Topical cannabidiol is well tolerated in individuals with a history of elite physical performance and chronic lower extremity pain.

INTRODUCTION: Cannabidiol (CBD) is a potential therapeutic for pain management. Yet, there exists a dearth of studies of its tolerability and efficacy, especially in special populations. Former elite athletes are a special population both susceptible to chronic pain and also highly trained and attuned to assess medication tolerability concerns. The purpose of the present open-label pilot study was to assess the tolerability of CBD in this population. MATERIALS AND METHODS: Retrospective analysis was conducted in deidentified data from 20 individuals who were all previously professional athletes in US/American football, track and field, or basketball, with careers ranging from 4 to 10 years. Participants received topical CBD (10 mg twice daily by controlled dispenser) for chronic pain resulting from acute lower extremity injuries. Assessments of tolerability and secondary analyses of pain, pain-related disability, and activities of daily living were collected by self-report over the 6-week study period. Data were analyzed by descriptive statistics, pairwise t-test, and linear regression. RESULTS: Seventy percent of participants completed the study. Of the individuals who completed the study, 50% reported minor adverse effects, none of which required medical attention, and 50% did not report any adverse effects. The mostly commonly reported effects were skin dryness (43% of study completers) and skin rash (21% of study completers), which rapidly resolved. There was a significant improvement in self-reported pain levels (intake mean 3.5 ± 0.29; exit mean 1.7 ± 0.23; P < 0.001) and pain-related disability, including family and home responsibilities, life support activities, occupational activities, recreational activities, self-care, sexual function, and social activities (all P < 0.001). DISCUSSION: To the best of our knowledge, this is the first study to assess CBD treatment in elite athletes, who are disproportionally susceptible to disabling injuries. Topical administration of CBD was tolerated well by this population and resulted in only minor adverse effects. As elite athletes are trained and attuned to assess their own bodies due to their professional lives, this population is likely to detect tolerability concerns. However, this study was limited to a convenience sample and self-reported data. These pilot findings warrant further study of topical CBD in randomized and controlled studies of elite athletes.

Mitochondrial dysfunction and autophagy activation are associated with cardiomyopathy developed by extended methamphetamine self-administration in rats.

The recent rise in illicit use of methamphetamine (METH), a highly addictive psychostimulant, is a huge health care burden due to its central and peripheral toxic effects. Mounting clinical studies have noted that METH use in humans is associated with the development of cardiomyopathy; however, preclinical studies and animal models to dissect detailed molecular mechanisms of METH-associated cardiomyopathy development are scarce. The present study utilized a unique very long-access binge and crash procedure of METH self-administration to characterize the sequelae of pathological alterations that occur with METH-associated cardiomyopathy. Rats were allowed to intravenously self-administer METH for 96 h continuous weekly sessions over 8 weeks. Cardiac function, histochemistry, ultrastructure, and biochemical experiments were performed 24 h after the cessation of drug administration. Voluntary METH self-administration induced pathological cardiac remodeling as indicated by cardiomyocyte hypertrophy, myocyte disarray, interstitial and perivascular fibrosis accompanied by compromised cardiac systolic function. Ultrastructural examination and native gel electrophoresis revealed altered mitochondrial morphology and reduced mitochondrial oxidative phosphorylation (OXPHOS) supercomplexes (SCs) stability and assembly in METH exposed hearts. Redox-sensitive assays revealed significantly attenuated mitochondrial respiratory complex activities with a compensatory increase in pyruvate dehydrogenase (PDH) activity reminiscent of metabolic remodeling. Increased autophagy flux and increased mitochondrial antioxidant protein level was observed in METH exposed heart. Treatment with mitoTEMPO reduced the autophagy level indicating the involvement of mitochondrial dysfunction in the adaptive activation of autophagy in METH exposed hearts. Altogether, we have reported a novel METH-associated cardiomyopathy model using voluntary drug seeking behavior. Our studies indicated that METH self-administration profoundly affects mitochondrial ultrastructure, OXPHOS SCs assembly and redox activity accompanied by increased PDH activity that may underlie observed cardiac dysfunction.

COVID-19 drive-through mass vaccination in Northwest Louisiana.

Background: Vaccinating susceptible populations quickly and safely is vital during a pandemic. Mass vaccination programs using a drive-through method have been shown to reach large numbers of people efficiently during vaccine campaigns. Methods: We performed a quantitative, cross-sectional study analyzing data collected by the COVID-19 mass vaccination program conducted by Louisiana State University Health Shreveport (LSUSH). Results: Between December 2020 and September 2021, the vaccination program administered 90,655 COVID-19 vaccines. Among those who received at least the first dose of the vaccine, there were 21,700 men and 28,269 women; 22,820 were ≥60 years of age; 28,031 identified as Caucasian, 19,249 as African American, 47,916 as non-Hispanic, and most of them reported that they had not tested positive for COVID-19 before vaccination. Discussion: The LSUHS vaccination center served people from different regions within Louisiana as well as those from outside Louisiana. Vaccination is a crucial public health measure in the fight against the COVID-19 pandemic. Conclusions: Our study showed that the mass vaccination program conducted by LSUHS had a considerable positive impact on communities in Northwest Louisiana. This drive-through method is an effective strategy with which to reach a significant number of people during a pandemic.

The Endocannabinoid System and Alcohol Dependence: Will Cannabinoid Receptor 2 Agonism be More Fruitful than Cannabinoid Receptor 1 Antagonism?

Alcohol-use disorder (AUD) remains a major public health concern. In recent years, there has been a heightened interest in components of the endocannabinoid system for the treatment of AUD. Cannabinoid type 1 (CB1) receptors have been shown to modulate the rewarding effects of alcohol, reduce the abuse-related effects of alcohol, improve cognition, exhibit anti-inflammatory, and neuroprotective effects, which are all favorable properties of potential therapeutic candidates for the treatment of AUD. However, CB1 agonists have not been investigated for the treatment of AUD because they stimulate the motivational properties of alcohol, increase alcohol intake, and have the tendency to be abused. Preclinical data suggest significant potential for the use of CB1 antagonists to treat AUD; however, a clinical phase I/II trial with SR14716A (rimonabant), a CB1 receptor antagonist/inverse agonist showed that it produced serious neuropsychiatric adverse events such as anxiety, depression, and even suicidal ideation. This has redirected the field to focus on alternative components of the endocannabinoid system, including cannabinoid type 2 (CB2) receptor agonists as a potential therapeutic target for AUD. CB2 receptor agonists are of particular interest because they can modulate the reward pathway, reduce abuse-related effects of alcohol, reverse neuroinflammation, improve cognition, and exhibit anti-inflammatory and neuroprotective effects, without exhibiting the psychiatric side effects seen with CB1 antagonists. Accordingly, this article presents an overview of the studies reported in the literature that have investigated CB2 receptor agonists with regards to AUD and provides commentary as to whether this receptor is a worthy target for continued investigation.

Docosahexaenoic acid protects motor function and increases dopamine synthesis in a rat model of Parkinson's disease via mechanisms associated with increased protein kinase activity in the striatum.

Parkinson's disease (PD) is a devastating neurodegenerative disease that leads to motor deficits and selective destruction of nigrostriatal dopaminergic neurons. PD is typically treated by dopamine replacement agents; however, dopamine replacement loses effectiveness in the later stages of the disease. Here, we describe the neuroprotective effects of the omega-3 fatty acid docosahexaenoic acid (DHA) in the medial forebrain bundle 6-hydroxydopamine (6-OHDA) model of advanced-stage PD in rats. We show that daily administration of DHA protects against core symptoms of PD, including deficits in postural stability, gait integrity, and dopamine neurochemistry in motor areas of the striatum. Our results also demonstrate that DHA increases striatal dopamine synthesis via phosphorylation of the rate-limiting catecholamine synthesizing enzyme tyrosine hydroxylase, in a manner dependent on the second messenger-linked protein kinases PKA and PKC. We also show that DHA specifically reverses dopamine loss in the nigrostriatal pathway, with no effect in the mesolimbic or mesocortical pathways. This suggests that DHA is unlikely to produce pharmacotherapeutic or adverse effects that depend on dopamine pathways other than the nigrostriatal pathway. To our knowledge, previous reports have not examined the effects of DHA in such an advanced-stage model, documented that the dopamine synthesizing effects of DHA in vivo are mediated through the activation of protein kinases and regulation of TH activity, or demonstrated specificity to the nigrostriatal pathway. These novel findings corroborate the beneficial effects of omega-3 fatty acids seen in PD patients and suggest that DHA provides a novel means of protecting patients for dopamine neurodegeneration.

The acute toxic and neurotoxic effects of 3,4-methylenedioxymethamphetamine are more pronounced in adolescent than adult mice.

3,4-methylenedioxymethamphetamine (MDMA) recently achieved breakthrough status from the Food and Drug Administration (FDA) for post-traumatic stress disorder (PTSD). However, evidence indicates that exposure to toxic doses of MDMA can lead to long-lasting dysregulation of brain monoaminergic neurotransmitters, primarily from studies conducted in young adult rodents. To date, there is a paucity of data on whether toxic doses of MDMA can differentially affect neurotransmitter systems in adolescents and mature adults, which is an important question as adolescents and adults may be differentially vulnerable to MDMA abuse. In the current study, adolescent (6-7 weeks of age) and mature adult (16-18 weeks of age) male, Swiss-Webster mice were exposed to MDMA (20 mg/kg) using a binge-like dosing regimen (4 administrations spaced every 2 h). Acute lethality, acute hyperthermia, and acute decreases in body weight following MDMA administration were more pronounced in adolescent than adult mice. Likewise, acute loss of striatal dopamine neurochemistry was also exacerbated in adolescents, as determined by high-pressure liquid chromatography coupled to electrochemical detection. Exposure to MDMA induced greater turnover of dopamine into its major metabolite dihydroxyphenylacetic acid (DOPAC) in adolescents, but not in adults, suggesting a novel mechanism through which adolescents may show increased vulnerability to the acute toxic and neurotoxic effects of MDMA, or conversely that mature adults show greater protection. These data caution that MDMA exposure in adolescence may be particularly dangerous and that the therapeutic window for MDMA may differ between adolescents and mature adults.

The sesquiterpene beta-caryophyllene oxide attenuates ethanol drinking and place conditioning in mice.

Approximately 20 million adults in the United States have an alcohol use disorder. In recent years, modulation of the behavioral effects of ethanol by phytochemicals has been explored. In this study, we used the ethanol-induced loss of righting reflex (LORR) assay to assess potency differences between the sesquiterpene phytochemical beta-caryophyllene (BCP) and its derivative caryophyllene oxide (BCPO). We also investigated the effects of BCPO on two bottle-choice ethanol drinking and the ethanol-induced conditioned place preference (CPP). We then determined whether there are any pharmacokinetic or pharmacodynamic interactions between BCPO and ethanol, using blood ethanol analysis and pretreatments with the selective cannabinoid receptor 2 (CB2) antagonist AM630, respectively. BCPO augmented the ethanol-induced LORR at a dose (30 mg/kg) tenfold lower than BCP (300 mg/kg). Swiss-Webster mice were found to split into stable high and low drinking groups. This same dose (30 mg/kg) of BCPO significantly decreased ethanol intake and preference for ethanol over water in mice that consumed high amounts of ethanol, without any effect on total fluid intake. BCPO had limited effects in mice that consumed low amounts of ethanol. BCPO also significantly attenuated the ethanol-induced CPP. Blood ethanol analysis showed no significant effect of ethanol on the pharmacokinetics of ethanol. Furthermore, the enhancement of the ethanol-induced LORR by BCPO was reversed by AM630. These findings demonstrate that BCPO more potently modulates the behavioral effects of ethanol than the parent compound BCP. Moreover, they suggest that BCPO modulates the behavioral effects of ethanol through pharmacodynamic rather than pharmacokinetic mechanisms.

M100907 and BD 1047 attenuate the acute toxic effects of methamphetamine.

There are no Food and Drug Administration approved pharmacotherapies for methamphetamine (METH) overdose, thus identifying novel drug targets to prevent this devastating adverse event is a public-health imperative. Previous research suggests that serotonin and sigma receptors may contribute to the adverse effects of METH. The present study assessed whether pretreatment with the 5-HT2A receptor antagonist M100907 or the sigma 1 (σ1) receptor antagonist BD 1047 attenuated METH-induced lethality, hyperthermia, convulsions, and seizures. Male, Swiss-Webster mice received intraperitoneal injections of M100907 (1 and 10 mg/kg), BD 1047 (10 mg/kg), or a combination of M100907 (1 mg/kg) and BD 1047 (10 mg/kg) prior to treatment with METH (78 mg/kg). Convulsions and lethality were assessed by observation, core body temperature was assessed by surgically implanted telemetric probes, and seizures were assessed by electroencephalography. M100907 reduced METH-elicited lethality from 67% to 33%, BD1047 reduced METH-elicited lethality from 67% to 50%, and combined administration of both agents eliminated lethality in all mice tested. Similarly, both agents and their combination reduced METH-elicited seizures and convulsions. None of the treatments decreased METH-induced hyperthermia. This research suggests that reducing METH-induced seizures is an important factor in reducing lethality associated with METH overdose. However, future studies should examine whether M100907 and BD 1047 modulate METH-induced hypertension and other adverse effects that may also contribute to METH overdose. Our data support the continued investigation of compounds that target 5-HT2A and σ1 receptors in METH-induced overdose, including their potential to yield emergency reversal agents.

The cannabinoid receptor 2 agonist, ß-caryophyllene, improves working memory and reduces circulating levels of specific proinflammatory cytokines in aged male mice.

Age-related cognitive decline has been associated with proinflammatory cytokines, yet the precise relationship between cognitive decline and cytokine load remains to be elucidated. ß-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist with established anti-inflammatory effects that is known to improve memory and increase lifespan. It is of interest to explore the potential of BCP to reduce age-related cognitive decline and proinflammatory cytokine load. In this study, we assessed changes in circulating cytokines across the lifespan, memory performance in young and aged mice, and the effects of BCP on memory function and cytokine load. The plasma levels of 12 cytokines were assessed in male Swiss-Webster mice at 3, 12, and 18 months of age using multiplexed flow cytometry. Working memory was compared in 3 and 12 month-old mice using spontaneous alternations. A dose-response function (100-300 mg/kg, subchronic administration) for BCP-induced memory restoration was determined in 3- and 12- month-old mice. Finally, the effects on cytokine levels of the peak memory enhancing dose of BCP were assessed in 18- month-old mice. Circulating levels of several cytokines significantly increased with age. Multilinear regression analysis showed that IL-23 levels were most strongly associated with age. Aged mice showed deficits in working memory and higher levels of IL-23, both of which were reversed by BCP treatment. BCP appears to reverse age-associated impairments in memory and modulates cytokine production. IL-23 may play a significant role in the aging process, and future research should determine whether it has utility as a biomarker for novel anti-aging therapeutics.

The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo.

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol.

Serotonin 2A receptors are a stress response system: implications for post-traumatic stress disorder.

Serotonin, one of the first neurotransmitters to be identified, is an evolutionarily old molecule that is highly conserved across the animal kingdom, and widely used throughout the brain. Despite this, ascribing a specific set of functions to brain serotonin and its receptors has been difficult and controversial. The 2A subtype of serotonin receptors (5-HT2A receptor) is the major excitatory serotonin receptor in the brain and has been linked to the effects of drugs that produce profound sensory and cognitive changes. Numerous studies have shown that this receptor is upregulated by a broad variety of stressors, and have related 5-HT2A receptor function to associative learning. This review proposes that stress, particularly stress related to danger and existential threats, increases the expression and function of 5-HT2A receptors. It is argued that this is a neurobiological adaptation to promote learning and avoidance of danger in the future. Upregulation of 5-HT2A receptors during stressful events forms associations that tune the brain to environmental cues that signal danger. It is speculated that life-threatening situations may activate this system and contribute to the symptoms associated with post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine, which activates 5-HT2A receptors, has been successful in the treatment of PTSD and has recently achieved status as a breakthrough therapy. An argument is presented that 3,4-methylenedioxymethamphetamine may paradoxically act through these same 5-HT2A receptors to ameliorate the symptoms of PTSD. The central thematic contention is that a key role of serotonin may be to function as a stress detection and response system.

Effects of the second-generation "bath salt" cathinone alpha-pyrrolidinopropiophenone (α-PPP) on behavior and monoamine neurochemistry in male mice.

RATIONALE: Synthetic cathinones ("bath salts") are ß-ketone analogs of amphetamines, yet few studies have examined their potential neurotoxic effects. OBJECTIVE: In the current study, we assessed the persistent behavioral and neurochemical effects of exposure to the second-generation synthetic cathinone α-pyrrolidinopropiophenone (α-PPP). METHODS: Male, Swiss-Webster mice were exposed to α-PPP (80 mg/kg) using a binge-like dosing regimen (QID, q2h). Behavior was assessed 4-5 days after the dosing regimen, and neurochemistry was assessed the following day. Behavior was studied using the elevated plus maze, Y-maze, and novel object recognition tests. Regional levels of dopamine, serotonin, norepinephrine, and the major dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the prefrontal cortex and striatum using high-pressure liquid chromatography. Additional experiments assessed the time courses of the effects of α-PPP on locomotor activity and core temperature using telemetry. RESULTS: Exposure to α-PPP significantly impaired performance in the Y-maze, decreased overall exploratory activity in the novel object recognition test, and resulted in regionally specific depletions in monoamine neurochemistry. In contrast, it had no significant effect on elevated plus maze performance or object discrimination in the novel object recognition test. The locomotor-stimulant effects of α-PPP were comparable to cocaine (30 mg/kg), and α-PPP (80 mg/kg) did not induce hyperthermia. CONCLUSIONS: α-PPP exposure results in persistent changes in exploratory behavior, spatial working memory, and monoamine neurochemistry. This research highlights potential dangers of α-PPP, including potential neurotoxicity, and suggests that the mechanisms underlying the persistent untoward effects of the cathinones may be distinct from those of the amphetamines.

Nanoparticle encapsulation increases the brain penetrance and duration of action of intranasal oxytocin.

The blood-brain barrier (BBB) limits the therapeutic use of large molecules as it prevents them from passively entering the brain following administration by conventional routes. It also limits the capacity of researchers to study the role of large molecules in behavior, as it often necessitates intracerebroventricular administration. Oxytocin is a large-molecule neuropeptide with pro-social behavioral effects and therapeutic promise for social-deficit disorders. Although preclinical and clinical studies are using intranasal delivery of oxytocin to improve brain bioavailability, it remains of interest to further improve the brain penetrance and duration of action of oxytocin, even with intranasal administration. In this study, we evaluated a nanoparticle drug-delivery system for oxytocin, designed to increase its brain bioavailability through active transport and increase its duration of action through encapsulation and sustained release. We first evaluated transport of oxytocin-like large molecules in a cell-culture model of the BBB. We then determined in vivo brain transport using bioimaging and cerebrospinal fluid analysis in mice. Finally, we determined the pro-social effects of oxytocin (50 µg, intranasal) in two different brain targeting and sustained-release formulations. We found that nanoparticle formulation increased BBB transport both in vitro and in vivo. Moreover, nanoparticle-encapsulated oxytocin administered intranasally exhibited greater pro-social effects both acutely and 3 days after administration, in comparison to oxytocin alone, in mouse social-interaction experiments. These multimodal data validate this brain targeting and sustained-release formulation of oxytocin, which can now be used in animal models of social-deficit disorders as well as to enhance the brain delivery of other neuropeptides.

Nanoparticle formulations that allow for sustained delivery and brain targeting of the neuropeptide oxytocin.

Oxytocin is a promising candidate for the treatment of social-deficit disorders such as Autism Spectrum Disorder, but oxytocin cannot readily pass the blood-brain barrier. Moreover, oxytocin requires frequent dosing as it is rapidly metabolized in blood. We fabricated four polymeric nanoparticle formulations using poly(lactic-co-glycolic acid) (PLGA) or bovine serum albumin (BSA) as the base material. In order to target them to the brain, we then conjugated the materials to either transferrin or rabies virus glycoprotein (RVG) as targeting ligands. The formulations were characterized in vitro for size, zeta potential, encapsulation efficiency, and release profiles. All formulations showed slightly negative charges and sizes ranging from 100 to 278 nm in diameter, with RVG-conjugated BSA nanoparticles exhibiting the smallest sizes. No formulation was found to be immunogenic or cytotoxic. The encapsulation efficiency was ≥75% for all nanoparticle formulations. Release studies demonstrated that BSA nanoparticle formulation exhibited a faster initial burst of release compared to PLGA particles, in addition to later sustained release. This initial burst release would be favorable for clinical dosing as therapeutic effects could be quickly established, especially in combination with additional sustained release to maintain the therapeutic effects. Our size and release profile data indicate that RVG-conjugated BSA nanoparticles are the most favorable formulation for brain delivery of oxytocin.

Effects of exposure to amphetamine derivatives on passive avoidance performance and the central levels of monoamines and their metabolites in mice: correlations between behavior and neurochemistry.

RATIONALE: Considerable evidence indicates that amphetamine derivatives can deplete brain monoaminergic neurotransmitters. However, the behavioral and cognitive consequences of neurochemical depletions induced by amphetamines are not well established. OBJECTIVES: In this study, mice were exposed to dosing regimens of 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH), or parachloroamphetamine (PCA) known to deplete the monoamine neurotransmitters dopamine and serotonin, and the effects of these dosing regimens on learning and memory were assessed. METHODS: In the same animals, we determined deficits in learning and memory via passive avoidance (PA) behavior and changes in tissue content of monoamine neurotransmitters and their primary metabolites in the striatum, frontal cortex, cingulate, hippocampus, and amygdala via ex vivo high-pressure liquid chromatography. RESULTS: Exposure to METH and PCA impaired PA performance and resulted in significant depletions of dopamine, serotonin, and their metabolites in several brain regions. Multiple linear regression analysis revealed that the tissue concentration of dopamine in the anterior striatum was the strongest predictor of PA performance, with an additional significant contribution by the tissue concentration of the serotonin metabolite 5-hydroxyindoleacetic acid in the cingulate. In contrast to the effects of METH and PCA, exposure to MDMA did not deplete anterior striatal dopamine levels or cingulate levels of 5-hydroxyindoleacetic acid, and it did not impair PA performance. CONCLUSIONS: These studies demonstrate that certain amphetamines impair PA performance in mice and that these impairments may be attributable to specific neurochemical depletions.

Nonhuman primate positron emission tomography neuroimaging in drug abuse research.

Positron emission tomography (PET) neuroimaging in nonhuman primates has led to significant advances in our current understanding of the neurobiology and treatment of stimulant addiction in humans. PET neuroimaging has defined the in vivo biodistribution and pharmacokinetics of abused drugs and related these findings to the time course of behavioral effects associated with their addictive properties. With novel radiotracers and enhanced resolution, PET neuroimaging techniques have also characterized in vivo drug interactions with specific protein targets in the brain, including neurotransmitter receptors and transporters. In vivo determinations of cerebral blood flow and metabolism have localized brain circuits implicated in the effects of abused drugs and drug-associated stimuli. Moreover, determinations of the predisposing factors to chronic drug use and long-term neurobiological consequences of chronic drug use, such as potential neurotoxicity, have led to novel insights regarding the pathology and treatment of drug addiction. However, similar approaches clearly need to be extended to drug classes other than stimulants. Although dopaminergic systems have been extensively studied, other neurotransmitter systems known to play a critical role in the pharmacological effects of abused drugs have been largely ignored in nonhuman primate PET neuroimaging. Finally, the study of brain activation with PET neuroimaging has been replaced in humans mostly by functional magnetic resonance imaging (fMRI). There has been some success in implementing pharmacological fMRI in awake nonhuman primates. Nevertheless, the unique versatility of PET imaging will continue to complement the systems-level strengths of fMRI, especially in the context of nonhuman primate drug abuse research.

Development of an apparatus and methodology for conducting functional magnetic resonance imaging (fMRI) with pharmacological stimuli in conscious rhesus monkeys.

Functional magnetic resonance imaging (fMRI) is a technique with significant potential to advance our understanding of multiple brain systems. However, when human subjects undergo fMRI studies they are typically conscious whereas pre-clinical fMRI studies typically utilize anesthesia, which complicates comparisons across studies. Therefore, we have developed an apparatus suitable for imaging conscious rhesus monkeys. In order to minimize subject stress and spatial motion, each subject was acclimated to the necessary procedures over several months. The effectiveness of this process was then evaluated, in fully trained subjects, by quantifying objective physiological measures. These physiological metrics were stable both within and across sessions and did not differ from when these same subjects were immobilized using standard primate handling procedures. Subject motion and blood oxygenation level dependent (BOLD) fMRI measurements were then evaluated by scanning subjects under three different conditions: the absence of stimulation, presentation of a visual stimulus, or administration of intravenous (i.v.) cocaine (0.3mg/kg). Spatial motion differed neither by condition nor along the three principal axes. In addition, maximum translational and rotational motion never exceeded one half of the voxel size (0.75 mm) or 1.5 degrees, respectively. Furthermore, the localization of changes in blood oxygenation closely matched those reported in previous studies using similar stimuli. These findings document the feasibility of fMRI data collection in conscious rhesus monkeys using these procedures and allow for the further study of the neural effects of psychoactive drugs.