Both the ostensibly aversive effects of unpredictable episodes of social stress and the intensely rewarding effects of drugs of abuse activate the mesocorticolimbic dopamine systems. Significant neuroadaptations in interacting stress and reward neurocircuitry may underlie the striking connection between stress and substance use disorders. In rodent models, recurring intermittent exposure to social defeat stress appears to produce a distinct profile of neuroadaptations that translates most readily to the repercussions of social stress in humans. In the present review, preclinical rodent models of social defeat stress and subsequent alcohol, cocaine or opioid consumption are discussed with regard to: (1) the temporal pattern of social defeat stress, (2) male and female protocols of social stress-escalated drug consumption, and (3) the neuroplastic effects of social stress, which may contribute to escalated drug-taking. Neuroadaptations in corticotropin-releasing factor (CRF) and CRF modulation of monoamines in the ventral tegmental area and the bed nucleus of the stria terminalis are highlighted as potential mechanisms underlying stress-escalated drug consumption. However, the specific mechanisms that drive CRF-mediated increases in dopamine require additional investigation as do the stress-induced neuroadaptations that may contribute to the development of compulsive patterns of drug-taking.
In pursuit of safer controlled-deactivation cannabinoids with high potency and short duration of action, we report the design, synthesis, and pharmacological evaluation of novel C9- and C11-hydroxy-substituted hexahydrocannabinol (HHC) and tetrahydrocannabinol (THC) analogues in which a seven atom long side chain, with or without 1′-substituents, carries a metabolically labile 2′,3′-ester group. Importantly, in vivo studies validated our controlled deactivation approach in rodents and non-human primates. The lead molecule identified here, namely, butyl-2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl]-2-methylpropanoate (AM7499), was found to exhibit remarkably high in vitro and in vivo potency with shorter duration of action than the currently existing classical cannabinoid agonists.
The primary psychoactive ingredient of marijuana, D 9-tetrahydrocannabinol (D 9 -THC), has medicinal value but also produces unwanted deleterious effects on cognitive function, promoting the search for improved cannabinergic therapeutics. The present studies used a battery of touchscreen procedures in squirrel monkeys to compare the effects of different types of cannabinergic drugs on several measures of performance including learning (repeated acquisition), cognitive flexibility (discrimination reversal), short-term memory (delayed matching-to-sample), attention (psychomotor vigilance), and motivation (progressive ratio). Drugs studied included the cannabinoid agonist D 9 -THC, fatty acid amide hydrolase (FAAH) inhibitor cyclohexylcarbamic acid 3-carbamoylbiphenyl-3-yl ester (URB597), and endocannabinoid anandamide and its stable synthetic analog methanandamide [(R)-(1)-arachidonyl-19-hydroxy-29-propylamide]. The effects of D 9 -THC and anandamide after treatment with the cannabinoid receptor type 1 inverse agonist/antagonist rimonabant [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1Hpyrazole-3-carboxamide] and the FAAH inhibitor URB597, respectively, also were examined. The results showed the following: 1) D 9 -THC produced dose-related impairments of discrimination-based cognitive behavior with potency that varied across tasks (discriminative capability , learning , flexibility , short-term memory); 2) anandamide alone and URB597 alone were without effect on all endpoints; 3) anandamide following URB597 pretreatment and methanandamide had negligible effects on discriminative capability, learning, and reversal, but following large doses affected delayed matchingto-sample performance in some subjects; 4) all drugs, except anandamide and URB597, disrupted attention; and 5) progressive ratio breakpoints were generally unaffected by all drugs tested, suggesting little to no effect on motivation. Taken together, these data indicate that metabolically stable forms of anandamide may have lesser adverse effects on cognitive functions than D 9 -THC, possibly offering a therapeutic advantage in clinical settings.
Rationale Exposure to intermittent social defeat stress elicits CRF release into the VTA, and induces long-term modulation of mesocorticolimbic dopamine activity in rats. These adaptations are associated with an intense cocaine-taking phenotype, which is prevented by CRF receptor antagonists. Objective The present studies examine whether infusion of CRF into the VTA is sufficient to escalate cocaine-taking behavior, in the absence of social defeat experience. Additionally, we aimed to characterize changes in cocaine valuation that may promote binge-like cocaine intake. Methods Male Long-Evans rats were microinjected into the VTA with CRF (50 or 500 ng/side), vehicle, or subjected to social defeat stress, intermittently over 10 days. Animals were then trained to self-administer IV cocaine (FR5). Economic demand for cocaine was evaluated using a within-session behavioral-economics threshold procedure, which was followed by a 24-hour extended-access “binge”. Results Rats that experienced social defeat or received intra-VTA CRF microinfusions (50ng) both took significantly more cocaine than controls over the 24-hour “binge”, but showed distinct patterns of intake. Behavioral economic analysis revealed that individual demand for cocaine strongly predicts binge-like consumption, and demand elasticity (i.e. α) is augmented by intra-VTA CRF, but not by social defeat. The effects of CRF on cocaine-taking were also prevented by intra-VTA pretreatment with CP376395, but not Astressin-2B. Conclusions Repeated infusion of CRF into the VTA persistently alters cocaine valuation, and intensifies binge-like drug intake in a CRF-R1-dependent manner. Conversely, the persistent pattern of cocaine bingeing induced by social defeat stress may suggest impaired inhibitory control, independent of reward valuation.
Alcohol drinking, in some individuals, culminates in pathologically aggressive and violent behaviors. Alcohol can escalate the urge to fight, despite causing disruptions in fighting performance. When orally administered under several dosing conditions the current study examined in a mouse model if repeated alcohol escalates the motivation to fight, the execution of fighting performance, or both. Specifically, seven daily administrations of alcohol (0, 1.8, or 2.2 g/kg) determined if changes in the motivation to initiate aggressive acts occur with, or without, shifts in the severity of fighting behavior. Responding under the control of a fixed interval (FI) schedule for aggression reinforcements across the initial daily sessions indicated the development of tolerance to alcohol’s sedative effect. By day 7, alcohol augmented FI response rates for aggression rewards. While alcohol escalated the motivation to fight, fighting performance remained suppressed across the entire 7 days. Augmented FI responding for aggression rewards in response to a low dose of alcohol (1.0 g/kg) proved to be persistent, as we observed sensitized rates of responding for more than a month after alcohol pretreatment. In addition, this sensitization of motivated aggression did not occur with a general enhancement of motor activity. Antagonism of NMDA or AMPA receptors with ketamine, dizocilpine, or NBQX during later challenges with alcohol were largely serenic without having any notable impact on the expression of alcohol-escalated rates of FI responding. The current dissociation of appetitive and performance measures indicates that discrete neural mechanisms controlling aggressive arousal can be distinctly sensitized by alcohol.
Compulsive eating behavior is hypothesized to be driven in part by reward deficits likely due to neuroadaptations to the mesolimbic dopamine (DA) system. Therefore, the aim of this study was to assess deficits in reward system functioning and mesolimbic DA after alternating a standard chow with palatable diet, a model of compulsive eating. In this model, rats in the control group (Chow/Chow) are provided a standard chow diet 7 days a week, while the experimental group (Chow/Palatable) is provided chow for 5 days a week ("C Phase"), followed by 2 days of access to a highly palatable sucrose diet ("P Phase"). We first tested the sensitivity to d-Amphetamine's stimulatory, reward-enhancing, and primary rewarding effects using a locomotor activity assay, an intracranial self-stimulation (ICSS) procedure, and a conditioned place preference test, respectively. We then quantified DA release in the nucleus accumbens (NAc) shell after treatment with d-Amphetamine using in vivo microdialysis, quantified levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA using quantitative polymerase chain reaction (qPCR), and lastly, quantified baseline extracellular DA and function of DAT in vivo using quantitative "no-net-flux" microdialysis. Chow/Palatable rats displayed blunted d-Amphetamine-induced locomotor activity, insensitivity to d-Amphetamine potentiation of ICSS threshold, and decreased place preference for d-Amphetamine during the P Phase. We found that Chow/Palatable rats had blunted DA efflux following d-Amphetamine treatment. Furthermore, DAT mRNA was increased in Chow/Palatable rats during the P Phase. Finally, quantitative "no-net-flux" microdialysis revealed reduced extracellular baseline DA and DAT function in Chow/Palatable rats. Altogether, these results provide evidence of reduced reward system functioning and related neuroadaptations in the DA and DAT systems in this model of compulsive eating. Reward deficits, resulting from repeated overeating, may in turn contribute to the perpetuation of compulsive eating behavior.
GABAergic neurons are important for controlling sleep and wakefulness but are difficult to identify, limiting their study. Knock-in mice with GABAergic neurons labeled by expression of green fluorescent protein (GFP) under control of the glutamate decarboxylase (GAD67/Gad1) promoter are now extensively used in neuroscience. However, it is unknown whether these mice have a normal sleep phenotype. Compared to adult wild type control mice (n=7), adult GAD67-GFP knock-in mice (n=7) had the same amount of NREM and REM sleep, a similar diurnal distribution of sleep, no NREM or REM sleep differences in EEG power, and normal sleep rebound following 6h sleep deprivation. Our results suggest GAD67-GFP knock-in mice are an excellent tool for study of GABAergic neurons involved in sleep-wake regulation.
An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type 1 (CB) receptor agonists such as Δ-tetrahydrocannabinol are increasingly used for their medicinal actions; however, their utility is constrained by concern regarding abuse-related subjective effects. This has led to growing interest in the clinical benefit of indirectly enhancing the activity of the highly labile endocannabinoids -arachidonoylethanolamine [AEA (or anandamide)] and/or 2-arachidonoylglycerol (2-AG) via catabolic enzyme inhibition. The present studies were conducted to determine whether such actions can lead to CB agonist-like subjective effects, as reflected in CB-related discriminative stimulus effects in laboratory subjects. Squirrel monkeys ( = 8) that discriminated the CB full agonist AM4054 (0.01 mg/kg) from vehicle were used to study, first, the inhibitors of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MGL) alone or in combination [FAAH (URB597, AM4303); MGL (AM4301); FAAH/MGL (JZL195, AM4302)] and, second, the ability of the endocannabinoids AEA and 2-AG to produce CB agonist-like effects when administered alone or after enzyme inhibition. Results indicate that CB-related discriminative stimulus effects were produced by combined, but not selective, inhibition of FAAH and MGL, and that these effects were nonsurmountably antagonized by low doses of rimonabant. Additionally, FAAH or MGL inhibition revealed CB-like subjective effects produced by AEA but not by 2-AG. Taken together, the present data suggest that therapeutic effects of combined, but not selective, enhancement of AEA or 2-AG activity via enzyme inhibition may be accompanied by CB receptor-mediated subjective effects.
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