Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats

Benzodiazepines and GABAA receptor subtypes: Effects in open-field, elevated plus maze-discriminative avoidance task, and conditioned place preference in male mice.

INTRODUCTION Benzodiazepines (GABAA receptor positive allosteric modulators) have been used for decades as effective and safe anxiolytic medications. However, they also have addiction/dependence liability and side effects that include sedative-motor and memory impairment. Several of these side effects have been associated with activity at GABAA receptors containing α1 subunits (α1GABAA receptors), suggesting that compounds with reduced efficacy at this receptor subtype might have an improved therapeutic profile. In the present study, we investigated the behavioral effects of the novel benzodiazepine-like compounds, HZ-166 and KRM-II-81, which show preferential efficacy for α2/3GABAA receptors, in comparison with the α1GABAA-selective compound, zolpidem. METHODS Adult male mice were treated with vehicle or one of the compounds (3, 10, or 30 mg/kg, i.p.) and tested in the open-field, the elevated plus maze-discriminative avoidance task, and conditioned place preference (CPP). RESULTS In the open-field test, HZ-166 and KRM-II-81 showed anxiolytic-like, but not sedative-like effects. In the discriminative avoidance task, only KRM-II-81 showed anxiolytic-like effects, but, unlike HZ-166, also induced memory deficits in mice. HZ-166 and KRM-II-81 did not have rewarding effects in CPP, with KRM-II-81 inducing conditioned place aversion instead. In contrast, zolpidem induced sedation, memory impairment, and rewarding effects, without displaying anxiolytic-like activity. CONCLUSIONS These findings reinforce the role of α1GABAA receptors in benzodiazepine-induced sedation, cognitive impairment, and addiction potential, and its lack of a role in anxiety-like behaviors. Drugs with selectivity for α2/3GABAA receptors might have an improved therapeutic profile compared to conventional benzodiazepines.

Effects of gabapentin on heroin and cocaine self-administration in rats.

Reports of gabapentin misuse among people with opioid use disorder have increased, as has the presence of gabapentin in opioid overdose deaths. Despite these trends and known interactions between these drugs in other settings (e.g. gabapentin as an 'opioid-sparing' agent), few studies have evaluated the impact of gabapentin on reinforcing effects of opioids. Intravenous self-administration in rats was used to determine whether gabapentin modifies the reinforcing effects of heroin or cocaine. Rats self-administered drugs under a progressive ratio schedule of reinforcement after saline or gabapentin pretreatment. Pretreatment with 32 mg/kg gabapentin increased the number of infusions earned on the ascending limb of the heroin dose-response curve but had no effect on cocaine self-administration. While the magnitude of effect was modest, these data suggest that gabapentin can potentiate the reinforcing effects of opioids and lays the groundwork for future studies characterizing interactions between gabapentinoids and opioids in the context of reinforcement.

Dissociable roles of dopamine D1 and nicotinic receptors in nicotine-motivated responding and impulsive action in a Go/No-Go self-administration task

Cigarette smoking remains one of the most important preventable causes of premature death worldwide. However, the mechanisms sustaining nicotine dependence and relapse are incompletely understood, particularly the role of impulsive action in persistent tobacco use. Dopamine D1 and nicotinic acetylcholine receptors both regulate nicotine-related behavior, but whether they contribute differently to nicotine-motivated responding and nicotine-induced impulsive action is unclear. The present study examined the effects of D1 receptor blockade and stimulation in male and female rats trained to self-administer nicotine intravenously in a Go/No- Go task. Nicotine was available during Go periods but not during No-Go periods, and impulsive action was measured as the percentage of active lever responses during No-Go periods. The D1 receptor antagonist SCH23390 reduced nicotine intake and active lever responding during Go periods and affected the percentage of active lever responses during No-Go periods. However, SCH23390 also reduced inactive lever responding, so its effect on impulsive action could not be separated from a general reduction in operant output. In contrast, the D1 receptor agonist A77636 reduced nicotine intake and Go-period responding without affecting No-Go responding, indicating that D1 receptor stimulation reduced nicotine-motivated responding without altering impulsive action. Rats showed greater No-Go responding during nicotine self-administration than during saline self-administration, indicating that nicotine increased impulsive action rather than general operant responding. The non-selective nicotinic antagonist mecamylamine reduced nicotine-motivated responding and decreased No-Go responding, indicating reduced impulsive action. These findings suggest that nicotinic acetylcholine receptor signaling plays a major role in nicotine-induced impulsive action, whereas D1 receptor signaling contributes more clearly to nicotine-motivated responding. D1 receptor agonism may reduce nicotine-motivated behavior without affecting nicotine-induced impulsive action.

Influence of intracerebroventricular or intraperitoneal administration of cannabinoid receptor agonist (WIN 55,212-2) and inverse agonist (AM 251) on the regulation of food intake and hypothalamic serotonin levels

Modulatory role of the mPFC orexin-2 receptors in the acquisition and expression in two paradigms of the natural- and drug-induced conditioned place preference in the rats.

The neuropeptide orexin/hypocretin regulates adaptive behaviors needed for survival, including food intake, sleep-wake regulation, mating, and maternal behavior. However, the orexinergic system plays a critical role in addictive behavior and promotes seeking and rewarding substances of abuse and palatable food. Plenty of orexin receptors exist in the medial prefrontal cortex (mPFC). The PFC input to the NAc mediates goal-directed behaviors such as seeking behavior and planning actions to obtain rewarding substances. This study investigated the role of mPFC orexin-2 receptors (Orx2Rs) in natural-and drug-reward-seeking behaviors. One hundred sixteen adult male Wistar rats received TCS OX2 29 (3, 10, and 30 nmol/0.5µl DMSO 12%) as an Orx2R antagonist in the mPFC during the acquisition and expression phases of two different CPP paradigms, morphine- and food-induced CPP protocols. Findings demonstrated that intra-mPFC administration of Orx2R antagonist reduced the acquisition and expression of morphine- and food-induced CPP in the rats. However, blockades of Orx2Rs in the mPFC have more inhibitory effects in food-induced CPP than in morphine-induced CPP. In conclusion, this study proposes a differential involvement of mPFC Orx2Rs in the acquisition and expression phases of CPP, suggesting distinguishable behavioral effects between food and morphine reward models. However, further mechanistic studies are required to clarify the underlying neural substrates.

Diazepam, a positive allosteric modulator of the GABAA receptor induces strain-specific responses in object recognition, ultrasonic vocalizations and monoaminergic profiles in the Wistar Kyoto rat model of endogenous depression.

Major depressive disorder (MDD) involves cognitive impairment, altered affective states and dysregulation of neurotransmitter homeostasis. The Wistar Kyoto (WKY) rat is characterized by inherent depressive-like behaviour, anxiety, cognitive deficits and dysregulated monoaminergic/GABAergic neurotransmission. This study investigated strain-specific differences in learning and memory, affective states and neurochemical responses to Diazepam (DZP), a positive allosteric modulator of the GABAA receptor, in Wistar and WKY rats. Learning and memory were assessed using the novel object recognition (NOR) paradigm, affective states through ultrasonic vocalizations (USVs) emitted, and monoaminergic levels in implicated brain areas using HPLC. DZPs significantly impaired NOR in Wistar, evidenced by reduced discrimination and recognition index (p < 0.05). DZP also increased contacts and approaches to familiar objects in Wistar (p < 0.05) and reduced approaches to novel objects in both Wistar (p < 0.01) and WKY (p < 0.001). DZP lowered bandwidth of 50-kHz USVs across both strains, though no DZP × strain interactions were observed on all acoustic and spectral parameters analyzed. WKYs displayed significantly lower baseline dopamine (DA) and serotonin (5-HT) in both PFC (DA: p < 0.001; 5-HT: p < 0.01) and hippocampus (DA: p < 0.01; 5-HT: p < 0.05). DZP reduced prefrontal (p < 0.001) and hippocampal DA (p < 0.001) levels in Wistar, with no effect in WKY, though DZP × strain interaction indicated differential effects on DA levels. Prefrontal 5-HT (p < 0.05) was also reduced in DZP-treated Wistars. Thus, strain-specific differences of the dopaminergic response to DZP and the finding that DZP's affected more cognitive measures in Wistar than in WKY underscores the importance of strain and individual variability in translational research.