EFFECTS OF AN OPIOID AGONIST (U50,488H) AND ANTAGONIST (NALTREXONE) ON THE SEEKING AND INTAKE OF SUCROSE AND ETHANOL IN SELECTED AND NONSELECTED RATS

poster abstractNaltrexone (NTX) is clinically efficacious at attenuating alcohol intake in non-abstinent alcoholics and, to a lesser extent, craving, independent of intake. While generally regarded as a nonselective opioid antagonist, NTX has been shown to have concentration dependent selectivity with lower doses (< 1.0 mg/kg) selective for the mu receptor and doses exceeding 1.0 mg/kg capable of binding to kappa receptors. While the mu system has been implicated in mediating the reinforcing effects of EtOH, the role of the kappa system is less clear. Recent evidence suggests that kappa activation may mediate EtOH aversion. Thus, the present study sought to evaluate the effects of the kappa agonist U50,488H (U50) in a paradigm that procedurally separates the motivation to seek vs. consume a reinforcer to assess whether U50 differentially affects these behaviors in both selected (alcohol-preferring P rats) and nonselected (Long Evans) rats, and whether these effects are specific to EtOH. The effects of a low (mu specific) and high (nonspecific) dose range of NTX were also assessed. Rats were trained to complete a single response requirement that resulted in access to either 2% sucrose or 10% EtOH for a 20-min drinking session. In three separate experiments, rats were injected (using a balanced design) with either saline or 1 of 3 doses of drug: U50 (IP; 2.5, 5.0, or 10.0mg/kg), low NTX (SC; 0.1, 0.3, or 1.0 mg/kg) or high NTX (SC; 1.0, 3.0, or 10.0 mg/kg) on both consummatory and appetitive treatment days. Following either a 15 (U50) or 30 minute (NTX) pretreatment, rats were placed into an operant chamber and intake (consummatory) or lever responses (appetitive) and response latencies were recorded. The results showed that overall, U50 and NTX attenuated intake and responding for sucrose and EtOH. Independent of reinforcer, LE rats were more sensitive to U50’s effects on intake while P rats were more sensitive to the effects on seeking. P rats were more sensitive overall to lower doses of NTX than LE rats and lower doses of NTX were more selective in attenuating EtOH responding vs. sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results demonstrate that craving and intake may be differentially regulated by the kappa and mu opioid receptor systems as a function of “family history” and suggest that different mechanisms of the same (opioid) system may differentially affect craving and intake. Supported by T32-AA00746

Effects of Group II Metabotropic Glutamate Receptor Modulation on Ethanol- and Sucrose-Seeking and Consumption in the Rat

Rationale Previous studies suggest that group II metabotropic glutamate receptors (mGluR2/3) are involved in regulating ethanol seeking and consumption. Objective The mGluR2/3 agonist LY379268 (LY37) and selective mGluR2 positive allosteric modulator biphenyl-indanone A (BINA) were used to investigate the relative contribution of mGlu2 and mGlu3 receptors on ethanol and sucrose seeking and consumption. A microinjection study was then performed to examine the role of nucleus accumbens (NAc) core mGluR2/3 on ethanol-seeking. Methods For the systemic experiments, separate groups of male Wistar rats [LY37 (0-2.0 mg/kg); BINA (0-20 mg/kg)] were trained to complete a response requirement (RR) resulting in access to 10% ethanol or 2% sucrose (in separate groups) for a 20-minute drinking period. Animals then underwent consummatory testing (weekly drug injections with RR1) followed by appetitive testing (weekly drug injections followed by extinction session). A separate group of male Wistar rats was surgically implanted with bilateral guide cannulae directed towards the NAc core and had weekly microinjections followed by an extinction session. Results Systemic administration of the mGluR2/3 agonist LY37 significantly reduced ethanol- and sucrose-seeking. The same treatment also reduced sucrose consumption and body weight (24-hours post injection). Systemic administration of the selective mGluR2 PAM BINA, however, had no effect on either seeking or consumption of ethanol or sucrose. Intra-accumbens core LY37 significantly reduced ethanol-seeking. Conclusions: These findings suggest that systemic mGluR2/3 agonism, but not allosteric modulation of mGluR2, reduces reinforcer seeking. In particular, NAc core group II mGluR may be involved in regulating ethanol-seeking

Increased delay discounting tracks with a high ethanol-seeking phenotype and subsequent ethanol seeking but not consumption

BACKGROUND: Increased levels of delay discounting have been associated with alcoholism and problematic levels of drinking. Attempts to assess the directionality of this relationship by studying individuals with a family history of alcoholism as well as rodent lines selectively bred for high home cage alcohol preference have yielded discordant results. One possible reason for this discordance is that increased levels of delay discounting may only track with specific processes that lead to addiction vulnerability. This study investigated this possibility by assessing 3 strains of rats previously identified to exhibit heritable differences in ethanol (EtOH) seeking and consumption. METHODS: In an adjusting amount delay discounting task, alcohol-preferring (P) rats who display high levels of both EtOH seeking and consumption were compared to high alcohol-drinking (HAD2) rats who only exhibit moderate EtOH seeking despite high levels of consumption, and Long Evans (LE) rats who display moderate seeking and consumption. EtOH-seeking and consumption phenotypes were subsequently confirmed in an operant self-administration task with a procedural separation between EtOH seeking and drinking. RESULTS: P rats discounted delayed rewards to a greater extent than both HAD2s and LE who did not show differences in discounting. Moreover, the EtOH-seeking and drinking phenotypes were replicated with P rats displaying greater EtOH seeking compared to both the HAD2s and LE, and both the HAD2s and P rats consuming more EtOH than LEs. CONCLUSIONS: Only the high-seeking strain, the P rats, exhibited increased levels of delay discounting. This suggests that this measure of behavioral under-control is specifically associated with alcohol-related appetitive, but not consummatory, processes as the moderate seeking/high drinking line did not show increased levels of impulsivity. This finding supports the hypothesis that delay discounting is specifically associated with only certain processes which are sufficient but not necessary to confer addiction vulnerability and therefore also supports increased levels of delay discounting as a predisposing risk factor for alcoholism

Neurotransmitter Specific Roles in the Basolateral Amygdala and Their Effect on Ethanol-Seeking and Intake

poster abstractRelapse is a major problem in alcoholism treatment. Environmental cues can act as triggers that can reinstate alcohol use. By understanding specific neurochemical processes in the brain we can develop new treatments which will be focused on relapse prevention. Specifically the basolateral amygdala (BLA) which is involved in motivated responding and cue-induced reinstatement is of key interest. The aim of this study was to dissect drinking behaviors in an animal model (Long Evans rats) into two parts: appetitive (related to cue-induced reinstatement) and consummatory (related to primary reinforcement). Using operant chambers, lever pressing was a measure of an appetitive response and intake measured consummatory response. We looked at involvement of specific neurotransmitters in the BLA via microinjections of a dopamine and a glutamate antagonist. After initial lever press training, the rats received weekly microinjections of the two drugs as well as artificial cerebrospinal fluid in a randomized order to study their effects on ethanol (n = 5-8/group) and sucrose (n = 6-11/group) responding. Preliminary findings suggest both neurotransmitter- and behavior- specific effects. That is, manipulations of the BLA do not affect the intake of either sucrose or ethanol. This is consistent with findings suggesting that this area is not involved in processing primary reinforcement. However, the administration of the glutamate antagonist (but not the dopamine antagonist) in the BLA had a tendency to decrease reinforcer-seeking at the highest dose (p<0.09). This effect was not reinforcer specific, suggesting that the BLA glutamate activity may be involved in reinforcer-seeking rather than specifically in ethanol-seeking. Overall, the findings of this study will provide new insight into neurotransmitter function in the BLA, its relationship to alcohol intake, and will hopefully drive future research into development of new drugs that will reduce alcohol cravings and chance of relapse

Alcohol Preferring P Rats Exhibit Elevated Motor Impulsivity Concomitant with Operant Responding and Self-Administration of Alcohol

BACKGROUND: Increased levels of impulsivity are associated with increased illicit drug use and alcoholism. Previous research in our laboratory has shown that increased levels of delay discounting (a decision-making form of impulsivity) are related to appetitive processes governing alcohol self-administration as opposed to purely consummatory processes. Specifically, the high-seeking/high-drinking alcohol-preferring P rats showed increased delay discounting compared to nonselected Long Evans rats (LE) whereas the high-drinking/moderate-seeking HAD2 rats did not. The P rats also displayed a perseverative pattern of behavior such that during operant alcohol self-administration they exhibited greater resistance to extinction. METHODS: One explanation for the previous findings is that P rats have a deficit in response inhibition. This study followed up on this possibility by utilizing a countermanding paradigm (stop signal reaction time [SSRT] task) followed by operant self-administration of alcohol across increasing fixed ratio requirements (FR; 1, 2, 5, 10, and 15 responses). In separate animals, 24-hour access 2-bottle choice (10% EtOH vs. water) drinking was assessed. RESULTS: In the SSRT task, P rats exhibited an increased SSRT compared to both LE and HAD2 rats indicating a decrease in behavioral inhibition in the P rats. Also, P rats showed increased operant self-administration across all FRs and the greatest increase in responding with increasing FR requirements. Conversely, the HAD2 and LE had shorter SSRTs and lower levels of operant alcohol self-administration. However, for 2-bottle choice drinking HAD2s and P rats consumed more EtOH and had a greater preference for EtOH compared to LE. CONCLUSIONS: These data extend previous findings showing the P rats to have increased delay discounting (decision-making impulsivity) and suggest that P rats also have a lack of behavioral inhibition (motor impulsivity). This supports the notion that P rats are a highly impulsive as well as "high-seeking" model of alcoholism, and that the HAD2s' elevated levels of alcohol consumption are not mediated via appetitive processes or impulsivity

Psychospołeczne determinanty chorób. Implikacje medyczne w podstawowej opiece zdrowotnej

The social determinants of diseases within the primary care settingThe article highlights the social determinants of diseases within the primary care setting. Since the introduction of the new paradigm of the bio-psycho-social model into medicine, the social impact on illness has gained recognition. This article discusses the new approach to patients, as well as the impact that socio-economic status, emotional factors and stress have on health. Furthermore, factors such as the stages of patients’ lives and their ethnic and cultural identity (as well as approaches, such as the general theory of systems) are taken into consideration. New problems in primary care, including multimorbidity, patient frailty and medically unexplained symptoms, which have recently come under intense scrutiny, are also presented. Finally, clinical aspects of frail patients and the economic cost of the treatment of patients who suffer from unexplained symptoms are pointed out

PSYCHLOPS in Polish primary care: how do clients conceptualise their problems on a patient-generated outcome measure?

PSYCHLOPS in Polish primary care: how do clients conceptualise their problems on a patient-generated outcome measure? Author links open overlay panel MariaKordowiczaSƚawomirCzachowskibPeterSchofieldaMarkAshwortha Show more https://doi.org/10.1016/j.heliyon.2019.e02209 Get rights and content Under a Creative Commons license open access Abstract Background PSYCHLOPS, a patient-generated mental health outcome questionnaire, invites clients to describe the problem that troubles them most. PSYCHLOPS was utilised in Polish primary care in the context of a brief CBT-based intervention for mild to moderate mental health problems. Aim To explore how patients conceptualise their problems and the consequences of these problems with the aid of PSYCHLOPS. Method 243 patients were recruited from a primary care setting; 241 completed PSYCHLOPS. Free-text data were obtained from the Problem and Function domains of PSYCHLOPS, blind translated into English and independently analysed using a pre-existing thematic framework. A total of 780 free-text responses were analysed. Results The most commonly reported responses to the pre-therapy Problem domain category were “somatic” (denoting responses relating to physical health); the most common responses to the Function domain category were “competence/performance” (denoting responses relating to the respondents’ perceived ability to achieve, cope, function). Compared with pre-therapy Problem 1 domain categories, during-therapy responses revealed a higher proportion of the “interpersonal” category (denoting responses relating to social relationships) and a lower proportion of the “somatic” category. Conclusions Despite the brevity of clients' responses, PSYCHLOPS allowed an insight into patients' most troubling problems and their consequences. Possible reasons underlying the transition from a somatic to an interpersonal problem reporting during the course of talking therapy are discussed

The Effects of Long-Term Varenicline Administration on Ethanol and Sucrose Seeking and Self-Administration in Male P Rats

Background Varenicline, a partial agonist at α4β2 and full agonist at α7 nicotinic cholinergic receptors, is FDA-approved for treatment of smoking cessation and has been found to reduce alcohol craving in clinical populations. In rodents, varenicline decreases free-choice ethanol (EtOH) intake with somewhat mixed findings in operant paradigms that utilize a combined appetitive/consummatory response. Methods The present experiment utilized an operant paradigm that procedurally separates appetitive from consummatory responding and a “reward-blocking” approach (i.e., rats were able to consume EtOH during treatment) to better understand the efficacy of varenicline as a treatment for EtOH self-administration and subsequent EtOH seeking. Separate groups of EtOH- and sucrose-reinforced alcohol-preferring, male P rats experienced alternating cycles of vehicle (2-week cycles) and varenicline (0.3, 1.0, and 2.0 mg/kg self-administered in a gelatin preparation) treatment (3-week cycles) prior to daily sessions where a single lever press resulted in 20 minutes of reinforcer access. At the end of each cycle, a single extinction session assessed the seeking response in the absence of drug pretreatment. Results Varenicline dose dependently decreased EtOH intake. Sucrose intake was largely unaffected, with no overall treatment effects and only sporadic days where the medium and high dose differed from vehicle. Neither sucrose nor EtOH seeking was significantly decreased by varenicline, and there were no treatment effects on either lick or lever-press latency. Overall effect sizes were much greater for both drinking and seeking in the EtOH group as compared to the sucrose group. Conclusions Varenicline effectively attenuates EtOH self-administration during treatment, but the experience with EtOH consumption while varenicline is “on board” is not sufficient to alter subsequent EtOH seeking. The overall pattern of findings indicates that varenicline blocks the rewarding properties of EtOH while not substituting for EtOH, that the nonspecific effects on an alternate reinforcer are negligible, and that blood levels of varenicline need to be maintained in order for treatment to remain effective

Tolcapone suppresses ethanol intake in alcohol-preferring rats performing a novel cued access protocol

BACKGROUND: Dopamine (DA) has been shown to play a central role in regulating motivated behavior and encoding reward. Chronic drug abuse elicits a state of hypodopaminergia in the mesocorticolimbic (MCL) system in both humans and preclinical rodent models of addiction, including those modeling alcohol use disorders (AUD). METHODS: Working under the hypothesis that reductions in the bioavailability of DA play an integral role in the expression of the excessive drinking phenotype, the catechol-O-methyltransferase (COMT) inhibitor tolcapone was used as a means to amplify cortical DA concentration and drinking behaviors were then assessed. Sucrose and ethanol (EtOH) consumption were measured in P and Wistar rats in both a free choice drinking protocol and a novel cued access protocol. RESULTS: Tolcapone attenuated the consumption of EtOH, and to a lesser extent sucrose, in P rats in the cued access protocol, while no effect was observed in the free choice drinking protocol. Tolcapone also decreased EtOH consumption in high drinking Wistar rats. A follow-up experiment using the indirect DA agonist d-amphetamine showed no change in EtOH consumption. CONCLUSIONS: Collectively, these data suggest that COMT inhibitors may be capable of alleviating the extremely motivating or salient nature of stimuli associated with alcohol. The hypothesis is put forth that the relative specificity of tolcapone for cortical DA systems may mediate the suppression of the high seeking/drinking phenotype

Measuring Psychological Change during Cognitive Behaviour Therapy in Primary Care: A Polish Study Using ‘PSYCHLOPS’ (Psychological Outcome Profiles)

Psychological outcome measures are evolving into measures that depict progress over time. Interval measurement during therapy has not previously been reported for a patient-generated measure in primary care. We aimed to determine the sensitivity to change throughout therapy, using ‘PSYCHLOPS’ (Psychological Outcome Profiles), and to determine if new problems appearing during therapy diminish overall improvement.Responses to PSYCHLOPS, pre-, during- and post-therapy were compared. Setting: patients offered brief cognitive behaviour therapy in primary care in Poland.238 patients completed the pre-therapy questionnaire, 194 (81.5%) the during-therapy questionnaire and 142 the post-therapy questionnaire (59.7%). For those completing all three questionnaires (n = 135), improvement in total scores produced an overall Effect Size of 3.1 (2.7 to 3.4). We estimated change using three methods for dealing with missing values. Single and multiple imputation did not significantly change the Effect Size; ‘Last Value Carried Forward’, the most conservative method, produced an overall Effect Size of 2.3 (1.9 to 2.6). New problems during therapy were reported by 81 patients (60.0%): new problem and original problem scores were of similar magnitude and change scores were not significantly different when compared to patients who did not report new problems.A large proportion of outcome data is lost when outcome measures depend upon completed end of therapy questionnaires. The use of a during-therapy measure increases data capture. Missing data still produce difficulties in interpreting overall effect sizes for change. We found no evidence that new problems appearing during therapy hampered overall recovery