The imidazoline I receptor agonist 2-BFI reduces abuse-related effects of morphine: self-administration and drug discrimination.

Rationale: Increasing evidence shows that imidazoline I receptor agonists enhance opioid-induced analgesia, suggesting that the combination of I receptor agonists with opioids could be a favorable strategy for pain control. However, the effect of I receptor agonists on the abuse liability of opioids is unknown. This study examined the impact of the I receptor agonist 2-BFI on some abuse-related behavioral effects of the opioid morphine in rats.

Lateral hypothalamic LEPR neurons drive appetitive but not consummatory behaviors.

Assigning behavioral roles to genetically defined neurons within the lateral hypothalamus (LH) is an ongoing challenge. We demonstrate that a subpopulation of LH GABAergic neurons expressing leptin receptors (LH) specifically drives appetitive behaviors in mice. Ablation of LH GABAergic neurons (LH) decreases weight gain and food intake, whereas LH ablation does not.

Hypothalamic control of interoceptive hunger.

While energy balance is critical to survival, many factors influence food intake beyond caloric need or "hunger." Despite this, some neurons that drive feeding in mice are routinely referred to as "hunger neurons," whereas others are not. To understand how specific hypothalamic circuits control interoceptive hunger, we trained mice to discriminate fasted from sated periods.

Fluorescence microendoscopy for in vivo deep-brain imaging of neuronal circuits.

Imaging neuronal activity in awake, behaving animals has become a groundbreaking method in neuroscience that has rapidly enhanced our understanding of how the brain works. In vivo microendoscopic imaging has enabled researchers to see inside the brains of experimental animals and thus has emerged as a technology fit to answer many experimental questions. By combining microendoscopy with cutting edge targeting strategies and sophisticated analysis tools, neuronal activity patterns that underlie changes in behavior and physiology can be identified.

Glutamatergic fast-spiking parvalbumin neurons in the lateral hypothalamus: Electrophysiological properties to behavior.

Throughout the central nervous system, neurons expressing the calcium-binding protein parvalbumin have been typically classified as GABAergic with fast-spiking characteristics. However, new methods that allow systematic characterization of the cytoarchitectural organization, connectivity, activity patterns, neurotransmitter nature, and function of genetically-distinct cell types have revealed populations of parvalbumin-positive neurons that are glutamatergic. Remarkably, such findings challenge longstanding concepts that fast-spiking neurons are exclusively GABAergic, suggesting conservation of the fast-spiking phenotype across at least two neurotransmitter systems.

A novel role for the actin-binding protein drebrin in regulating opiate addiction.

Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc.

Lateral hypothalamic fast-spiking parvalbumin neurons modulate nociception through connections in the periaqueductal gray area.

A pivotal role of the lateral hypothalamus (LH) in regulating appetitive and reward-related behaviors has been evident for decades. However, the contributions of LH circuits to other survival behaviors have been less explored. Here we examine how lateral hypothalamic neurons that express the calcium-binding protein parvalbumin (PVALB; LH neurons), a small cluster of neurons within the LH glutamatergic circuitry, modulate nociception in mice.

Activation of a lateral hypothalamic-ventral tegmental circuit gates motivation.

Across species, motivated states such as food-seeking and consumption are essential for survival. The lateral hypothalamus (LH) is known to play a fundamental role in regulating feeding and reward-related behaviors. However, the contributions of neuronal subpopulations in the LH have not been thoroughly identified.

Further pharmacological comparison of D-methamphetamine and L-methamphetamine in rats: abuse-related behavioral and physiological indices.

Previous preclinical research suggests that L-methamphetamine (L -MA) has potential therapeutic utility to treat psychostimulant abuse. This study examined potential abuse-related and adverse physiological effects of D -MA and L -MA alone and in combination in rats, as these effects had not been previously characterized. Potential abuse-related effects were examined in locomotor sensitization and conditioned place preference paradigms.

Effects of imidazoline I2 receptor agonists on reserpine-induced hyperalgesia and depressive-like behavior in rats.

Pharmacotherapies for fibromyalgia treatment are lacking. This study examined the antinociceptive and antidepressant-like effects of imidazoline I2 receptor (I2R) agonists in a reserpine-induced model of fibromyalgia in rats. Rats were treated for 3 days with vehicle or reserpine.

Neuroanatomical characterization of imidazoline I receptor agonist-induced antinociception.

Chronic pain is a significant public health problem with a lack of safe and effective analgesics. The imidazoline I receptor (I R) is a promising analgesic target, but the neuroanatomical structures involved in mediating I R-associated behaviors are unknown. I Rs are enriched in the arcuate nucleus, dorsal raphe (DR), interpeduncular nucleus, lateral mammillary body, medial habenula, nucleus accumbens (NAc) and paraventricular nucleus; thus, this study investigated the antinociceptive and hypothermic effects of microinjections of the I R agonist 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI).

Role of trace amine-associated receptor 1 in nicotine's behavioral and neurochemical effects.

Nicotine addiction and abuse remains a global health issue. To date, the fundamental neurobiological mechanism of nicotine addiction remains incompletely understood. Trace amine-associated receptor 1 (TAAR1) is thought to directly modulate dopaminergic system and are thought to be a neural substrate underlying addictive-like behaviors.

Mechanisms of imidazoline I receptor agonist-induced antinociception in rats: involvement of monoaminergic neurotransmission.

Background And Purpose: Although the antinociceptive efficacies of imidazoline I receptor agonists have been established, the exact post-receptor mechanisms remain unknown. This study tested the hypothesis that monoaminergic transmission is critical for I receptor agonist-induced antinociception.

Experimental Approach: von Frey filaments were used to assess antinociceptive effects of two I receptor agonists, 2-BFI and CR4056 on chronic constriction injury (CCI)-induced neuropathic pain or complete Freund's adjuvant (CFA)-induced inflammatory pain in rats.

The imidazoline I receptor agonist 2-BFI attenuates hypersensitivity and spinal neuroinflammation in a rat model of neuropathic pain.

Chronic pain is a large, unmet public health problem. Recent studies have demonstrated the importance of neuroinflammation in the establishment and maintenance of chronic pain. However, pharmacotherapies that reduce neuroinflammation have not been successfully developed to treat chronic pain thus far.

Methamphetamine-induced impulsivity during chronic methamphetamine treatment in rats: Effects of the TAAR 1 agonist RO5263397.

Impulsivity is an important personality trait associated with several clinical syndromes including drug abuse. While repeated drug exposure is known to increase certain behavioral responses, such as locomotion, to subsequent drug exposure, few studies have examined whether such sensitization develops for impulsive behavior. In the current study we tested the effects of methamphetamine acutely, during the course of, and upon discontinuation of chronic methamphetamine treatment on impulsive behavior in two models, the 5-choice serial reaction time task (5-CSRTT) and the delay-discounting task which measure impulsive action and impulsive choice, respectively.

Role of intracellular Ca signaling in the antinociceptive and discriminative stimulus effects of the imidazoline I receptor agonist 2-BFI in rats.

Rationale: Recent research has established the imidazoline I receptor as a promising target for the development of novel analgesics. However, despite an increasing understanding of imidazoline I receptor-mediated behavioral effects, little is known about post-I-receptor signaling mechanisms.

Objective: This study examined the effects of several inhibitors of Ca signaling mechanisms on two behavioral effects of the prototypical imidazoline I receptor ligand 2-(2-benzofuranyl)-2-imidazoline (2-BFI).

Discovery of Novel Proline-Based Neuropeptide FF Receptor Antagonists.

The neuropeptide FF (NPFF) system has been implicated in a number of physiological processes including modulating the pharmacological activity of opioid analgesics and several other classes of drugs of abuse. In this study, we report the discovery of a novel proline scaffold with antagonistic activity at the NPFF receptors through a high throughput screening campaign using a functional calcium mobilization assay. Focused structure-activity relationship studies on the initial hit 1 have resulted in several analogs with calcium mobilization potencies in the submicromolar range and modest selectivity for the NPFF1 receptor.

Trace amine-associated receptor 1 agonists RO5263397 and RO5166017 attenuate quinpirole-induced yawning but not hypothermia in rats.

Increasing evidence suggests that trace amine-associated receptor 1 (TAAR1) is an important modulator of the dopaminergic system. Existing molecular evidence indicates that TAAR1 regulates dopamine levels through interactions with dopamine transporters and D2 receptors. However, investigations to date have not been exhaustive and other pathways may be involved.

Comparison of some behavioral effects of d- and l-methamphetamine in adult male rats.

Rationale: Both l- and d-methamphetamine (l- and d-MA) are more potent to release norpepinephrine (NE) than dopamine, and the selectivity is greater for l-MA than d-MA. Little is known of the in vivo pharmacology of l-MA.

Objective: This study compared the effects of l-MA and d-MA in assays of nociception, behavioral disruption, and impulsivity.

Antinociceptive Effects of a Novel α2/α3-Subtype Selective GABA Receptor Positive Allosteric Modulator.

Pain remains a challenging clinical condition and spinal GABA receptors are crucial modulators of pain processing. α2/α3-subtype GABA receptors mediate the analgesic actions of benzodiazepines. Positive allosteric modulators (PAMs) at α2/α3-subtype GABA receptors may have analgesic potential.

Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior.

Unlabelled: A novel G-protein coupled receptor, trace amine-associated receptor 1 (TAAR1), has been shown to be a promising target to prevent stimulant relapse. Our recent studies showed that systemic administration of TAAR1 agonists decreased abuse-related behaviors of cocaine. However, the role of TAAR1 in specific subregions of the reward system in drug addiction is unknown.

Antinociceptive Interactions between the Imidazoline I2 Receptor Agonist 2-BFI and Opioids in Rats: Role of Efficacy at the μ-Opioid Receptor.

Although μ-opioids have been reported to interact favorably with imidazoline I2 receptor (I2R) ligands in animal models of chronic pain, the dependence on the μ-opioid receptor ligand efficacy on these interactions had not been previously investigated. This study systematically examined the interactions between the selective I2 receptor ligand 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI) and three μ-opioid receptor ligands of varying efficacies: fentanyl (high efficacy), buprenorphine (medium-low efficacy), and 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl) acetamido] morphine (NAQ; very low efficacy). The von Frey test of mechanical nociception and Hargreaves test of thermal nociception were used to examine the antihyperalgesic effects of drug combinations in complete Freund's adjuvant-induced inflammatory pain in rats.

Interactions between imidazoline I2 receptor ligands and acetaminophen in adult male rats: antinociception and schedule-controlled responding.

Rationale: Recent evidence suggests that imidazoline I2 receptor ligands are suitable for combination therapy with opioids. Quantitative analysis of I2 receptor ligands combined with non-opioid drugs is necessary for the justification of alternative pain therapies.

Objective: This study systematically examined the antihyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with acetaminophen.

Anti-hyperalgesic effects of imidazoline I2 receptor ligands in a rat model of inflammatory pain: interactions with oxycodone.

Rationale: Emerging preclinical evidence suggests that imidazoline I2 receptor ligands may be effective analgesics. Quantitative analysis of the combined I2 receptor ligands and opioids is needed for the justification of combination therapy.

Objective: This study systematically examined the anti-hyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with oxycodone in rats.