Neuropharmacology
Central Nervous System Agents
Serotonin Agents
Behavior, Addictive
Recent advances in neuropharmacology of cutaneous nociceptors. (1/57)
Cutaneous nociceptors are peripheral receptive endings of primary sensory neurons activated by noxious stimuli. Nociceptors detect and signal the presence of tissue-damaging stimuli or the existence of tissue damage. In this short review, we will focus on the molecular mechanism of maintenance, activation, inhibition and sensitization in cutaneous nociceptors. Neurotrophic factors are essential to the development of nociceptors during embryogenesis. Recent evidences have indicated that nociceptors in the adult are maintained by either nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF). A selective activator of nociceptors is capsaicin, natural product of capsicum peppers. Recently, the receptor for capsaicin (the vanilloid receptor 1: VR1) has been cloned, identified and characterized. VR1 seems to play an important role in the activation and sensitization of nociceptors. In contrast, peripheral endogenous cannabinoids such as anandamide are novel candidates for mediators that inhibit the excitation of nociceptors. Intracellular messengers and the mechanisms of signal transduction in nociceptors have also been studied. Our recent findings provide evidences demonstrate that an activation of both cAMP- and cGMP-second messenger systems is required to induce the sensitization of nociceptors. Such emerging evidences reviewed here would make a significant contribution to further understanding of the molecular mechanism of nociceptors. (+info)Detouring destruction: a role for inhibitory neuronal activity in preventing neuronal loss--implications for Alzheimer's disease. (2/57)
Recent results from the author's efforts and others have indicated approaches that may eventually lead to new therapeutic strategies for combating neurodegenerative effects associated with dementia and Alzheimer's disease (AD). These strategies include unraveling mechanisms that decrease senile plaque accumulation and delay or slow the neurodegenerative progression associated with AD. Recent work addresses whether normally functioning inhibitory brain circuitry can protect and detour neurodegeneration. The aim of these research efforts is that one or a combination of these approaches will develop into an applied therapy that will enhance brain protection mechanisms and add to quality of life for patients with AD. (+info)Pharmacological findings on the biochemical bases of memory processes: a general view. (3/57)
We have advanced considerably in the past 2 to 3 years in understanding the molecular mechanisms of consolidation, retrieval, and extinction of memories, particularly of fear memory. This advance was mainly due to pharmacological studies in many laboratories using localized brain injections of molecularly specific substances. One area in which significant advances have been made is in understanding that many different brain structures are involved in different memories, and that often several brain regions are involved in processing the same memory. These regions can cooperate or compete with each other, depending on circumstances that are beginning to be identified quite clearly. Another aspect in which major advances were made was retrieval and post-retrieval events, especially extinction, pointing to new therapeutic approaches to fear-motivated mental disorders. (+info)Strains of rodents and the pharmacology of learning and memory. (4/57)
Mendelian genetic tools have extensively been used to improve the description of the pharmacological mechanisms involved in learning and memory. The first part of this short review describes experiments involving the bidirectional selection of rats or mice for extreme behavioral characteristics or for sensitivity to pharmacological treatments. The second part focuses specifically on in-breeding. In conclusion, the advantages and the limits of a Mendelian pharmacogenetic approach of learning and memory are discussed. (+info)A chronically implantable, hybrid cannula-electrode device for assessing the effects of molecules on electrophysiological signals in freely behaving animals. (5/57)
We describe a device for assessing the effects of diffusible molecules on electrophysiological recordings from multiple neurons. This device allows for the infusion of reagents through a cannula located among an array of micro-electrodes. The device can easily be customized to target specific neural structures. It is designed to be chronically implanted so that isolated neural units and local field potentials are recorded over the course of several weeks or months. Multivariate statistical and spectral analysis of electrophysiological signals acquired using this system could quantitatively identify electrical "signatures" of therapeutically useful drugs. (+info)Electrophysiological and pharmacological validation of vagal afferent fiber type of neurons enzymatically isolated from rat nodose ganglia. (6/57)
An unavoidable consequence of enzymatic dispersion of sensory neurons from intact ganglia is loss of the axon and thus the ability to classify afferent fiber type based upon conduction velocity (CV). An intact rat nodose ganglion preparation was used to randomly sample neurons (n=76) using the patch clamp technique. Reliable electrophysiological and chemophysiological correlates of afferent fiber type were established for use with isolated neuron preparations. Myelinated afferents (approximately 25%) formed two groups exhibiting strikingly different functional profiles. One group (n=10) exhibited CVs in excess of 10 m/s and narrow (<1 ms) action potentials (APs) while the other (n=9) had CVs as low as 4m/s and broad (>2 ms) APs that closely approximated those identified as unmyelinated afferents (n=57) with CVs less than 1m/s. A cluster analysis of select measures from the AP waveforms strongly correlated with CV, producing three statistically unique populations (p<0.05). These groupings aligned with our earlier hypothesis (Jin et al., 2004) that a differential sensitivity to the selective purinergic and vanilloid receptor agonists can be used as reliable pharmacological indicators of vagal afferent fiber type. These metrics were further validated using an even larger population of isolated (n=240) nodose neurons. Collectively, these indicators of afferent fiber type can be used to provide valuable insight concerning the relavence of isolated cellular observations to integrated afferent function of visceral organ systems. (+info)Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466. (7/57)
One of the most recently identified serotonin (5-hydroxytryptamine (5-HT)) receptor subtypes is the 5-HT6 receptor. Although in-depth localization studies reveal an exclusive distribution of 5-HT6 mRNA in the central nervous system, the precise biological role of this receptor still remains unknown. In the present series of experiments, we report the pharmacological and neurochemical characterization of two novel and selective 5-HT6 receptor agonists. WAY-181187 and WAY-208466 possess high affinity binding (2.2 and 4.8 nM, respectively) at the human 5-HT6 receptor and profile as full receptor agonists (WAY-181187: EC50=6.6 nM, Emax=93%; WAY-208466: EC50=7.3 nM; Emax=100%). In the rat frontal cortex, acute administration of WAY-181187 (3-30 mg/kg, subcutaneous (s.c.)) significantly increased extracellular GABA concentrations without altering the levels of glutamate or norepinephrine. Additionally, WAY-181187 (30 mg/kg, s.c.) produced modest yet significant decreases in cortical dopamine and 5-HT levels. Subsequent studies showed that the neurochemical effects of WAY-181187 in the frontal cortex could be blocked by pretreatment with the 5-HT6 antagonist, SB-271046 (10 mg/kg, s.c.), implicating 5-HT6 receptor mechanisms in mediating these responses. Moreover, the effects of WAY-181187 on catecholamines were attenuated by an intracortical infusion of the GABA A receptor antagonist, bicuculline (10 microM), confirming a local relationship between 5-HT6 receptors and GABAergic systems in the frontal cortex. In the dorsal hippocampus, striatum, and amygdala, WAY-181187 (10-30 mg/kg, s.c.) elicited robust elevations in extracellular levels of GABA without producing similar effects on concentrations of norepinephrine, serotonin, dopamine, or glutamate. In contrast to these brain regions, WAY-181187 had no effect on the extracellular levels of GABA in the nucleus accumbens or thalamus. Additional studies showed that WAY-208466 (10 mg/kg, s.c.) preferentially elevated cortical GABA levels following both acute and chronic (14 day) administration, indicating that neurochemical tolerance does not develop following repeated 5-HT6 receptor stimulation. In hippocampal slice preparations (in vitro), 5-HT(6) receptor agonism attenuated stimulated glutamate levels elicited by sodium azide and high KCl treatment. Furthermore, in the rat schedule-induced polydipsia model of obsessive compulsive disorder (OCD), acute administration of WAY-181187 (56-178 mg/kg, po) decreased adjunctive drinking behavior in a dose-dependent manner. In summary, WAY-181187 and WAY-208466 are novel, selective, and potent 5-HT6 receptor agonists displaying a unique neurochemical signature in vivo. Moreover, these data highlight a previously undescribed role for 5-HT6 receptors to modulate basal GABA and stimulated glutamate transmission, as well as reveal a potential therapeutic role for this receptor in the treatment of some types of anxiety-related disorders (eg OCD). (+info)Towards a clinical methodology for neuropsychopharmacological research. (8/57)
Neuropsychopharmacology is dedicated to the study of the pathophysiology and treatment of mental pathology with the employment of centrally acting drugs. In neuropsychopharmacological research the clinical effects of a psychotropic drug are linked to the effects of the substance on brain structures involved in its mode of action. It is assumed, that knowledge about the mode of action of a selectively effective psychotropic drug will provide clues about the pathophysiology of the illness, and conversely, that knowledge about the pathophysiology of an illness, will provide clues for developing clinically more effective psychotropic drugs. Since the currently employed clinical methodology for the demonstration of therapeutic efficacy links the mode of action of psychotropic drugs to pharmacologically heterogeneous populations, neuropsychopharmacological research does not provide the necessary feedback for developing more effective drugs. To resolve the pharmacological heterogeneity within currently used diagnoses, attempts were made to split syndrome-based psychiatric diagnoses into discrete neurobiological deficits, and to replace traditional psychiatric nosology by a genetic psychiatric nosology. Yet, to date, there is no alternative methodology to psychopathology-based psychiatric nosology for classifying mental pathology in a clinically relevant manner. As we are moving from the "neurotransmitter era" to a "genetic era" in neuropsychopharmacology, the need for identifying pharmacologically homogenous populations is becoming imminent. All primary targets of psychotropic drugs in the brain are encoded by genes which are identified, and any nosologic entity or psychiatric syndrome that corresponds with a treatment responsive population is a candidate for the generation of genetic hypotheses relevant to mental illness. Recognition that progress in neuropsychopharmacology, and molecular genetic research, depends on the speed clinical research can resolve the pharmacological heterogeneity within currently used diagnoses, led to the development of methodologies for the identification of treatment responsive form(s) of illness, such as the Composite Diagnostic Evaluation (CODE) System, and nosologic homotyping. The CODE System is a methodology for the identification of treatment responsive forms of illness if covered up by consensus-based diagnoses; it consists of a set of diagnostic algorithms that can assign simultaneously a diagnosis from several classifications to a patient. Nosologic homotypes are identical in elementary units of mental illness and are assigned the same position in the nosologic matrix, based on three "nosologic organizing principles. The empirically derived diagnostic categories are suitable for testing hypotheses relevant to the relationship between the "processing of mental events" and "signal transduction" in the central nervous system. (+info)Neuropharmacology is a branch of pharmacology that deals with the study of how drugs affect the nervous system and its cells or organs. It involves investigating the interactions between neurochemical communication systems, such as neurotransmitters and neuromodulators, and drugs that alter their function. This field also includes understanding the effects of drugs on behavior, cognition, and other neurological processes. Neuropharmacology can be further divided into two main areas: behavioral neuropharmacology, which focuses on the study of drugs that affect behavior, and molecular neuropharmacology, which deals with the molecular and cellular mechanisms of drug action in the nervous system.
Central nervous system (CNS) agents are drugs or substances that act on the central nervous system, which includes the brain and spinal cord. These agents can affect the CNS in various ways, depending on their specific mechanism of action. They may be used for therapeutic purposes, such as to treat medical conditions like pain, anxiety, seizures, or sleep disorders, or they may be abused for their psychoactive effects.
CNS agents can be broadly classified into several categories based on their primary site of action and the nature of their effects. Some common categories of CNS agents include:
1. Depressants: These drugs slow down the activity of the CNS, leading to sedative, hypnotic, or anxiolytic effects. Examples include benzodiazepines, barbiturates, and sleep aids like zolpidem.
2. Stimulants: These drugs increase the activity of the CNS, leading to alertness, energy, and improved concentration. Examples include amphetamines, methylphenidate, and caffeine.
3. Analgesics: These drugs are used to treat pain and can act on various parts of the nervous system, including the peripheral nerves, spinal cord, and brain. Examples include opioids (such as morphine and oxycodone), non-opioid analgesics (such as acetaminophen and ibuprofen), and adjuvant analgesics (such as antidepressants and anticonvulsants).
4. Antiepileptics: These drugs are used to treat seizure disorders and work by modulating the electrical activity of neurons in the brain. Examples include phenytoin, carbamazepine, valproic acid, and lamotrigine.
5. Antipsychotics: These drugs are used to treat psychosis, schizophrenia, and other mental health disorders by blocking dopamine receptors in the brain. Examples include haloperidol, risperidone, and clozapine.
6. Antidepressants: These drugs are used to treat depression and anxiety disorders by modulating neurotransmitter activity in the brain. Examples include selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and sertraline, tricyclic antidepressants like amitriptyline, and monoamine oxidase inhibitors (MAOIs) like phenelzine.
7. Anxiolytics: These drugs are used to treat anxiety disorders and work by modulating the activity of the neurotransmitter gamma-aminobutyric acid (GABA) in the brain. Examples include benzodiazepines like diazepam and alprazolam, and non-benzodiazepine anxiolytics like buspirone.
8. Stimulants: These drugs are used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy by increasing the activity of dopamine and norepinephrine in the brain. Examples include methylphenidate, amphetamine salts, and modafinil.
9. Sedative-hypnotics: These drugs are used to treat insomnia and other sleep disorders by depressing the activity of the central nervous system. Examples include benzodiazepines like triazolam and zolpidem, and non-benzodiazepine sedative-hypnotics like eszopiclone and ramelteon.
10. Antipsychotics: These drugs are used to treat psychotic disorders like schizophrenia, bipolar disorder, and major depressive disorder by blocking the activity of dopamine in the brain. Examples include typical antipsychotics like haloperidol and chlorpromazine, and atypical antipsychotics like risperidone and aripiprazole.
11. Antidepressants: These drugs are used to treat depression and anxiety disorders by increasing the activity of serotonin, norepinephrine, or dopamine in the brain. Examples include selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and sertraline, tricyclic antidepressants like amitriptyline, and monoamine oxidase inhibitors (MAOIs) like phenelzine.
12. Anticonvulsants: These drugs are used to treat seizure disorders like epilepsy, as well as chronic pain and bipolar disorder. They work by stabilizing the electrical activity of the brain. Examples include valproic acid, lamotrigine, and carbamazepine.
13. Anxiolytics: These drugs are used to treat anxiety disorders by reducing anxiety and promoting relaxation. Examples include benzodiazepines like diazepam and alprazolam, and non-benzodiazepine anxiolytics like buspirone.
14. Hypnotics: These drugs are used to treat insomnia and other sleep disorders by promoting sleep. Examples include benzodiazepines like triazolam and temazepam, and non-benzodiazepine hypnotics like zolpidem and eszopiclone.
15. Stimulants: These drugs are used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy by increasing alertness and focus. Examples include amphetamine salts, methylphenidate, and modafinil.
16. Antihistamines: These drugs are used to treat allergies and allergic reactions by blocking the activity of histamine, a chemical that is released during an allergic response. Examples include diphenhydramine, loratadine, and cetirizine.
17. Antipsychotics: These drugs are used to treat psychosis, schizophrenia, bipolar disorder, and other mental health conditions by reducing the symptoms of these conditions. Examples include risperidone, olanzapine, and quetiapine.
18. Antidepressants: These drugs are used to treat depression, anxiety disorders, and some chronic pain conditions by increasing the levels of certain neurotransmitters in the brain. Examples include selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and sertraline, and tricyclic antidepressants like amitriptyline and imipramine.
19. Anticonvulsants: These drugs are used to treat seizure disorders and some chronic pain conditions by stabilizing the electrical activity of the brain. Examples include valproic acid, lamotrigine, and carbamazepine.
20. Muscle relaxants: These drugs are used to treat muscle spasms and pain by reducing muscle tension. Examples include cyclobenzaprine, methocarbamol, and baclofen.
Serotonin agents are a class of drugs that work on the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) in the brain and elsewhere in the body. They include several types of medications such as:
1. Selective Serotonin Reuptake Inhibitors (SSRIs): These drugs block the reabsorption (reuptake) of serotonin into the presynaptic neuron, increasing the availability of serotonin in the synapse to interact with postsynaptic receptors. SSRIs are commonly used as antidepressants and include medications such as fluoxetine, sertraline, and citalopram.
2. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): These drugs block the reabsorption of both serotonin and norepinephrine into the presynaptic neuron, increasing the availability of these neurotransmitters in the synapse. SNRIs are also used as antidepressants and include medications such as venlafaxine and duloxetine.
3. Serotonin Receptor Agonists: These drugs bind to and activate serotonin receptors, mimicking the effects of serotonin. They are used for various indications, including migraine prevention (e.g., sumatriptan) and Parkinson's disease (e.g., pramipexole).
4. Serotonin Receptor Antagonists: These drugs block serotonin receptors, preventing the effects of serotonin. They are used for various indications, including nausea and vomiting (e.g., ondansetron) and as mood stabilizers in bipolar disorder (e.g., olanzapine).
5. Serotonin Synthesis Inhibitors: These drugs block the enzymatic synthesis of serotonin, reducing its availability in the brain. They are used as antidepressants and include medications such as monoamine oxidase inhibitors (MAOIs) like phenelzine and tranylcypromine.
It's important to note that while these drugs all affect serotonin, they have different mechanisms of action and are used for various indications. It's essential to consult a healthcare professional before starting any new medication.
Addictive behavior is a pattern of repeated self-destructive behavior, often identified by the individual's inability to stop despite negative consequences. It can involve a variety of actions such as substance abuse (e.g., alcohol, drugs), gambling, sex, shopping, or using technology (e.g., internet, social media, video games).
These behaviors activate the brain's reward system, leading to feelings of pleasure and satisfaction. Over time, the individual may require more of the behavior to achieve the same level of pleasure, resulting in tolerance. If the behavior is stopped or reduced, withdrawal symptoms may occur.
Addictive behaviors can have serious consequences on an individual's physical, emotional, social, and financial well-being. They are often associated with mental health disorders such as depression, anxiety, and bipolar disorder. Treatment typically involves a combination of behavioral therapy, medication, and support groups to help the individual overcome the addiction and develop healthy coping mechanisms.