraries, more precise phenotypic definition of disorders utilizing advances in human genetics and brain imaging, and novel clinical trial designs. Background: Drug discovery for schizophrenia has resulted in minimal progress since the 1952 introduction of chlorpromazine. The modest clozapine superiority in treatment resistant patients is the only documented superiority claim, and the partial agonist effect of aripiprazole is the only variation on the D2 antagonism mechanism of action theme. Core pathologies such as primary negative symptoms and impaired cognition have been neglected, and no drug has documented efficacy in these domains. The advantages sometimes observed in comparison to substantial doses of haloperidol tend to vanish with low dose haloperidol comparison, and the FDA has not approved any drug for a cognition or primary negative symptom indication. The purpose of this report is to determine the reasons for lack of progress, and to identify best opportunities for drug discovery for schizophrenia. Method: National concern with low innovation in drug discovery has prompted the Institute of Medicine to establish a Forum to address barriers and opportunities. Background reports have been commissioned to identify the issues as they relate to schizophrenia/psychosis, depression/anxiety, and molecular targets. The report on schizophrenia is based on a review of paradigms used in drug discovery, ascertainment of key factors which impede innovation, a review of clinical effects of drugs, and a review of animal and human models which may be informative in early proof of principle/concept studies. Results: Nine barriers were identified including absence of specific molecular pathology knowledge, the influence of the disease entity paradigm, misinterpretation of antipsychotic drug effects on schizophrenia, the lack of ambitious treatment goals, and the substantial market available to new drugs based on the antipsychotic development platform [the "me-too" problem]. Opportunities include a shift in paradigm to domains of pathology including cognition and avolition, establishing development platforms related to domains, relating animal models to specific domains, the application of genotype/phenotype knowledge in development and testing of compounds, a focus on pathologies responsible for long-term morbidity and poor functional outcomes, and development goals that include cure and prevention. Discussion: Drug development for schizophrenia based on psychosis as a proxy for schizophrenia pathology has resulted in little progress since the introduction of chlorpromazine. An alternative paradigm calls attention to multiple domains of pathology. These domains, rather than schizophrenia as a class, represent the pathologies for which molecular pathology must be identified. At present, these domains represent the clinical therapeutic targets for which drug discover should be focused. These domains stimulate interest in novel mechanisms and provide a framework for relating molecular neuroscience to animal models, human models and clinical targets. Investment in high-risk drug development is required to break from the D2 tradition. This is essential if progress on functional outcomes, recovery, cure and prevention is to be achieved. Introduction: As part of an Institute of Medicine sponsored study, we evaluated preclinical predictors of success and failure for CNS drug discovery. Not surprisingly, CNS drug discovery has, historically, been designated as an extraordinarily risky endeavor. To gain further insight into the reasons for failure and success in CNS drug discovery, we focused on 3 target areas: schizophrenia, depression and anxiety and examined the success rate for drugs that had entered at least the later stages of preclinical research. Methods: A total of 140 antipsychotics were initially classified based on their molecular target(s) and then evaluated using three overall ACNP 2006 Annual Meeting S6 criteria: (1) type of preclinical validation; (2) whether or not preclinical studies predicted clinical efficacy; and (3) whether the compound was of greater efficacy than "conventional treatment". Results: For the treatment of schizophrenia, we found that preclinical models were highly effective at predicting whether or not a candidate molecule would have 'atypical' properties (i.e., produce fewer EPS than a conventional antipsychotic drug such as haloperidol). On the other hand, the various preclinical models were only fair at predicting overall efficacy and ineffective at predicting efficacy greater than 'conventional treatment' . Thus, many classes of compounds (e.g. sigma1-, D1 and D4-selective compounds) were predicted by multiple preclinical animal models to be effective, but were subsequently found to be ineffective in humans. Finally, it was clear that 'multi-receptor' compounds were uniformly more effective than 'single-target' compounds for treating schizophrenia and related disorders (Roth et al., Nature Rev Drug Discov 2004). Because it is difficult to 'design-in' the preferential ability of a drug to hit multiple identified molecular targets, we and others have suggested that novel chemical scaffolds and novel chemistries should be attempted to generate 'multi-receptorial compounds.' Conclusions: None of the available animals models accurately predicts the propensity of various antipsychotic drugs to induce weight gain and associated side-effects, although this might be able to be predicted based on a knowledge of in vitro receptor pharmacology. Finally, in terms of the domains of efficacy (e.g., improving cognition, diminishing suicidality, diminishing deficit symptoms), none of the commonly used animal models are highly predictive, although preclinical memory models may be useful for predicting the ability of selected agents to enhance cognition, and receptor-based studies might predict whether or not a compound may diminish suicidality. Thus, for instance, the M1-muscarinic agonist properties of N-desmethylclozapine have been proposed to be predictive of the pro-cognitive actions of clozapine. Additionally, the greater potency of clozapine for 5-HT7 receptors can be used to predict the greater efficacy of clozapine versus olanzapine in preventing suicidal behavior. These findings imply that M1-agonists might be useful as 'add-on medications' for enhancing cognition while 5-HT7 antagonists may have anti-suicide actions. It appears to be impossible to predict using the currently available models whether or not compounds lacking D2dopamine receptor activity (either as antagonists or partial agonists) will prove effective in treating schizophrenia. Additionally, although enhancing cognition in schizophrenia remains a laudatory goal, there is no guarantee that any of the currently available preclinical models will predict efficacy in human domains of cognition in schizophrenia. Background: NMDA receptor dysfunction has been postulated in schizophrenia and this hypothesis is variably supported by a number of studies that have found abnormal NMDA receptor subunit and binding site expression in the schizophrenic brain. One limitation of these studies is that they do not account for alterations in receptor assembly, trafficking, or turnover, processes that rely, in part, on alternative splicing of the NR1 subunit, as well as a series of protein-protein interactions between specific NMDA receptor subunits and several recently characterized receptor interacting proteins. Alternative spliced variants of the NR1 subunit confer differential intracellular interactions for receptor processing and trafficking. C1 exon-con-taining splice variants of the NR1 subunit modulate an interaction between the NMDA receptor and neurofilament-light (NF-L), stabilizing the NMDA receptor in the cell membrane. Exclusion of the C2 exon yields a novel stop codon, resulting in a shorter splice variant expressed at the C-terminus (called C2'). This alternative splicing of the C2 cassette regulates NMDA receptor trafficking and cell surface expression. We hypothesize that NMDA receptor abnormalities in
doi:10.1038/sj.npp.1301265 fatcat:6odqjmshuncm5muxk5g5knprui