ABSTRACT
Partner engagement in antenatal care can improve care for pregnant people living with HIV. However, concerns about engaging unsupportive non-pregnant partners warrant further study to avoid engaging partners who pressure their pregnant partner to refuse testing or treatment and/or perpetuate intimate partner violence. We adapted established relationship functioning and partner behaviour questionnaires among pregnant people living with HIV initiating antenatal care in rural South Africa. We identified 13 previously validated psychometric scales with 255 items that assess relationship functioning and partner behaviour, but, to our knowledge, had not been used in Southern Africa. After item translation and cognitive interviewing with 30 pregnant people, we recruited an additional 208 pregnant people living with HIV receiving antenatal care. We conducted an exploratory factor analysis with maximum-likelihood extraction and oblique promax rotation with the 58 items and 10 scales that remained after translation and cognitive interviewing. We used parallel analysis, scree plots, and the Kaiser criterion to guide factor retention and assessed internal factor consistency via Cronbach's alpha. Of the 208 participants recruited, 197 (95%) answered each question and were included in the analysis. Exploratory factor analysis revealed 7 factors that assessed partner social support, sexual relationship power, emotional intimacy, threatened or enacted violence, sexual intimacy, violence in relationships, and partner engagement in pregnancy care via 37 items. Factor absolute Spearman correlations ranged from 0.012 to 0.518 and Cronbach's alpha ranged from 0.84 to 0.92. This preliminary analysis will guide further scale development. Future developments will also include relevant clinical outcomes to assess the predictive validity of the resulting measures. These steps will further refine these questions into a succinct screening tool to assess relationship functioning and partner behaviour. This screening tool may eventually guide the selection of partner-based interventions during pregnancy to improve outcomes for pregnant people and their partners.
Subject(s)
HIV Infections , Intimate Partner Violence , Female , Humans , Pregnancy , South Africa , Sexual Behavior , Sexual Partners/psychology , Prenatal Care , HIV Infections/prevention & controlABSTRACT
INTRODUCTION: Evidence strongly shows that a supportive, involved male partner facilitates maternal HIV testing during pregnancy, increases maternal antiretroviral (ART) adherence and increases HIV-free infant survival. Partner engagement in antenatal care (ANC) is influential; however, the most effective strategy to engage male partners is currently unknown. Engaging pregnant women to understand whether male partner involvement is welcome in ANC, what this involvement entails and how best to invite their partner is an important first step in determining how best to engage male partners. METHODS: We interviewed 36 pregnant women receiving ANC services at a district hospital in rural Mpumalanga, South Africa to assess the strengths and weaknesses of their current relationship, the type of partner support they receive, whether they would like their male partner to be involved in their ANC, and how best to invite their male partner to their appointments. We conducted a thematic analysis of the qualitative interviews using MAXQDA software. RESULTS: Financial, emotional, and physical support were noted as important aspects of support currently provided by male partners, with most pregnant women wanting their partners to engage in ANC services during pregnancy. Preferred engagement strategies included participation in couple-based HIV testing and counseling, regular ANC appointment attendance, and delivery room presence. Women who reported a positive relationship with her partner were more likely to prefer inviting their partner without health facility assistance, while those who reported challenges in their relationship preferred assistance through a letter or community health worker. Pregnant women perceived regular business hours (due to their partner being employed and unable to take off work) and having a partner involved in multiple relationships as barriers in getting their partner to attend ANC services. DISCUSSION: Rural South African women, even those in unsatisfactory relationships want their male partners to attend their ANC visits and birth. To make this possible, health facilities will have to tailor male partner engagement outreach strategies to the preferences and needs of the pregnant woman.
Subject(s)
HIV Infections , Prenatal Care , Humans , Female , Male , Pregnancy , Prenatal Care/psychology , Pregnant Women , South Africa , Qualitative Research , ParturitionABSTRACT
OBJECTIVES: To explore healthcare professionals' views on, and attitudes, towards recommending online resources for persistent pain self-management. METHODS: This study was the qualitative phase of a two-phase mixed method study. Thirty-one New Zealand health professionals involved in the management of persistent pain were interviewed via focus groups and individual interviews. Data were analysed using the general inductive approach. RESULTS: The major themes were as follows: (1) risks and limits of online information outweigh benefits, (2) a blended model, of online resources with healthcare professional support, could work, (3) only trustworthy resources can be recommended, (4) need for personalisation and (5) perceived barriers to adoption. CONCLUSION: Online resources were perceived as a useful adjunct to support pain self-management; however, due to potential risks of misinterpretation and misinformation, healthcare professionals proposed a 'blended model' where curated online resources introduced during face-to-face consultations could be used to support self-management. Participants needed 'trustworthy online resources' that provide evidence-based, updated information that is personalised to clients' health literacy and cultural beliefs. PRACTICE IMPLICATIONS: Training for healthcare professionals on critical appraisal of online resources or curation of evidence-based online resources could increase recommendation of online resources to support pain self-management as an adjunct to in-person care.
ABSTRACT
BACKGROUND: Non-invasive brain stimulation is being increasingly used to interrogate neurophysiology and modulate brain function. Despite the high scientific and therapeutic potential of non-invasive brain stimulation, experience in the developing brain has been limited. OBJECTIVE: To determine the safety and tolerability of non-invasive neurostimulation in children across diverse modalities of stimulation and pediatric populations. METHODS: A non-invasive brain stimulation program was established in 2008 at our pediatric, academic institution. Multi-disciplinary neurophysiological studies included single- and paired-pulse Transcranial Magnetic Stimulation (TMS) methods. Motor mapping employed robotic TMS. Interventional trials included repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS). Standardized safety and tolerability measures were completed prospectively by all participants. RESULTS: Over 10 years, 384 children underwent brain stimulation (median 13 years, range 0.8-18.0). Populations included typical development (n = 118), perinatal stroke/cerebral palsy (n = 101), mild traumatic brain injury (n = 121) neuropsychiatric disorders (n = 37), and other (n = 7). No serious adverse events occurred. Drop-outs were rare (<1%). No seizures were reported despite >100 participants having brain injuries and/or epilepsy. Tolerability between single and paired-pulse TMS (542340 stimulations) and rTMS (3.0 million stimulations) was comparable and favourable. TMS-related headache was more common in perinatal stroke (40%) than healthy participants (13%) but was mild and self-limiting. Tolerability improved over time with side-effect frequency decreasing by >50%. Robotic TMS motor mapping was well-tolerated though neck pain was more common than with manual TMS (33% vs 3%). Across 612 tDCS sessions including 92 children, tolerability was favourable with mild itching/tingling reported in 37%. CONCLUSIONS: Standard non-invasive brain stimulation paradigms are safe and well-tolerated in children and should be considered minimal risk. Advancement of applications in the developing brain are warranted. A new and improved pediatric NIBS safety and tolerability form is included.
Subject(s)
Brain Concussion/therapy , Epilepsy/therapy , Stroke/therapy , Transcranial Direct Current Stimulation/methods , Transcranial Magnetic Stimulation/methods , Child , Female , Headache/etiology , Humans , Male , Pruritus/etiology , Seizures/etiology , Transcranial Direct Current Stimulation/adverse effects , Transcranial Magnetic Stimulation/adverse effectsABSTRACT
Due to the higher incidence of hormone responsive tumours in women >50, the safety of hormone replacement therapy (HRT) in older breast cancer survivors may differ from younger age groups. The primary outcome in this review was the risk of tumour recurrence and secondary outcome the relationship with breast cancer-related mortality. Medline, CINAHL, Cochrane, Google Scholar and EMBASE databases were searched through August 2018 for studies reporting exposure to HRT in survivors ≥50â¯at primary diagnosis. Random effects models were used to estimate the combined relative risk (RR) of tumour recurrence and breast cancer-related mortality using the Mantel-Haenszel method and the quality of evidence determined for the primary outcome. Overall, nine studies (four cohort, one case-control, four RCTs; nâ¯=â¯16,002) were included. Very low quality evidence from observational studies demonstrated no adverse effect on tumour recurrence with HRT use (RR 0.80, 95% CI 0.53 to 1.19; I2â¯=â¯66%; nâ¯=â¯11,984), while moderate quality evidence from RCTS demonstrated an adverse effect (RR 1.46, 95% CI 1.20 to 1.77; I2â¯=â¯17%; nâ¯=â¯4108). Similarly, observational studies demonstrated no adverse effect on breast cancer-related mortality (RR 0.32, 95% CI 0.21 to 1.49; I2â¯=â¯0%, nâ¯=â¯2182), while RCTs demonstrated a non-significant higher risk (RR 1.07, 95% CI 0.77 to 1.49; I2â¯=â¯0%; nâ¯=â¯3918). Ultimately, despite conflicting findings, evidence of sufficient quality suggests that HRT may increase the risk of tumour recurrence in older survivors. However, adverse effect on mortality is unlikely. Caution with HRT use in survivors is further advised.
Subject(s)
Breast Neoplasms/drug therapy , Cancer Survivors , Hormone Replacement Therapy/adverse effects , Neoplasm Recurrence, Local/chemically induced , Age Factors , Aged , Aged, 80 and over , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Case-Control Studies , Disease-Free Survival , Female , Follow-Up Studies , Geriatric Assessment , Hormone Replacement Therapy/methods , Humans , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Neoplasm Recurrence, Local/physiopathology , Randomized Controlled Trials as Topic , Risk , Survival AnalysisABSTRACT
The currently available antismoking medications have limited efficacy and often fail to prevent relapse. Thus, there is a pressing need for newer, more effective treatment strategies. Recently, we demonstrated that enhancing endogenous levels of kynurenic acid (KYNA, a neuroinhibitory product of tryptophan metabolism) counteracts the rewarding effects of cannabinoids by acting as a negative allosteric modulator of α7 nicotinic receptors (α7nAChRs). As the effects of KYNA on cannabinoid reward involve nicotinic receptors, in the present study we used rat and squirrel monkey models of reward and relapse to examine the possibility that enhancing KYNA can counteract the effects of nicotine. To assess specificity, we also examined models of cocaine reward and relapse in monkeys. KYNA levels were enhanced by administering the kynurenine 3-monooxygenase (KMO) inhibitor, Ro 61-8048. Treatment with Ro 61-8048 decreased nicotine self-administration in rats and monkeys, but did not affect cocaine self-administration. In rats, Ro 61-8048 reduced the ability of nicotine to induce dopamine release in the nucleus accumbens shell, a brain area believed to underlie nicotine reward. Perhaps most importantly, Ro 61-8048 prevented relapse-like behavior when abstinent rats or monkeys were reexposed to nicotine and/or cues that had previously been associated with nicotine. Ro 61-8048 was also effective in monkey models of cocaine relapse. All of these effects of Ro 61-8048 in monkeys, but not in rats, were reversed by pretreatment with a positive allosteric modulator of α7nAChRs. These findings suggest that KMO inhibition may be a promising new approach for the treatment of nicotine addiction.
Subject(s)
Kynurenic Acid/metabolism , Nicotine/pharmacology , Reinforcement, Psychology , Sulfonamides/pharmacology , Thiazoles/pharmacology , Animals , Cocaine/administration & dosage , Cocaine/pharmacology , Dopamine/metabolism , Isoxazoles/pharmacology , Male , Nicotine/administration & dosage , Nucleus Accumbens/drug effects , Phenylurea Compounds/pharmacology , Rats , Recurrence , Saimiri , Secondary Prevention , Self Administration , Sulfonamides/antagonists & inhibitors , Thiazoles/antagonists & inhibitorsABSTRACT
Nicotine, the main psychoactive component of tobacco, and (-)-Δ(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior. Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC, but their clinical use is hindered by potentially serious side effects. The recently developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence. Here we compare attenuation of nicotine and THC reinforcement and reinstatement in squirrel monkeys by the CB1-receptor inverse agonist rimonabant and by the recently developed CB1-receptor neutral antagonist AM4113. Both rimonabant and AM4113 reduced two effects of nicotine and THC that play major roles in tobacco and marijuana dependence: (1) maintenance of high rates of drug-taking behavior, and (2) priming- or cue-induced reinstatement of drug-seeking behavior in abstinent subjects (models of relapse). In contrast, neither rimonabant nor AM4113 modified cocaine-reinforced or food-reinforced operant behavior under similar experimental conditions. However, both rimonabant and AM4113 reduced cue-induced reinstatement in monkeys trained to self-administer cocaine, suggesting the involvement of a common cannabinoid-mediated mechanism in the cue-induced reinstatement for different drugs of abuse. These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.
Subject(s)
Dronabinol/administration & dosage , Drug-Seeking Behavior/drug effects , Nicotine/administration & dosage , Piperidines/administration & dosage , Pyrazoles/administration & dosage , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Reinforcement, Psychology , Animals , Conditioning, Operant/drug effects , Cues , Male , Marijuana Abuse/prevention & control , Recurrence , Rimonabant , Saimiri , Self Administration , Tobacco Use Disorder/prevention & controlABSTRACT
RATIONALE: N-(4-hydroxyphenyl)-arachidonamide (AM404) is an anandamide transport inhibitor shown to reduce rewarding and relapse-inducing effects of nicotine in several animal models of tobacco dependence. However, the reinforcing/rewarding effects of AM404 are not clear. OBJECTIVES: We investigated whether AM404 maintains self-administration behavior or reinstates extinguished drug seeking in squirrel monkeys. METHODS AND RESULTS: In monkeys with a history of anandamide or cocaine self-administration, we substituted injections of AM404 (1-100 µg/kg/injection). Using a 10-response, fixed-ratio schedule, self-administration behavior was maintained by AM404. Dose-response curves had inverted U shapes, with peak response rates occurring at a dose of 10 µg/kg/injection. In anandamide-experienced monkeys, we also demonstrated self-administration of another anandamide transport inhibitor VDM11. In addition to supporting self-administration, priming injections of AM404 (0.03-0.3 mg/kg) reinstated drug-seeking behavior previously reinforced by cannabinoids (∆(9)-tetrahydrocannabinol (THC) or anandamide) or cocaine. Both AM404 self-administration behavior and reinstatement of drug seeking by AM404 were reduced by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist rimonabant (0.3 mg/kg). Moreover, the reinforcing effects of AM404 were potentiated by the treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg) suggesting a major role of anandamide in these effects. Finally, AM404 (0.3 mg/kg) potentiated the reinforcing effects of anandamide but not those of cocaine. CONCLUSIONS: In non-human primates, AM404 effectively reinforced self-administration behavior and induced reinstatement of drug-seeking behavior in abstinent monkeys. These effects appeared to be mediated by cannabinoid CB1 receptors. Therefore, compounds that promote actions of endocannabinoids throughout the brain by inhibiting their membrane transport may have a potential for abuse.
Subject(s)
Arachidonic Acids/administration & dosage , Drug-Seeking Behavior/drug effects , Animals , Arachidonic Acids/antagonists & inhibitors , Arachidonic Acids/metabolism , Benzamides/pharmacology , Cannabinoid Receptor Antagonists/pharmacology , Carbamates/pharmacology , Cocaine/pharmacology , Dose-Response Relationship, Drug , Dronabinol/pharmacology , Endocannabinoids/antagonists & inhibitors , Endocannabinoids/metabolism , Male , Nicotine/pharmacology , Piperidines/pharmacology , Polyunsaturated Alkamides/antagonists & inhibitors , Polyunsaturated Alkamides/metabolism , Polyunsaturated Alkamides/pharmacology , Pyrazoles/pharmacology , Reinforcement, Psychology , Reward , Rimonabant , Saimiri , Self AdministrationABSTRACT
RATIONALE: Group II metabotropic glutamate receptors (mGluR2 and mGluR3) have been suggested to play an important role in mediation of drug-reinforced behaviors, as well as in the mechanisms underlying relapse in abstinent subjects. The prototypical mGluR2/3 agonist, LY379268, has been shown to attenuate nicotine reinforcement and cue-induced reinstatement of drug seeking in rats, as well as reinstatement induced by drug-associated stimuli and contexts across different drugs of abuse (i.e., cocaine, heroin, and methamphetamine). However, in primates, LY379268 has been shown to produce conflicting results on abuse-related effects of cocaine, and there are no data available for nicotine. OBJECTIVES: To explore the therapeutic potential of mGluR2/3 agonists, we compared the effects of LY379268 (0.03-1.0 mg/kg) on nicotine, cocaine, and food self-administration under a fixed-ratio (FR10) schedule in three separate groups of squirrel monkeys. Moreover, we studied the effects of LY379268 on nicotine/cocaine priming-induced and cue-induced reinstatement of drug-seeking behavior in nicotine- and cocaine-experienced groups of animals. RESULTS: LY379268 blocked nicotine, but not cocaine, self-administration in monkeys. There was a partial overlap between doses that affected nicotine and food self-administration. In abstinent monkeys, LY379268 dose-dependently blocked nicotine, but not cocaine, priming-induced reinstatement of drug seeking. In both cocaine-experienced and nicotine-experienced groups of animals, LY379268 potently reduced cue-induced reinstatement of drug-seeking behavior. CONCLUSIONS: The present findings provide strong support for the potential utility of mGlu2/3 receptor agonists for the treatment of nicotine dependence and suggest their utility for prevention of relapse induced by environmental cues associated with drug taking.
Subject(s)
Amino Acids/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cocaine-Related Disorders/drug therapy , Cocaine/administration & dosage , Drug-Seeking Behavior/drug effects , Nicotine/administration & dosage , Tobacco Use Disorder/drug therapy , Animals , Cues , Dose-Response Relationship, Drug , Drug Interactions , Male , Receptors, Metabotropic Glutamate/agonists , Recurrence , Reinforcement, Psychology , Saimiri , Self AdministrationABSTRACT
Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell--consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement.
Subject(s)
Benzamides/pharmacology , Carbamates/pharmacology , Mixed Function Oxygenases/antagonists & inhibitors , Nicotine/administration & dosage , Nicotinic Agonists/administration & dosage , Reward , Animals , Biphenyl Compounds/pharmacology , Brain/drug effects , Brain/enzymology , Cues , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug-Seeking Behavior/drug effects , Extinction, Psychological/drug effects , Male , Mixed Function Oxygenases/metabolism , Models, Animal , Rats , Rats, Sprague-Dawley , Recurrence , Saimiri , Self Administration , Time FactorsABSTRACT
BACKGROUND: Based on rodent studies, group II metabotropic glutamate receptors (mGluR2 and mGluR3) were suggested as targets for addiction treatment. However, LY379268 and other group II agonists do not discriminate between the mainly presynaptic inhibitory mGluR2 (the proposed treatment target) and mGluR3. These agonists also produce tolerance over repeated administration and are no longer considered for addiction treatment. Here, we determined the effects of AZD8529, a selective positive allosteric modulator of mGluR2, on abuse-related effects of nicotine in squirrel monkeys and rats. METHODS: We first assessed modulation of mGluR2 function by AZD8529 using functional in vitro assays in membranes prepared from a cell line expressing human mGluR2 and in primate brain slices. We then determined AZD8529 (.03-10 mg/kg, intramuscular injection) effects on intravenous nicotine self-administration and reinstatement of nicotine seeking induced by nicotine priming or nicotine-associated cues. We also determined AZD8529 effects on food self-administration in monkeys and nicotine-induced dopamine release in accumbens shell in rats. RESULTS: AZD8529 potentiated agonist-induced activation of mGluR2 in the membrane-binding assay and in primate cortex, hippocampus, and striatum. In monkeys, AZD8529 decreased nicotine self-administration at doses (.3-3 mg/kg) that did not affect food self-administration. AZD8529 also reduced nicotine priming- and cue-induced reinstatement of nicotine seeking after extinction of the drug-reinforced responding. In rats, AZD8529 decreased nicotine-induced accumbens dopamine release. CONCLUSIONS: These results provide evidence for efficacy of positive allosteric modulators of mGluR2 in nonhuman primate models of nicotine reinforcement and relapse. This drug class should be considered for nicotine addiction treatment.
Subject(s)
Drug-Seeking Behavior/drug effects , Excitatory Amino Acid Agents/pharmacology , Indoles/pharmacology , Oxadiazoles/pharmacology , Tobacco Use Disorder/drug therapy , Animals , Brain/drug effects , Brain/metabolism , CHO Cells , Cricetulus , Disease Models, Animal , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug-Seeking Behavior/physiology , Excitatory Amino Acid Agents/blood , Feeding Behavior/drug effects , Feeding Behavior/physiology , HEK293 Cells , Humans , Indoles/blood , Male , Nicotine/administration & dosage , Nicotinic Agonists/administration & dosage , Oxadiazoles/blood , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/genetics , Receptors, Metabotropic Glutamate/metabolism , Saimiri , Self Administration , Tobacco Use Disorder/physiopathologyABSTRACT
Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8-[(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione] were found previously to either decrease or increase self-administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 [2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose-response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results show that selectively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of THC.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Dronabinol/pharmacology , Receptor, Adenosine A2A/drug effects , Receptors, Presynaptic/drug effects , Synapses/drug effects , Animals , Conditioning, Operant/drug effects , Dose-Response Relationship, Drug , Dronabinol/antagonists & inhibitors , Male , Marijuana Abuse/drug therapy , Purines/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Reinforcement, Psychology , Reward , Saimiri , Self Administration , Xanthines/pharmacologyABSTRACT
In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse.
Subject(s)
Brain/metabolism , Kynurenic Acid/metabolism , Substance-Related Disorders , Analgesics/administration & dosage , Animals , Benzoxazines/administration & dosage , Cannabinoid Receptor Agonists/pharmacology , Conditioning, Operant/drug effects , Cues , Discrimination, Psychological/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Dronabinol/pharmacology , Drug-Seeking Behavior/drug effects , Male , Memory, Short-Term/drug effects , Morpholines/administration & dosage , Naphthalenes/administration & dosage , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Reinforcement, Psychology , Saimiri , Secondary Prevention , Self Administration , Substance-Related Disorders/drug therapy , Substance-Related Disorders/metabolism , Substance-Related Disorders/pathology , Sulfonamides/pharmacology , Thiazoles/pharmacology , Time Factors , WakefulnessABSTRACT
Although substantial research effort has focused on developing pharmacological treatments for cocaine abuse, no effective medications have been developed. Recent studies show that enzymes that metabolize cocaine in the periphery, forestalling its entry into the brain, can prevent cocaine toxicity and its behavioral effects in rodents. Here we report on effects of one such enzyme (Albu-CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys. Albu-CocH was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic studies showed that Albu-CocH (5 mg/kg) had a half-life of 56.6 hours in squirrel monkeys. In these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced 2 hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hours following Albu-CocH administration. In behavioral experiments in monkeys, pre-treatment with 5 mg/kg Albu-CocH dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 µg/kg/injection) for over 24 hours. Pre-treatment with 5 mg/kg Albu-CocH also attenuated the reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine (0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative-stimulus effects of cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine abuse and toxicity is warranted.
Subject(s)
Albumins/pharmacology , Butyrylcholinesterase/pharmacology , Cocaine-Related Disorders/drug therapy , Cocaine/pharmacokinetics , Dopamine Uptake Inhibitors/pharmacokinetics , Albumins/pharmacokinetics , Analysis of Variance , Animals , Antibody Formation/drug effects , Biocatalysis , Butyrylcholinesterase/pharmacokinetics , Cocaine/administration & dosage , Cocaine/antagonists & inhibitors , Discrimination Learning/drug effects , Dopamine Uptake Inhibitors/administration & dosage , Dopamine Uptake Inhibitors/antagonists & inhibitors , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions/prevention & control , Drug-Seeking Behavior/drug effects , Half-Life , Humans , Male , Reinforcement, Psychology , Saimiri , Self AdministrationABSTRACT
Experimental drugs that activate α-type peroxisome proliferator-activated receptors (PPARα) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARα-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine's effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.
Subject(s)
Clofibrate/pharmacology , Drug Evaluation, Preclinical/psychology , Hypolipidemic Agents/pharmacology , Nicotine/pharmacology , Reward , Action Potentials/drug effects , Action Potentials/physiology , Animals , Clofibrate/therapeutic use , Disease Models, Animal , Dopamine/metabolism , Drug Evaluation, Preclinical/methods , Indoles/pharmacology , Male , Neurons/physiology , Nicotine/administration & dosage , Nicotine/antagonists & inhibitors , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , PPAR alpha/agonists , PPAR alpha/antagonists & inhibitors , Rats , Rats, Sprague-Dawley , Saimiri , Secondary Prevention , Self Administration , Tobacco Use Disorder/drug therapy , Ventral Tegmental Area/drug effects , Ventral Tegmental Area/physiologyABSTRACT
Forest fragmentation and selective logging are two main drivers of global environmental change and modify biodiversity and environmental conditions in many tropical forests. The consequences of these changes for the functioning of tropical forest ecosystems have rarely been explored in a comprehensive approach. In a Kenyan rainforest, we studied six animal-mediated ecosystem processes and recorded species richness and community composition of all animal taxa involved in these processes. We used linear models and a formal meta-analysis to test whether forest fragmentation and selective logging affected ecosystem processes and biodiversity and used structural equation models to disentangle direct from biodiversity-related indirect effects of human disturbance on multiple ecosystem processes. Fragmentation increased decomposition and reduced antbird predation, while selective logging consistently increased pollination, seed dispersal and army-ant raiding. Fragmentation modified species richness or community composition of five taxa, whereas selective logging did not affect any component of biodiversity. Changes in the abundance of functionally important species were related to lower predation by antbirds and higher decomposition rates in small forest fragments. The positive effects of selective logging on bee pollination, bird seed dispersal and army-ant raiding were direct, i.e. not related to changes in biodiversity, and were probably due to behavioural changes of these highly mobile animal taxa. We conclude that animal-mediated ecosystem processes respond in distinct ways to different types of human disturbance in Kakamega Forest. Our findings suggest that forest fragmentation affects ecosystem processes indirectly by changes in biodiversity, whereas selective logging influences processes directly by modifying local environmental conditions and resource distributions. The positive to neutral effects of selective logging on ecosystem processes show that the functionality of tropical forests can be maintained in moderately disturbed forest fragments. Conservation concepts for tropical forests should thus include not only remaining pristine forests but also functionally viable forest remnants.
Subject(s)
Biodiversity , Ecosystem , Human Activities , Trees , Animals , Behavior, Animal , Humans , Models, Theoretical , Tropical ClimateABSTRACT
Two endogenous ligands for cannabinoid CB1 receptors, anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol (2-AG), have been identified and characterized. 2-AG is the most prevalent endogenous cannabinoid ligand in the brain, and electrophysiological studies suggest 2-AG, rather than anandamide, is the true natural ligand for cannabinoid receptors and the key endocannabinoid involved in retrograde signaling in the brain. Here, we evaluated intravenously administered 2-AG for reinforcing effects in nonhuman primates. Squirrel monkeys that previously self-administered anandamide or nicotine under a fixed-ratio schedule with a 60 s timeout after each injection had their self-administration behavior extinguished by vehicle substitution and were then given the opportunity to self-administer 2-AG. Intravenous 2-AG was a very effective reinforcer of drug-taking behavior, maintaining higher numbers of self-administered injections per session and higher rates of responding than vehicle across a wide range of doses. To assess involvement of CB1 receptors in the reinforcing effects of 2-AG, we pretreated monkeys with the cannabinoid CB(1) receptor inverse agonist/antagonist rimonabant [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide]. Rimonabant produced persistent blockade of 2-AG self-administration without affecting responding maintained by food under similar conditions. Thus, 2-AG was actively self-administered by monkeys with or without a history of cannabinoid self-administration, and the reinforcing effects of 2-AG were mediated by CB1 receptors. Self-administration of 2-AG by squirrel monkeys provides a valuable procedure for studying abuse liability of medications that interfere with 2-AG signaling within the brain and for investigating mechanisms involved in the reinforcing effects of endocannabinoids.
Subject(s)
Arachidonic Acids/administration & dosage , Behavior, Animal/drug effects , Glycerides/administration & dosage , Motivation/drug effects , Analysis of Variance , Animals , Endocannabinoids , Extinction, Psychological/drug effects , Infusions, Intravenous , Injections, Intravenous , Male , Piperidines/pharmacology , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Reinforcement, Psychology , Rimonabant , Saimiri , Self AdministrationABSTRACT
Several recent studies suggest functional and molecular interactions between striatal adenosine A(2A) and cannabinoid CB(1) receptors. Here, we demonstrate that A(2A) receptors selectively modulate reinforcing effects of cannabinoids. We studied effects of A(2A) receptor blockade on the reinforcing effects of delta-9-tetrahydrocannabinol (THC) and the endogenous CB(1) receptor ligand anandamide under a fixed-ratio schedule of intravenous drug injection in squirrel monkeys. A low dose of the selective adenosine A(2A) receptor antagonist MSX-3 (1 mg/kg) caused downward shifts of THC and anandamide dose-response curves. In contrast, a higher dose of MSX-3 (3 mg/kg) shifted THC and anandamide dose-response curves to the left. MSX-3 did not modify cocaine or food pellet self-administration. Also, MSX-3 neither promoted reinstatement of extinguished drug-seeking behavior nor altered reinstatement of drug-seeking behavior by non-contingent priming injections of THC. Finally, using in vivo microdialysis in freely-moving rats, a behaviorally active dose of MSX-3 significantly counteracted THC-induced, but not cocaine-induced, increases in extracellular dopamine levels in the nucleus accumbens shell. The significant and selective results obtained with the lower dose of MSX-3 suggest that adenosine A(2A) antagonists acting preferentially at presynaptic A(2A) receptors might selectively reduce reinforcing effects of cannabinoids that lead to their abuse. However, the appearance of potentiating rather than suppressing effects on cannabinoid reinforcement at the higher dose of MSX-3 would likely preclude the use of such a compound as a medication for cannabis abuse. Adenosine A(2A) antagonists with more selectivity for presynaptic versus postsynaptic receptors could be potential medications for treatment of cannabis abuse.
Subject(s)
Adenosine A2 Receptor Antagonists/pharmacology , Arachidonic Acids/pharmacology , Cannabinoid Receptor Modulators/pharmacology , Cocaine/pharmacology , Dronabinol/pharmacology , Polyunsaturated Alkamides/pharmacology , Psychotropic Drugs/pharmacology , Receptor, Adenosine A2A/drug effects , Receptor, Cannabinoid, CB1/agonists , Xanthines/pharmacology , Animals , Corpus Striatum/drug effects , Dopamine/metabolism , Dose-Response Relationship, Drug , Endocannabinoids , Injections, Intravenous , Male , Marijuana Abuse/physiopathology , Marijuana Abuse/rehabilitation , Microdialysis , Nucleus Accumbens/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Presynaptic/drug effects , Reinforcement, Psychology , Saimiri , Self AdministrationABSTRACT
BACKGROUND: Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of FAAH increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide, which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly acting PPAR-α agonists can modulate reward-related effects of nicotine. METHODS: We combined behavioral, neurochemical, and electrophysiological approaches to evaluate effects of the PPAR-α agonists [[4-Chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid (WY14643) and methyl oleoylethanolamide (methOEA; a long-lasting form of OEA) on 1) nicotine self-administration in rats and squirrel monkeys; 2) reinstatement of nicotine-seeking behavior in rats and monkeys; 3) nicotine discrimination in rats; 4) nicotine-induced electrophysiological activity of ventral tegmental area dopamine neurons in anesthetized rats; and 5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely moving rats. RESULTS: The PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. The PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist 1-[(4-Chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)-1H-Indole-2-propanoic acid (MK886). CONCLUSIONS: These findings indicate that PPAR-α might provide a valuable new target for antismoking medications.
Subject(s)
Nicotine/administration & dosage , Nicotinic Agonists/administration & dosage , PPAR alpha/metabolism , Reinforcement, Psychology , Reward , Action Potentials/drug effects , Animals , Behavior, Animal/drug effects , Conditioning, Operant/drug effects , Dopamine/metabolism , Dose-Response Relationship, Drug , Drug Interactions , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Male , Microdialysis/methods , Neurons/drug effects , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Oligosaccharides/pharmacology , Peroxisome Proliferators/pharmacology , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Saimiri , Self Administration , Ventral Tegmental Area/cytologyABSTRACT
BACKGROUND: CB(1) cannabinoid receptors in the brain are known to participate in the regulation of reward-based behaviors. However, the contribution of each of the endocannabinoid transmitters, anandamide and 2-arachidonoylglycerol (2-AG), to these behaviors remains undefined. To address this question, we assessed the effects of URB597, a selective anandamide deactivation inhibitor, as a reinforcer of drug-seeking and drug-taking behavior in squirrel monkeys. METHODS: We investigated the reinforcing effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597 in monkeys trained to intravenously self-administer Delta(9)-tetrahydrocannabinol (THC), anandamide, or cocaine and quantified brain endocannabinoid levels using liquid chromatography/mass spectrometry. We measured brain FAAH activity using an ex vivo enzyme assay. RESULTS: URB597 (.3 mg/kg, intravenous) blocked FAAH activity and increased anandamide levels throughout the monkey brain. This effect was accompanied by a marked compensatory decrease in 2-AG levels. Monkeys did not self-administer URB597, and the drug did not promote reinstatement of extinguished drug-seeking behavior previously maintained by THC, anandamide, or cocaine. Pretreatment with URB597 did not modify self-administration of THC or cocaine, even though, as expected, it significantly potentiated anandamide self-administration. CONCLUSIONS: In the monkey brain, the FAAH inhibitor URB597 increases anandamide levels while causing a compensatory down-regulation in 2-AG levels. These effects are accompanied by a striking lack of reinforcing properties, which distinguishes URB597 from direct-acting cannabinoid agonists such as THC. Our results reveal an unexpected functional heterogeneity within the endocannabinoid signaling system and suggest that FAAH inhibitors might be used therapeutically without risk of abuse or triggering of relapse to drug abuse.