Modulation of Opiate-Related Signaling Molecules in Morphine-Dependent Conditioned Behavior: Conditioned Place Preference to Morphine Induces CREB Phosphorylation

Opiate addiction is a chronic, relapsing behavioral disorder where learned associations that develop between the abused opiate and the environment in which it is consumed are brought about through Pavlovian (classical) conditioning processes. However, the signaling mechanisms/pathways regulating the mechanisms that underlie the responses to opiate-associated cues or the development of sensitization as a consequence of repeated context-independent administration of opiates are unknown. In this study we examined the phosphorylation levels of various classic signaling molecules in brain regions implicated in addictive behaviors after acute and repeated morphine administration. An unbiased place conditioning protocol was used to examine changes in phosphorylation that are associated with (1) the expression of the rewarding effects of morphine and (2) the sensitization that develops to this effect. We also examined the effects of a δ-receptor antagonist on morphine-induced conditioned behavior and on the phosphorylation of classic signaling molecules in view of data showing that blockade of δ-opioid receptor (δOR) prevents the development of sensitization to the rewarding effects of morphine. We find that CREB phosphorylation is specifically induced upon the expression of a sensitized response to morphine-induced conditioned behavior in brain areas related to memory consolidation, such as the hippocampus and cortex. A similar effect is also observed, albeit to a lesser extent, in the case of the GluR1 subunit of AMPA glutamate receptor. These increases in the phosphorylation levels of CREB and pGluR1 are significantly blocked by pretreatment with a δOR antagonist. These results indicate a critical role for phospho-CREB, AMPA, and δOR activities in mediating the expression of a sensitized response to morphine-dependent conditioned behavior.     

Convergent Evidence that Choline Acetyltransferase Gene Variation is Associated with Prospective Smoking Cessation and Nicotine Dependence

The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry after 8 weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 single-nucleotide polymorphisms (SNPs) in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pretreatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non-treatment-seeking cohort, we used data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.     

Telephone counseling for young Brazilian cocaine and/or crack users. Who are these users?

Objective

To describe the users’ drug abuse characteristics, problematic behaviors associated with addiction, the motivation of teenagers and young adults to quit cocaine and/or crack abuse, and then compare these characteristics.

Patterns of simultaneous polysubstance use in drug using university students

Simultaneous polysubstance use (SPU) is a common phenomenon, yet little is known about how various substances are used with one another. In the present study 149 drug-using university students completed structured interviews about their use of various substances. For each substance ever used, participants provided details about the type, order and amount of all substances co-administered during its most recent administration. Alcohol, tobacco and cannabis were frequently co-administered with each other and with all other substances. Chi-squared tests revealed that when alcohol was used in combination with any of cannabis, psilocybin, MDMA, cocaine, amphetamine, methylphenidate (ps < 0.01) or LSD (p < 0.05) its initial use preceded the administration of the other substance. Paired samples t-tests revealed that when alcohol was used with cocaine (p < 0.01) or methylphenidate (p < 0.05) it was ingested in greater quantities than when used in their absence. Patterns of cannabis use were not systematically related to other substances administered. Finally, using one-sample t-tests, tobacco use was demonstrated to be increased relative to 'sober' smoking rates when used with alcohol, cannabis, psilocybin, MDMA, cocaine, amphetamine (ps < 0.001), LSD (p < 0.01) or methylphenidate (p < 0.05). Results suggest that many substances are routinely used in a SPU context and that the pattern in which a substance is used may be related to other substances co-administered.     

Contextual cues associated with nicotine administration increase arc mRNA expression in corticolimbic areas of the rat brain

Conditioned responses to cues associated with the administration of drugs of misuse are an impediment to continued abstinence for drug-free addicted individuals. In order to study the neuroanatomical and cellular response of the brain to cues associated with nicotine administration, we conditioned Sprague-Dawley rats to receive an ascending dose regimen of nicotine over 14 days in two distinct non-home cage environments and assessed expression of the early response gene arc in corticolimbic areas in response to the nicotine-associated context. All of the rats received the same dose regimen of nicotine. Three days after the last training day, the rats were exposed to the test environment. The rats that had previously received nicotine exhibited increased motor activity compared with the rats that had received saline in the test environment. After 45 min in the test environment, brains were taken for Northern blotting and in situ hybridization analysis, which revealed an increase in levels of activity-regulated, dendritically localized mRNA for arc in a variety of brain regions (medial and lateral prefrontal cortices, cingulate cortex, primary sensory cortex, sensorimotor cortex, ventral striatum and amygdala). Plasma corticosterone levels were not different between the groups, suggesting that exposure to nicotine cues is insufficient to activate the hypothalamo-pituitary-adrenal axis. Given that Arc plays a direct role in neuronal plasticity and memory consolidation, its induction by nicotine-associated cues in brain regions critical for cognitive and emotional processing suggests that rats may be learning that these cues are no longer necessarily predictive of nicotine administration. Further work will be needed in order to assess the role of arc expression in the extinction of conditioned responses to drug-paired cues.     

The opioid fentanyl affects light input, electrical activity and Per gene expression in the hamster suprachiasmatic nuclei

The suprachiasmatic nuclei (SCN) contain a major circadian pacemaker, which is regulated by photic and nonphotic stimuli. Although enkephalins are present in the SCN, their role in phase regulation of the pacemaker is largely unknown. The opioid agonist fentanyl, a homologue of morphine, is an addictive drug that induces phase shifts of circadian rhythms in hamsters. We observed that these phase shifts are blocked by naloxone, which is a critical test for true opioid receptor involvement, and conclude that opioid receptors are the sole mediators of the actions of fentanyl on the circadian timing system. A strong interaction between opioids and light input was shown by the ability of fentanyl and light to completely block each other's phase shifts of behavioural activity rhythms. Neuronal ensemble recordings in vitro provide first evidence that SCN cells show direct responses to fentanyl and react with a suppression of firing rate. Moreover, we show that fentanyl induces a strong attenuation of light-induced Syrian hamster Period 1 (shPer1) gene expression during the night. During the subjective day, we found no evidence for a role of shPer1 in mediation of fentanyl-induced phase shifts. Based on the present results, however, we cannot exclude the involvement of shPer2. Our data indicate that opioids can strongly modify the photic responsiveness of the circadian pacemaker and may do so via direct effects on SCN electrical activity and regulation of Per genes. This suggests that the pathways regulating addictive behaviour and the circadian clock intersect.     

Ventral pallidal neurons code incentive motivation: amplification by mesolimbic sensitization and amphetamine

Neurons in ventral pallidum fire to reward and its predictive cues. We tested mesolimbic activation effects on neural reward coding. Rats learned that a Pavlovian conditioned stimulus (CS+1 tone) predicted a second conditioned stimulus (CS+2 feeder click) followed by an unconditioned stimulus (UCS sucrose reward). Some rats were sensitized to amphetamine after training. Electrophysiological activity of ventral pallidal neurons to stimuli was later recorded under the influence of vehicle or acute amphetamine injection. Both sensitization and acute amphetamine increased ventral pallidum firing at CS+2 (population code and rate code). There were no changes at CS+1 and minimal changes to UCS. With a new 'Profile Analysis', we show that mesolimbic activation by sensitization/amphetamine incrementally shifted neuronal firing profiles away from prediction signal coding (maximal at CS+1) and toward incentive coding (maximal at CS+2), without changing hedonic impact coding (maximal at UCS). This pattern suggests mesolimbic activation specifically amplifies a motivational transform of CS+ predictive information into incentive salience coded by ventral pallidal neurons. Our results support incentive-sensitization predictions and suggest why cues temporally proximal to drug presentation may precipitate cue-triggered relapse in human addicts.     

Phospholipase C gamma in distinct regions of the ventral tegmental area differentially regulates morphine-induced locomotor activity

Neurotrophic factors and the signaling pathways they activate play a role in mediating long-term molecular, cellular, and behavioral adaptations associated with drug addiction. Here we mimicked the biological response of phospholipase C-gamma (PLC gamma) induction in the ventral tegmental area (VTA) observed after chronic morphine using viral-mediated gene transfer. Using a behavioral sensitization paradigm, we demonstrate that microinjections of PLC gamma 1 into distinct (rostral vs. caudal) regions of the VTA result in differential locomotor responses to morphine.     

Using concept mapping to design an indicator framework for addiction treatment centres.

OBJECTIVE: The objective of this study is to determine an indicator framework for addiction treatment centres based on the demands of stakeholders and in alignment with the European Foundation for Quality Management (EFQM) Excellence Model. SETTING: The setting is the Jellinek Centre based in Amsterdam, the Netherlands, which serves as a prototype for an addiction treatment centre. METHOD: Concept mapping was used in the construction of the indicator framework. During the 1-day workshop, 16 stakeholders generated, prioritized and sorted 73 items concerning quality and performance. Multidimensional scaling and cluster analysis was applied in constructing a framework consisting of two dimensions and eight clusters. RESULTS: The horizontal axis of the indicator framework is named 'Organization' and has two poles, namely, 'Processes' and 'Results'. The vertical axis is named ' Task' and the poles are named 'Efficient treatment' and 'Prevention programs'. The eight clusters in the two-dimensional framework are arranged in the following, prioritized sequence: 'Efficient treatment network', 'Effective service', ' Target group', 'Quality of life', 'Efficient service', 'Knowledge transfer', 'Reducing addiction related problems', and 'Prevention programs'. The most important items in the framework are: 'patients are satisfied with their treatment', 'early interventions', and 'efficient treatment chain'. CONCLUSION: The indicator framework aligns with three clusters of the results criteria of the EFQM Excellence Model. It is based on the stakeholders' perspectives and is believed to be specific for addiction treatment centres. The study demonstrates that concept mapping is a suitable strategy for generating indicator frameworks.