Toll-like receptor 4 antagonists reduce cocaine-primed reinstatement of drug seeking.

Rationale: Cocaine can increase inflammatory neuroimmune markers, including chemokines and cytokines characteristic of innate inflammatory responding. Prior work indicates that the Toll-like receptor 4 (TLR4) initiates this response, and administration of TLR4 antagonists provides mixed evidence that TLR4 contributes to cocaine reward and reinforcement.

Objective: These studies utilize (+)-naltrexone, the TLR4 antagonist, and mu-opioid inactive enantiomer to examine the role of TLR4 on cocaine self-administration and cocaine seeking in rats.

Enduring disruption of reward and stress circuit activities by early-life adversity in male rats.

In humans, early-life adversity (ELA) such as trauma, poverty, and chaotic environment is linked to increased risk of later-life emotional disorders including depression and substance abuse. These disorders involve underlying disruption of reward circuits and likely vary by sex. Accordingly, we previously found that ELA leads to anhedonia for natural rewards and cocaine in male rodents, whereas in females ELA instead increases vulnerability to addiction-like use of opioid drugs and palatable food.

Developmental Trajectories of Anhedonia in Preclinical Models.

This chapter discusses how the complex concept of anhedonia can be operationalized and studied in preclinical models. It provides information about the development of anhedonia in the context of early-life adversity, and the power of preclinical models to tease out the diverse molecular, epigenetic, and network mechanisms that are responsible for anhedonia-like behaviors.Specifically, we first discuss the term anhedonia, reviewing the conceptual components underlying reward-related behaviors and distinguish anhedonia pertaining to deficits in motivational versus consummatory behaviors.

Neurodevelopmental origins of substance use disorders: Evidence from animal models of early-life adversity and addiction.

Addiction is a chronic relapsing disorder with devastating personal, societal, and economic consequences. In humans, early-life adversity (ELA) such as trauma, neglect, and resource scarcity are linked with increased risk of later-life addiction, but the brain mechanisms underlying this link are still poorly understood. Here, we focus on data from rodent models of ELA and addiction, in which causal effects of ELA on later-life responses to drugs and the neurodevelopmental mechanisms by which ELA increases vulnerability to addiction can be determined.

The Developmental Origins of Opioid Use Disorder and Its Comorbidities.

Opioid use disorder (OUD) rarely presents as a unitary psychiatric condition, and the comorbid symptoms likely depend upon the diverse risk factors and mechanisms by which OUD can arise. These factors are heterogeneous and include genetic predisposition, exposure to prescription opioids, and environmental risks. Crucially, one key environmental risk factor for OUD is early life adversity (ELA).

On the early life origins of vulnerability to opioid addiction.

The origins and neural bases of the current opioid addiction epidemic are unclear. Genetics plays a major role in addiction vulnerability, but cannot account for the recent exponential rise in opioid abuse, so environmental factors must contribute. Individuals with history of early life adversity (ELA) are disproportionately prone to opioid addiction, yet whether ELA interacts with factors such as increased access to opioids to directly influence brain development and function, and cause opioid addiction vulnerability, is unknown.

Role of dopamine D-like receptors and their modulation by adenosine receptor stimulation in the reinstatement of methamphetamine seeking.

Rationale And Objective: Previous work has demonstrated that dopamine and adenosine receptors are involved in drug-seeking behaviors, yet the pharmacological interactions between these receptors in methamphetamine (MA) seeking are not well characterized. The present studies examined the role of the dopamine D-like receptors in MA seeking and identified the interactive effects of adenosine receptor stimulation.

Methods: Adult male Sprague-Dawley rats were trained to lever press for MA in daily 2-h self-administration sessions on a fixed-ratio 1 schedule for 10 consecutive days.

Innate immune signaling in the ventral tegmental area contributes to drug-primed reinstatement of cocaine seeking.

Cocaine addiction is a chronic relapsing disorder characterized by persistent perturbations to an organism's homeostatic processes that result in maladaptive drug seeking. Although considerable attention has been directed at the consequences of neuronal changes following chronic cocaine taking, few studies have examined the role of microglia, the brain's resident immune cells, following chronic cocaine administration. Toll-Like Receptor 4 (TLR4) is a molecular pattern receptor that recognizes pathogens, danger signals, and xenobiotics and induces proinflammatory signaling in the central nervous system.

Adolescent caffeine consumption increases adulthood anxiety-related behavior and modifies neuroendocrine signaling.

Caffeine is a commonly used psychoactive substance and consumption by children and adolescents continues to rise. Here, we examine the lasting effects of adolescent caffeine consumption on anxiety-related behaviors and several neuroendocrine measures in adulthood. Adolescent male Sprague-Dawley rats consumed caffeine (0.

Effects of adolescent caffeine consumption on cocaine sensitivity.

Caffeine is the most commonly used psychoactive substance, and consumption by adolescents has risen markedly in recent years. We identified the effects of adolescent caffeine consumption on cocaine sensitivity and determined neurobiological changes within the nucleus accumbens (NAc) that may underlie caffeine-induced hypersensitivity to cocaine. Male Sprague-Dawley rats consumed caffeine (0.

Role of adenosine receptor subtypes in methamphetamine reward and reinforcement.

The neurobiology of methamphetamine (MA) remains largely unknown despite its high abuse liability. The present series of studies explored the role of adenosine receptors on MA reward and reinforcement and identified alterations in the expression of adenosine receptors in dopamine terminal areas following MA administration in rats. We tested whether stimulating adenosine A1 or A2A receptor subtypes would influence MA-induced place preference or MA self-administration on fixed and progressive ratio schedules in male Sprague-Dawley rats.

Persistent reduction of cocaine seeking by pharmacological manipulation of adenosine A1 and A 2A receptors during extinction training in rats.

Rationale: Adenosine receptor stimulation and blockade have been shown to modulate a variety of cocaine-related behaviors.

Objectives: These studies identify the direct effects of adenosine receptor stimulation on cocaine seeking during extinction training and the persistent effects on subsequent reinstatement to cocaine seeking.

Methods: Rats self-administered cocaine on a fixed ratio one schedule in daily sessions over 3 weeks.

Adenosine A1 and dopamine d1 receptor regulation of AMPA receptor phosphorylation and cocaine-seeking behavior.

AMPAR (α-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptor) stimulation in the nucleus accumbens (NAc) is critical in cocaine seeking. Here, we investigate the functional interaction between D1 dopamine receptors (D1DR) and AMPARs in the NAc, and explore how A1 adenosine receptor (A1AR) stimulation may reduce dopamine-induced facilitation of AMPARs and cocaine seeking. All animals were trained to self-administer cocaine and were tested for reinstatement of cocaine seeking following extinction procedures.