Neurochemical and Cardiovascular Effects of 4-Chloro Ring-Substituted Synthetic Cathinones in Rats.

Synthetic cathinones are a class of new psychoactive substances that display psychomotor stimulant properties, and novel cathinone analogs continue to emerge in illicit drug markets worldwide. The aim of the present study was to characterize the pharmacology of 4-chloro ring-substituted cathinones that are appearing in illicit drug markets compared with the effects of 4-methylmethcathinone (mephedrone). Synaptosomes were prepared from rat caudate for dopamine transporter (DAT) assays or from whole brain minus caudate and cerebellum for norepinephrine transporter (NET) and serotonin transporter (SERT) assays.

Reinforcing effects of phenethylamine analogs found in dietary supplements.

Rationale: Synthetic phenethylamine (PEA) analogs, such as β-methylphenethylamine (BMPEA) and N,α-diethylphenethylamine (DEPEA), are often found in dietary supplements, despite regulations prohibiting their sale. PEA analogs are structurally related to amphetamine, and we have shown that BMPEA and DEPEA produce cardiovascular stimulation mimicking the effects of amphetamine. However, few studies have examined behavioral effects of BMPEA, DEPEA, and other PEA analogs.

Amphetamine-like Neurochemical and Cardiovascular Effects of -Ethylphenethylamine Analogs Found in Dietary Supplements.

Dietary supplements often contain additives not listed on the label, including -ethyl homologs of amphetamine such as ,-diethylphenethylamine (DEPEA). Here, we examined the neurochemical and cardiovascular effects of -ethylphenethylamine (AEPEA), -methyl--ethylphenethylamine (MEPEA), and DEPEA as compared with the effects of amphetamine. All drugs were tested in vitro using uptake inhibition and release assays for monoamine transporters.

Stereoselective neurochemical, behavioral, and cardiovascular effects of α-pyrrolidinovalerophenone enantiomers in male rats.

The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP) continues to be abused despite being banned by regulatory agencies. The abused formulation of α-PVP is a racemic mixture consisting of two enantiomers, S-α-PVP and R-α-PVP. In this study, we investigated the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP and its enantiomers in male rats.

Newly Developed Dopamine D Receptor Antagonists, -VK4-40 and -VK4-116, Do Not Potentiate Cardiovascular Effects of Cocaine or Oxycodone in Rats.

Opioid and cocaine abuse are major public health burdens. Existing medications for opioid use disorder are limited by abuse liability and side effects, whereas no treatments are currently approved in the United States for cocaine use disorder. Dopamine D receptor (DR) antagonists have shown promise in attenuating opioid and cocaine reward and mitigating relapse in preclinical models.

The Supplement Adulterant -Methylphenethylamine Increases Blood Pressure by Acting at Peripheral Norepinephrine Transporters.

-Methylphenethylamine [(BMPEA), 2-phenylpropan-1-amine] is a structural isomer of amphetamine (1-phenylpropan-2-amine) that has been identified in preworkout and weight loss supplements, yet little information is available about its pharmacology. Here, the neurochemical and cardiovascular effects of BMPEA and its analogs, -methyl-2-phenylpropan-1-amine (MPPA) and ,-dimethyl-2-phenylpropan-1-amine (DMPPA), were compared with structurally related amphetamines. As expected, amphetamine and methamphetamine were potent substrate-type releasing agents at dopamine transporters (DATs) and norepinephrine transporters (NETs) in rat brain synaptosomes.

Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats.

Background: The misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Δ-tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters.

Methods: Biotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats.

Attenuating Nicotine Reinforcement and Relapse by Enhancing Endogenous Brain Levels of Kynurenic Acid in Rats and Squirrel Monkeys.

The currently available antismoking medications have limited efficacy and often fail to prevent relapse. Thus, there is a pressing need for newer, more effective treatment strategies. Recently, we demonstrated that enhancing endogenous levels of kynurenic acid (KYNA, a neuroinhibitory product of tryptophan metabolism) counteracts the rewarding effects of cannabinoids by acting as a negative allosteric modulator of α7 nicotinic receptors (α7nAChRs).

Pharmacological mechanisms underlying the cardiovascular effects of the "bath salt" constituent 3,4-methylenedioxypyrovalerone (MDPV).

Background And Purpose: 3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with stimulatory cardiovascular effects that can lead to serious medical complications. Here, we examined the pharmacological mechanisms underlying these cardiovascular actions of MDPV in conscious rats.

Experimental Approach: Male Sprague-Dawley rats had telemetry transmitters surgically implanted for the measurement of BP and heart rate (HR).

Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats.

Rationale: Manipulations of the endocannabinoid system could potentially produce therapeutic effects with minimal risk of adverse cannabis-like side effects. Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of the cannabinoid-receptor agonist, anandamide, and show promise for treating a wide range of disorders. However, their effects on learning and memory have not been fully characterized.

Reinforcing and neurochemical effects of the "bath salts" constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats.

Rationale: 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called "bath salts" products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT).

Persistent palatable food preference in rats with a history of limited and extended access to methamphetamine self-administration.

Recent studies have shown that when given a mutually exclusive choice between cocaine and palatable foods, most rats prefer the non-drug rewards over cocaine. Here, we used a discrete choice procedure to assess whether palatable food preference generalizes to rats with a history of limited (3 hours/day) or extended (6 or 9 hours/day) access to methamphetamine self-administration. On different daily sessions, we trained rats to lever-press for either methamphetamine (0.

Effects of 3,4-methylenedioxymethamphetamine (MDMA) and its main metabolites on cardiovascular function in conscious rats.

Background And Purpose: The cardiovascular effects produced by 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats.

Experimental Approach: Radiotelemetry was employed to evaluate the effects of s.

Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products.

The abuse of psychoactive 'bath salts' containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods. In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices.

Combined effects of THC and caffeine on working memory in rats.

Background And Purpose: Cannabis and caffeine are two of the most widely used psychoactive substances. Δ(9) -Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, induces deficits in short-term memory. Caffeine, a non-selective adenosine receptor antagonist, attenuates some memory deficits, but there have been few studies addressing the effects of caffeine and THC in combination.

Rapid delivery of cocaine facilitates acquisition of self-administration in rats: an effect masked by paired stimuli.

In general, faster infusions of cocaine are more likely to support behavior related to abuse than are slower infusions. However, some studies of cocaine self-administration in rats have failed to support this finding, possibly because the effect was masked by other factors. One such factor may be the pairing of a stimulus with the infusion, a procedure that is known to facilitate acquisition of drug self-administration.

Automatic recording of mediating behavior in delayed matching- and nonmatching-to-position procedures in rats.

Rationale: Delayed matching-to-position and nonmatching-to-position procedures are widely used to model working memory in rodents. Mediating behavior-which enhances performance but is not explicitly required by the task-is generally considered an obstacle to the measurement of memory, but often occurs despite attempts to prevent it. The ubiquitous nature of mediating behavior suggests it might be analogous to rehearsal, an important component of learning and memory in humans.

Effect of rate of delivery of intravenous cocaine on self-administration in rats.

Many studies of drug self-administration in primates have shown that faster infusions of a drug are more reinforcing than slower infusions. Similar effects have not been shown in rats. We assessed the influence of delivery rate by allowing rats to choose between the same doses of intravenous cocaine delivered over two different infusion speeds.

A stimulus-control account of dysregulated drug intake.

Drug self-administration typically occurs in a regular temporal pattern, with a consistent pause following each injection. We have proposed that this patterning results from differential reinforcement of post-injection pausing. In this view, even when every response produces an injection, some injections are not reinforcing because they occur when the level of drug effect is already maximal; consequently, drug reinforcement occurs on an intermittent schedule, and the interoceptive drug effect functions as a cue, indicating when another injection will be reinforcing.

A stimulus-control account of regulated drug intake in rats.

Rationale: Patterns of drug self-administration are often highly regular, with a consistent pause after each self-injection. This pausing might occur because the animal has learned that additional injections are not reinforcing once the drug effect has reached a certain level, possibly due to the reinforcement system reaching full capacity. Thus, interoceptive effects of the drug might function as a discriminative stimulus, signaling when additional drug will be reinforcing and when it will not.

Differential involvement of dopamine receptors in conditioned suppression induced by cocaine.

Cocaine-paired stimuli can suppress food-reinforced operant behavior in rats, providing an animal model of conditioned drug effects. To study the neuropharmacological basis of this phenomenon, we examined the effects of various dopamine receptor antagonists on the acquisition and expression of cocaine-induced conditioned suppression in rats. Superimposed on an ongoing baseline of food-reinforced operant responding, a stimulus was paired with response-independent cocaine (3.

Blocking of conditioning to a cocaine-paired stimulus: testing the hypothesis that cocaine perpetually produces a signal of larger-than-expected reward.

According to a recent account of addiction, dopaminergic effects of drugs like cocaine mimic the neuronal signal that occurs when a natural reward has a larger value than expected. Consequently, the drug's expected reward value increases with each administration, leading to an over-selection of drug-seeking behavior. One prediction of this hypothesis is that the blocking effect, a cornerstone of contemporary learning theory, should not occur with drug reinforcers.

Cocaine self-administration under variable-dose schedules in squirrel monkeys.

Squirrel monkeys self-administered cocaine under a variable-dose schedule, with the dose varied from injection to injection. As in earlier studies with rats, post-injection pauses varied as a monotonic function of dose, allowing a cocaine dose-effect curve to be obtained during each session. These curves were shifted by pretreatment with dopamine antagonists, demonstrating that this procedure may provide an efficient means of evaluating treatments that affect drug self-administration.

Lorazepam reinstates punishment-suppressed remifentanil self-administration in rats.

Rationale: We recently described a reinstatement procedure that models relapse to drug abuse in cases where abstinence results from aversive consequences of drug use. The potential value of this punishment-based model of relapse depends on its sensitivity to relapse-inducing events that are ineffective in the widely used extinction-based model.

Objectives: It is known that certain drugs can have anti-punishment effects, but these drugs have not been tested in the punishment-based reinstatement procedure.

Role of central and peripheral adenosine receptors in the cardiovascular responses to intraperitoneal injections of adenosine A1 and A2A subtype receptor agonists.

1. The cardiovascular effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and the adenosine A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) were investigated in rats implanted with telemetry transmitters for the measurement of blood pressure and heart rate. 2.