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RATIONALE: The use of illicit opioids has arguably never been more risky; street drug potency can be dangerously high, is often unknown to the consumer, and results in multiple daily fatalities worldwide. Furthermore, substance use disorder (SUD) is associated with increased maladaptive, risky decisions in laboratory-based gambling tasks. Animal studies can help determine whether this decision-making deficit is a cause or consequence of drug use. However, most experiments have only assessed psychostimulant drugs. OBJECTIVES: To assess differences in decision-making strategies both before, during, and after self-administration of fentanyl in male and female Long Evans rats. METHODS: Male and female Long Evans rats were trained to perform the rat gambling task (rGT), loosely based on the Iowa Gambling Task (IGT) used clinically, and/or self-administer fentanyl. We used the cued version of the rGT, in which sound and light stimuli signal sugar pellet rewards, as cocaine self-administration has the greatest effects on decision making in this task variant. RESULTS: After training on the cued rGT, female rats self-administered fentanyl more readily, an effect that was most apparent in optimal decision-makers. Contrary to previous reports using cocaine self-administration, decision-making was unaffected during fentanyl self-administration training in either sex. However, risky decision-making increased throughout forced abstinence from fentanyl in males. CONCLUSIONS: These findings complement those from human subjects, in whom preference for uncertain outcomes increased before relapse. These data highlight an abstinence-induced change in cognition that is unique to opiates as compared to psychostimulants, and which may critically contribute to the maintenance of addiction and relapse.
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BACKGROUND: Both psychostimulant use and engagement with probabilistic schedules of reward sensitize the mesocorticolimbic dopamine (DA) system. Such behaviors may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation. METHODS: To probe these interactions, we sensitized ventral tegmental area DA neurons via chronic chemogenetic stimulation while rats (n = 134) learned a rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort (n = 25), we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine and potentiated phasic excitability of ventral tegmental area DA neurons through in vivo electrophysiological recordings. RESULTS: In the absence of cues, sensitization promoted risk taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males while attenuating cue-induced risk taking in females. CONCLUSIONS: While these results provide further confirmation that ventral tegmental area DA neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact that dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision making on the cued rat gambling task increased as both males and females learned to self-administer cocaine. The combination of DA sensitization and win-paired cues while gambling led to significantly greater cocaine taking, but these rats did not show any increase in risky choice as a result. Therefore, cocaine and heavily cued gambles may partially substitute for each other once the DA system has been rendered labile through sensitization, thereby compounding addiction risk across modalities.
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Cocaína , Jogo de Azar , Humanos , Ratos , Masculino , Feminino , Animais , Sinais (Psicologia) , Neurônios Dopaminérgicos , Cocaína/farmacologia , Dopamina , Área Tegmentar Ventral , Tomada de Decisões/fisiologiaRESUMO
Social isolation is an established risk factor for mental illness and impaired immune function. Evidence suggests that neuroinflammatory processes contribute to mental illness, possibly via cytokine-induced modulation of neural activity. We examined the effects of lipopolysaccharide (LPS) administration and social home cage environment on cognitive performance in the 5-Choice Serial Reaction Time Task (5CSRTT), and their effects on corticosterone and cytokines in serum and brain tissue. Male Long-Evans rats were reared in pairs or in isolation before training on the 5CSRTT. The effects of saline and LPS (150 µg/kg i.p.) administration on sickness behaviour and task performance were then assessed. LPS-induced sickness behaviour was augmented in socially-isolated rats, translating to increased omissions and slower response times in the 5CSRTT. Both social isolation and LPS administration reduced impulsive responding, while discriminative accuracy remained unaffected. With the exception of reduced impulsivity in isolated rats, these effects were not observed following a second administration of LPS, revealing behavioural tolerance to repeated LPS injections. In a separate cohort of animals, social isolation potentiated the ability of LPS to increase serum corticosterone and IL-6, which corresponded to increased IL-6 in the orbitofrontal and medial prefrontal cortices and the nucleus accumbens. Basal IL-4 levels in the nucleus accumbens were reduced in socially-isolated rats. These findings are consistent with the adaptive response of reduced motivational drive following immune challenge, and identify social isolation as an exacerbating factor. Enhanced IL-6 signalling may play a role in mediating the potentiated behavioural response to LPS administration in isolated animals.
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Corticosterona , Lipopolissacarídeos , Animais , Cognição/fisiologia , Citocinas , Humanos , Interleucina-6 , Lipopolissacarídeos/farmacologia , Masculino , Ratos , Ratos Long-EvansRESUMO
Previous research has indicated that reward-paired cues can enhance disadvantageous risky choice in both humans and rodents. Systemic administration of a serotonin 2C receptor antagonist can attenuate this cue-induced risk preference in rats. However, the neurocognitive mechanisms mediating this effect are currently unknown. We therefore assessed whether the serotonin 2C receptor antagonist RS 102221 is able to attenuate cue-enhanced risk preference via its actions in the lateral orbitofrontal cortex (lOFC) or prelimbic (PrL) area of the medial prefrontal cortex (mPFC). A total of 32 male Long-Evans rats were trained on the cued version of the rat gambling task (rGT), a rodent analog of the human Iowa gambling task, and bilateral guide cannulae were implanted into the lOFC or PrL. Intra-lOFC infusions of the 5-HT2C antagonist RS 102221 reduced risky choice in animals that showed a preference for the risky options of the rGT at baseline. This effect was not observed in optimal decision-makers, nor those that received infusions targeting the PrL. Given prior data showing that 5-HT2C antagonists also improve reversal learning through the same neural locus, we hypothesized that reward-concurrent cues may amplify risky decision-making through cognitive inflexibility. We therefore devalued the sugar pellet rewards used in the cued rGT (crGT) through satiation and observed that decision-making patterns did not shift unless animals also received intra-lOFC RS 102221. Collectively, these data suggest that the lOFC is one critical site through which reward-concurrent cues promote risky choice patterns that are insensitive to reinforcer devaluation, and that 5-HT2C antagonism may optimize choice by facilitating exploration.
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Sinais (Psicologia) , Serotonina , Animais , Tomada de Decisões , Masculino , Córtex Pré-Frontal , Ratos , Ratos Long-Evans , RecompensaRESUMO
Gambling and substance use disorders are highly comorbid. Both clinical populations are impulsive and exhibit risky decision-making. Drug-associated cues have long been known to facilitate habitual drug-seeking, and the salient audiovisual cues embedded within modern gambling products may likewise encourage problem gambling. The dopamine neurons of the ventral tegmental area (VTA) are exquisitely sensitive to drugs of abuse, uncertain rewards, and reward-paired cues and may therefore be the common neural substrate mediating synergistic features of both disorders. To test this hypothesis, we first gained specific inhibitory control over VTA dopamine neurons by transducing a floxed inhibitory DREADD (AAV5-hSyn-DIO-hM4D(Gi)-mCherry) in rats expressing Cre recombinase in tyrosine hydroxylase neurons. We then trained rats in our cued rat gambling task (crGT), inhibiting dopamine neurons throughout task acquisition and performance, before allowing them to self-administer cocaine in the same diurnal period as crGT sessions. The trajectories of addiction differ in women and men, and the dopamine system may differ functionally across the sexes; therefore, we used male and female rats here. We found that inhibition of VTA dopamine neurons decreased cue-induced risky choice and reduced motor impulsivity in males, but surprisingly, enhanced risky decision making in females. Inhibiting VTA dopamine neurons also prevented cocaine-induced changes in decision making in both sexes, but nevertheless drove all animals to consume more cocaine. These findings show that chronic dampening of dopamine signalling can have both protective and deleterious effects on addiction-relevant behaviours, depending on biological sex and dependent variable of interest.
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Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Comportamento Animal/efeitos dos fármacos , Tomada de Decisões/efeitos dos fármacos , Tomada de Decisões/fisiologia , Neurônios Dopaminérgicos/fisiologia , Feminino , Jogo de Azar/fisiopatologia , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Integrases/metabolismo , Masculino , Ratos , Autoadministração , Fatores Sexuais , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/metabolismoRESUMO
Introduction: Cannabinoid hyperemesis syndrome is becoming a more prominently reported side effect of cannabis containing high-dose Δ9-tetrahydrocannabinol (THC) and designer cannabinoid drugs such as "Spice." One active ingredient that has been found in "Spice" is 1-pentyl-3-(1-naphthoyl)indole (JWH-018), a synthetic full agonist of the cannabinoid 1 (CB1) receptor. In this study, we evaluated the potential of different doses of JWH-018 to produce conditioned gaping in rats, an index of nausea. Materials and Methods: Rats received 3 daily conditioning trials in which saccharin was paired with JWH-018 (0.0, 0.1, 1, and 3 mg/kg, intraperitoneal [i.p.]). Then the potential of pretreatment with the CB1 antagonist, rimonabant (SR), to prevent JWH-018-induced conditioned gaping was determined. To begin to understand the potential mechanism underlying JWH-018-induced nausea, serum collected from trunk blood was subjected to a corticosterone (CORT) analysis in rats receiving three daily injections with vehicle (VEH) or JWH-018 (3 mg/kg). Results: At doses of 1 and 3 mg/kg (i.p.), JWH-018 produced nausea-like conditioned gaping reactions. The conditioned gaping produced by 3 mg/kg JWH-018 was reversed by pretreatment with rimonabant, which did not modify gaping on its own. Treatment with JWH-018 elevated serum CORT levels compared to vehicle-treated rats. Conclusions: As we have previously reported with high-dose THC, JWH-018 produced conditioned gaping in rats, reflective of a nausea effect mediated by its action on CB1 receptors and accompanied by elevated CORT, reflective of hypothalamic-pituitary-adrenal (HPA) activation.
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Δ9-tetrahydracannabinol (THC) is recognized as an effective treatment for nausea and vomiting via its action on the cannabinoid 1 (CB1) receptor. Paradoxically, there is evidence that THC can also produce nausea and vomiting. Using the conditioned gaping model of nausea in rats, we evaluated the ability of several doses of THC (0.0, 0.5, 5 and 10â¯mg/kg, i.p.) to produced conditioned gaping reactions. We then investigated the ability of the CB1 receptor antagonist, rimonabant, to block the establishment of THC-induced conditioned gaping. Real-time polymerase chain reaction (RT-PCR) was then used to investigate changes in endocannabinoid related genes in various brain regions in rats chronically treated with vehicle (VEH), 0.5 or 10â¯mg/kg THC. THC produced dose-dependent gaping, with 5 and 10â¯mg/kg producing significantly more gaping reactions than VEH or 0.5â¯mg/kg THC, a dose known to have anti-emetic properties. Pre-treatment with rimonabant reversed this effect, indicating that THC-induced conditioned gaping was CB1 receptor mediated. The RT-PCR analysis revealed an upregulation of genes for the degrading enzyme, monoacylglycerol lipase (MAGL), of the endocannabinoid, 2-arachidolyl glycerol (2-AG), in the hypothalamus of rats treated with 10â¯mg/kg THC. No changes in the expression of relevant genes were found in nausea (interoceptive insular cortex) or vomiting (dorsal vagal complex) related brain regions. These findings support the hypothesis that THC-induced nausea is a result of a dysregulated hypothalamic-pituitary-adrenal axis leading to an overactive stress response.
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Ácidos Araquidônicos/biossíntese , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Endocanabinoides/biossíntese , Glicerídeos/biossíntese , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Monoacilglicerol Lipases/biossíntese , Náusea/prevenção & controle , Animais , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Dronabinol/antagonistas & inibidores , Masculino , Náusea/induzido quimicamente , Ratos , Rimonabanto/farmacologia , Nervo Vago/metabolismoRESUMO
RATIONALE: Unlike other drugs of abuse, Δ9-tetrahydrocanabinol (THC) is generally aversive in rodent conditioned place preference models, but little is known about how stress may modify THC affective properties. OBJECTIVE: We evaluate the potential of footshock stress to enhance the rewarding effects of THC and the fatty acid amide hydrolase inhibitor, URB597, as it has been shown to enhance their anxiolytic effects. MATERIALS AND METHODS: The effect of footshock stress 24 h prior to each conditioning trial on the rewarding/aversive effects of THC (1, 0.1, 0.5 mg/kg, ip) and URB597 (0.3 mg/kg, ip) was evaluated in an unbiased place conditioning procedure in rats. Subsequently, the same stressor was given immediately prior to conditioning with THC (1 and 0.1 mg/kg). Locomotor activity was also measured during conditioning. RESULTS: A dose of 1 mg/kg THC, but not 0.1-0.5 mg/kg, produced a conditioned place aversion (CPA) that was not modified by footshock delivered 24 h prior to conditioning trials; however, footshock delivered immediately prior to conditioning trials prevented that CPA. Lower doses of THC and URB597 produced no place conditioning regardless of footshock conditions. A dose of 1 mg/kg THC produced locomotor suppression during conditioning trials that was prevented by footshock delivered 24 h before and reversed to locomotor activation by footshock delivered immediately before conditioning. CONCLUSIONS: Unlike the effect of footshock on THC- and URB597-induced anxiolytic effects, footshock does not promote THC or URB597-induced reward in a conditioned place preference paradigm. However, footshock stress reverses the sedative effects of 1 mg/kg THC.