sb-334867-a and Cocaine-Related-Disorders

The orexin/hypocretin system is involved in multiple cocaine addiction processes that involve drug-associated environmental cues, including cue-induced reinstatement of extinguished cocaine seeking and expression of conditioned place preference. However, the orexin system does not play a role in several behaviors that are less cue-dependent, such as cocaine-primed reinstatement of extinguished cocaine seeking and low-effort cocaine self-administration. We hypothesized that cocaine-associated cues, but not cocaine alone, engage signaling at orexin-1 receptors (OX1Rs), and this cue-engaged OX1R signaling increases motivation for cocaine. Motivation for cocaine was measured in Sprague-Dawley rats with behavioral-economic demand curve analysis after pretreatment with the OX1R antagonist SB-334867 (SB) or vehicle with and without light + tone cues. Demand for cocaine was higher when cocaine-associated cues were present, and SB only reduced cocaine demand in the presence of these cues. We then investigated whether cocaine demand was linked to the cued reinstatement of cocaine seeking, as both procedures are partially driven by cocaine-associated cues in an orexin-dependent manner. SB blocked cue-induced reinstatement behavior, and baseline demand predicted SB efficacy with the largest effect in high-demand animals, i.e. animals with the greatest cue-dependent behavior. We conclude that OX1R signaling increases the reinforcing efficacy of cocaine-associated cues but not that of cocaine alone. This supports our view that orexin plays a prominent role in the ability of conditioned cues to activate motivational responses.

Topics: Animals; Benzoxazoles; Cocaine-Related Disorders; Cues; Male; Motivation; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Signal Transduction; Urea

Recent evidence suggests that blockade of the hypocretin receptor 1 may act as a useful pharmacotherapy for cocaine abuse. Here we investigated the extent to which various doses of a hypocretin receptor 1 antagonist, SB-334867, affect cocaine self-administration at varying doses of cocaine and across a range of effort requirements, and tested if these SB-334867 doses produce sedative effects. First, we trained animals to self-administer one of three doses of cocaine on a progressive ratio schedule, and then tested the effects of three doses of SB-334867. Responding for cocaine was then analyzed to segregate features of relatively high and low effort requirements across the progressive ratio session. In another set of experiments, we tested potential sleep-promoting effects of the same doses of SB-334867. Our data indicate that blockade of hypocretin receptor 1 preferentially reduces high effort responding for cocaine at levels that do not promote sedation.

Topics: Animals; Appetitive Behavior; Benzoxazoles; Brain; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Hypnotics and Sedatives; Male; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Rats, Sprague-Dawley; Reinforcement Schedule; Self Administration; Sleep; Urea

Hypothalamic orexin/hypocretin (Orx/Hcrt) peptides participate in the regulation of a wide range of physiological processes and are recruited by drugs of abuse. To advance our understanding of the potential of the Orx/Hcrt receptor-1 (Hcrt-r1) as a treatment target for cocaine addiction, the effect of SB334867 [N-(2-methyl-6-benzoxazolyl)-N'-1,5-n-aphthyridin-4-yl urea], a specific Hcrt-r1 antagonist, on reinstatement elicited by cocaine-associated stimuli versus stimuli associated with a highly palatable conventional reinforcer [sweetened condensed milk (SCM)] was tested. Two separate groups of male Wistar rats were trained to associate a discriminative stimulus (S⁺) with the response-contingent availability of cocaine (0.25 mg/0.1 ml/infusion) or SCM [2/1 (v/v)] and subjected to reinstatement tests following extinction of cocaine-reinforced or SCM-reinforced behavior, during which the reinforcers and S⁺ were withheld. Following extinction, presentation of the cocaine or SCM S⁺ produced comparable recovery of responding. Hcrt-r1 blockade by SB334867 (1-10 mg/kg, intraperitoneal) dose-dependently and selectively reversed conditioned reinstatement induced by cocaine-related stimuli, without interfering with reward seeking produced by the same stimulus when conditioned to SCM. The findings suggest an important role for Hcrt-r1 in appetitive behavior controlled by reward-related stimuli with selectivity for cocaine seeking and identify Hcrt-r1 as a potential treatment target for cocaine relapse prevention.

Topics: Analysis of Variance; Anesthetics, Local; Animals; Benzoxazoles; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Extinction, Psychological; Male; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Rats; Rats, Wistar; Reward; Self Administration; Sweetening Agents; Urea

Previous studies have shown that female rats exhibit enhanced cocaine seeking during multiple phases of cocaine addiction compared with males. The orexin/hypocretin system recently has been implicated in drug addiction in male rats. Based on the known sex differences in cocaine addiction, in the current study we examined orexin-mediated cocaine seeking during self-administration, extinction, and reinstatement in age-matched male (initial weight 250-300 g) and female (initial weight 175-225 g) Sprague-Dawley rats by using the orexin-1 receptor (OX1R) antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea (SB-334867) (10-30 mg/kg). OX1R blockade had no effect on established cocaine self-administration, but attenuated cocaine seeking during extinction in both male and female rats. It is noteworthy that OX1R blockade potently attenuated cue-induced reinstatement in males but had no effect on females. SB-334867 also reduced cocaine seeking during pharmacological stress-induced (yohimbine, 2.5 mg/kg) and yohimbine + cue-induced reinstatement in both sexes. SB-334867 failed to affect reinstatement induced by cocaine (10 mg/kg) in either male or female rats, but selectively reduced cocaine + cue-induced reinstatement only in males. In separate experiments examining basal and cocaine-induced locomotion, SB-334867 attenuated locomotion in both male and female rats. Finally, assessment of plasma and brain levels of SB-334867 showed that estrus females had slightly higher plasma levels than diestrus females, but no overall sex differences or estrous cycle differences were observed in plasma or brain SB-334867 concentrations. These results show that OX1R signaling plays a role in mediating cocaine seeking, but differs between the sexes for cue-induced reinstatement.

Topics: Animals; Benzoxazoles; Cocaine-Related Disorders; Cues; Extinction, Psychological; Female; Male; Motor Activity; Naphthyridines; Orexin Receptors; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Self Administration; Sex Characteristics; Urea; Yohimbine

Orexinergic signalling is critical to drug relapse-like behaviour; however, the CNS sites(s) of action remain unknown. Two candidate brain regions are the paraventricular thalamus (PVT) and ventral tegmental area (VTA). We assessed the effect of intra-PVT or -VTA administration of the orexin-1 receptor (OrxR1) antagonist SB-334867 on discriminative cue-induced cocaine-seeking. Animals received either PVT- or VTA-directed SB-334867 (0, 3 or 6 μg; 0, 1 or 3 μg, respectively) prior to reinstatement testing elicited by presenting cocaine-paired stimuli (S+). The effect of VTA-directed injections of SB-334867 (0 or 3 μg) on locomotor activity was also assessed. Intra-VTA, but not -PVT, SB-334867 dose-dependently attenuated S+-induced reinstatement (3 μg dose, p<0.01). Intra-VTA SB-334867 had no effect on locomotor activity. We conclude that OrxR1 signalling within the VTA, but not the PVT, mediates cue-induced cocaine-seeking behaviour. We hypothesize that blockade of VTA OrxR1 signalling may reduce nucleus accumbens dopamine in response to drug cue presentation.

Topics: Animals; Benzoxazoles; Cocaine; Cocaine-Related Disorders; Cues; Dopamine Uptake Inhibitors; Extinction, Psychological; Male; Motor Activity; Naphthyridines; Orexin Receptors; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Self Administration; Thalamus; Urea; Ventral Tegmental Area

Orexin/hypocretin signaling at the orexin 1 receptor (OX(1)R) has recently been implicated in addiction and relapse. We examined the role of the orexin system in cocaine-seeking elicited by a drug-associated context following abstinence or extinction from chronic cocaine self-administration. Male Sprague-Dawley rats self-administered cocaine in 2-h sessions for 10 days, followed by extinction training or extended abstinence in the home cage. The OX(1)R antagonist SB-334867 (SB; 10, 20, or 30 mg/kg, i.p.) was administered prior to re-exposure to the cocaine self-administration environment. We found that pretreatment with SB significantly attenuated cocaine-seeking when rats were placed back into the self-administration environment following either 1 day or 2 weeks of abstinence (no extinction), or following extinction of cocaine-seeking in an alternative environment (distinct from the training environment). These results indicate that orexin signaling at OX(1)R is critical for conditioned cocaine-seeking elicited by a drug-associated context, following either extinction or abstinence.

Topics: Analysis of Variance; Animals; Benzoxazoles; Cocaine; Cocaine-Related Disorders; Conditioning, Operant; Disease Models, Animal; Extinction, Psychological; Intracellular Signaling Peptides and Proteins; Male; Naphthyridines; Neuropeptides; Orexin Receptors; Orexins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Reinforcement, Psychology; Self Administration; Time Factors; Urea

The orexin/hypocretin system has recently been implicated in reward-processing and addiction. We examined the involvement of the orexin system in cue-induced reinstatement of extinguished cocaine-seeking by administering the orexin 1 receptor antagonist SB-334867 (SB) or the orexin 2 receptor antagonist 4-pyridylmethyl (S)-tert-leucyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4PT) prior to reinstatement testing. Male Sprague Dawley rats self-administered cocaine in 2-h sessions for 10 days, followed by extinction training. Reinstatement of cocaine-seeking was elicited by presentation of tone + light cues previously paired with cocaine infusions. SB (10, 20 and 30 mg/kg) dose-dependently decreased cue-induced reinstatement of cocaine-seeking without significantly affecting responding during late extinction. 4PT (10 and 30 mg/kg) did not significantly alter cue-induced reinstatement. In separate experiments, the highest doses of SB and 4PT had no significant effect on established cocaine self-administration, and 4PT reduced spontaneous activity in a locomotor test to a greater extent than SB. Finally, SB (30 mg/kg) had no effect on the acquisition of cocaine-paired cues during a Pavlovian cocaine-stimulus conditioning session in the operant chamber. Pretreatment with SB prior to the Pavlovian acquisition session had no effect on subsequent cue-induced reinstatement of cocaine-seeking elicited by those cues. However, pretreatment with SB prior to a second reinstatement session in the same animals significantly attenuated the expression of cue-induced reinstatement. These results show that orexin transmission at the orexin 1 receptor, but not the orexin 2 receptor, is necessary for the reinstatement of cocaine-seeking elicited by drug-paired cues and that orexin signaling is not critical for cocaine reinforcement or cocaine-stimulus conditioning.

Topics: Animals; Behavior, Addictive; Benzoxazoles; Brain; Cocaine; Cocaine-Related Disorders; Cues; Dopamine Uptake Inhibitors; Extinction, Psychological; Intracellular Signaling Peptides and Proteins; Male; Naphthyridines; Neuropeptides; Orexin Receptors; Orexins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Reinforcement, Psychology; Signal Transduction; Urea

Orexin A/hypocretin-1 (oxA/hcrt-1) is known to be a modulator of dopamine-dependent neuronal activity and behaviors. However, the role of this system in driving motivated behaviors remains poorly understood. Here, we show that orexin/hypocretin receptor-1 (ox/hcrt-1R) signaling is important for motivation for highly salient, positive reinforcement. Blockade of ox/hcrt-1R selectively reduced work to self-administer cocaine or high fat food pellets. Moreover, oxA/hcrt-1 strengthened presynaptic glutamatergic inputs to the ventral tegmental area (VTA) only in cocaine or high fat self-administering rats. Finally, oxA/hcrt-1-mediated excitatory synaptic transmission onto VTA neurons was not potentiated following an arousing, aversive stimulus, suggesting that oxA/hcrt-1-mediated glutamatergic synaptic transmission was potentiated selectively with highly salient positive reinforcers. These experiments provide evidence for a selective role of oxA/hcrt-1 signaling in motivation for highly salient reinforcers and may represent a unique opportunity to design novel therapies that selectively reduce excessive drive to consume positive reinforcers of high salience.

Topics: Animals; Benzoxazoles; Choice Behavior; Cocaine-Related Disorders; Dietary Fats; Intracellular Signaling Peptides and Proteins; Male; Motivation; Naphthyridines; Neural Pathways; Neuropeptides; Orexin Receptors; Orexins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Reinforcement, Psychology; Urea

Hypocretin-1 and -2 (Hcrt-1 and Hcrt-2), also referred to as orexin-A and -B, are neuropeptides synthesized by a few thousand neurons in the lateral hypothalamus. Hypocretin-containing neurons project throughout the brain, with a prominent input to basal forebrain structures involved in motivation, reward, and stress. However, the role of hypocretins in addiction-related behaviors remains largely unexplored. Here we show that intracerebroventricular infusions of Hcrt-1 lead to a dose-related reinstatement of cocaine seeking without altering cocaine intake in rats. Hcrt-1 also dramatically elevates intracranial self-stimulation thresholds, indicating that, unlike treatments with reinforcing properties such as cocaine, Hcrt-1 negatively regulates the activity of brain reward circuitries. Hypocretin-induced reinstatement of cocaine seeking was prevented by blockade of noradrenergic and corticotropin-releasing factor systems, suggesting that Hcrt-1 reinstated drug seeking through induction of a stress-like state. Consistent with this interpretation, the selective Hcrt-1 receptor antagonist SB-334867 blocked footshock-induced reinstatement of previously extinguished cocaine-seeking behavior. These findings reveal a previously unidentified role for hypocretins in driving drug seeking through activation of stress pathways in the brain.

Topics: Analysis of Variance; Animals; Behavior, Addictive; Benzoxazoles; Brain; Cocaine; Cocaine-Related Disorders; Dose-Response Relationship, Drug; Intracellular Signaling Peptides and Proteins; Male; Models, Statistical; Naphthyridines; Neuropeptides; Orexins; Rats; Rats, Wistar; Reward; Self Administration; Time Factors; Urea