mdl-100907 and Amphetamine-Related-Disorders

Repeated administration of psychostimulants elicits a progressive enhancement of locomotor activity known as behavioral sensitization. Central dopamine (DA) neurons play key roles as the neural substrates mediating behavioral sensitization, but the role of the serotonin (5-HT) system in the sensitization is not fully elucidated. We have recently demonstrated that osemozotan, a specific 5-HT(1A)-receptor agonist, and ritanserin, a 5-HT(2)-receptor antagonist, inhibited the expression and development of both methamphetamine- and cocaine-induced behavioral sensitization in mice and that these drugs attenuated the maintenance of behavioral sensitization of methamphetamine, but not that of cocaine. We also found that azasetron, a 5-HT(3)-receptor antagonist, inhibited the expression and development of the sensitization induced by methamphetamine and cocaine, respectively. Neurochemical studies using a microdialysis technique showed that repeated methamphetamine enhanced the methamphetamine-induced increase in 5-HT release in the prefrontal cortex. The sensitization of 5-HT release in methamphetamine-treated mice was attenuated by osemozotan and ritanserin. These findings suggest that the 5-HT system plays an important role in methamphetamine- and cocaine-induced behavioral sensitization in mice and imply that 5-HT(1A)-receptor agonists and 5-HT(2)-receptor antagonists may have a potential therapeutic value for the treatment of methamphetamine abuse or psychosis.

Topics: Amphetamine-Related Disorders; Animals; Behavior, Animal; Brain; Bridged Bicyclo Compounds, Heterocyclic; Central Nervous System Stimulants; Cocaine; Cocaine-Related Disorders; Dioxanes; Dioxoles; Disease Models, Animal; Ligands; Methamphetamine; Mice; Motor Activity; Oxazines; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT3 Receptor Antagonists; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT(2A) receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.

Topics: Adult; Amphetamine-Related Disorders; Benzylamines; Brain Mapping; Carbon Radioisotopes; Female; Fluorobenzenes; Humans; Male; N-Methyl-3,4-methylenedioxyamphetamine; Neocortex; Piperidines; Positron-Emission Tomography; Protein Binding; Receptor, Serotonin, 5-HT2A; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists; Serotonin Plasma Membrane Transport Proteins; Young Adult

Chronic stress precipitates drug seeking behavior and alters the effects of drugs of abuse. Although it is known that chronic stress potentiates acute neurochemical and hyperthermic responses to the drug of abuse methamphetamine, no studies have investigated if and how chronic stress alters other physiological responses to methamphetamine. Therefore the objective of these studies was to determine if 10 days of chronic unpredictable stress modulates corticosterone (CORT) responses to methamphetamine and furthermore how chronic stress may modulate methamphetamine-induced increases in hyperthermia and CORT. As chronic stress potentiates hyperthermic responses to serotonin 2 (5-HT2) stimulation and 5-HT2 receptors are important in mediating both hyperthermic and CORT responses, we also investigated if 5-HT2 antagonism would block hyperthermia and CORT secretion by the serial exposure to stress and methamphetamine (stress/methamphetamine). The results of these studies illustrate that stress potentiates methamphetamine-induced increases in body temperature and CORT secretion and that these increases are blocked by the 5-HT2 antagonist ketanserin. Furthermore, the combination of stress and methamphetamine depletes 5-HT content in the hippocampus 7 days after methamphetamine administration which is blocked by the 5-HT2 antagonist ketanserin. Overall, these results indicate a pharmacological mechanism for the depletion of hippocampal 5-HT by the serial exposure to stress and methamphetamine and further illustrate the deleterious interactions between chronic stress and methamphetamine use.

Topics: Amphetamine-Related Disorders; Animals; Behavior, Animal; Body Temperature Regulation; Central Nervous System Stimulants; Corticosterone; Drug Administration Schedule; Fever; Hippocampus; Ketanserin; Male; Methamphetamine; Periodicity; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT2; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Stress, Psychological