Neuropharmacological Mechanisms Research Articles

Inhibition of ultrasonic vocalizations by beta‐adrenoceptor agonists

Infant rat ultrasonic vocalizations (USVs) are widely believed to result from the induction of an emotional state of anxiety or distress. This perspective, however, is not easily reconciled with the demonstration by W. J. Farrell and J. R. Alberts 2000 that norepinephrine, a nonselective beta-adrenoceptor agonist with anxiogenic properties, inhibits production of USVs. Here, Farrell and Alberts' finding was replicated and extended with 12-day-old rats using a conventional isolation paradigm. First, treatment with norepinephrine (1 mg/kg) significantly inhibited ultrasound production while also increasing body temperature. Next, treatment with the beta-2 agonist terbutaline (1 mg/kg) and the beta-3 agonist CL-316243 (1 mg/kg), but not the beta-1 agonist dobutamine (1 mg/kg), inhibited ultrasound production; only CL-316243 increased body temperature. The unexpected inhibition of USVs by terbutaline, a potent bronchodilator, was replicated using a slightly modified procedure; again, body temperature was unaffected by terbutaline administration. In no experiment was inhibition of USVs related to changes in motor activity. Altogether, these results suggest either that ultrasound production is not a valid indicator of anxiety or that anxiety in infant rats is produced by neuropharmacological mechanisms that differ fundamentally from those in adults.

Modulation of nicotine-induced attentional enhancement in rats by adrenoceptor antagonists.

Understanding the neuropharmacological mechanisms mediating attentional enhancement by nicotine would help a targeted search for nicotinic compounds with retained therapeutic but reduced unwanted side-effects. Previous studies suggested that the dopamine-releasing effects of nicotine may not be of primary importance for its attention-enhancing properties. The present study examined the role of noradrenergic neurotransmission for the effects of nicotine on different response indices of an attentional paradigm. The effects of systemic injections of the alpha(1)-adrenoceptor antagonist prazosin that also displays significant affinity at alpha(2B) and alpha(2C)-adrenoceptors and the beta-adrenoceptor antagonist propranolol were tested in both the presence and absence of nicotine in rats trained in a version of the five-choice serial reaction time task. Nicotine generally enhanced the accuracy of signal detection, reduced omission errors and shortened response latencies. At the largest doses tested, both prazosin (1 mg/kg) and propranolol (10 mg/kg) impaired performance. For propranolol, these effects depended on the rate of target signal presentation. The two compounds differentially modulated the effects of nicotine. Propranolol (6 mg/kg and 10 mg/kg) but not prazosin reduced its effects on omission errors and accuracy. By contrast, prazosin (0.5 mg/kg) reversed the nicotine-induced reductions in response latency. The data provide the first evidence that beta-adrenoceptors are involved in mediating the effects of nicotine on signal detection, while activation of alpha-adrenoceptors may contribute to its effects on response speed. This is a further indication that, from among nicotine's wide range of neuropharmacological effects, specific facets can be dissociated that are responsible for its attention-enhancing properties.

Clinical neuropharmacology of drugs of abuse: a comparison of drug-discrimination and subject-report measures.

Advances in molecular pharmacology and behavioral science have helped elucidate the structure and function of the central nervous system and its relationship to behavior and has sparked the development of pharmacological agents that have increasingly selective and potent effects with fewer adverse side effects. The sensitivity and predictive validity of the two most commonly used methodologies for assessing the neuropharmacological effects of centrally active drugs, subject report of drug effects and drug discrimination, were examined. The sensitivity of the measures was comparable across stimulant, sedative, and opioid drugs. Results with drug-discrimination methodologies were generally consistent with hypothesized neuropharmacological mechanisms across all drug classes, whereas subject reports conformed under more limited testing conditions. Firm conclusions regarding the relative utility of drug-discrimination and subject-report measures for clinical studies of neuropharmacological mechanisms are limited by the small number of studies in which the two methodologies have been tested using identical pharmacological pretreatment manipulations.

Pharmacology of acamprosate: an overview.

In the last years important advances have been made in the development of drugs for the treatment of alcohol addiction. Acamprosate (calcium bis-acetylhomotaurine) is one of the better established drugs in this field on the European market. This review focuses first on the pharmacokinetics of acamprosate. The published data and the recent advances in our knowledge on the mechanisms involved in the intestinal absorption and elimination of this drug are summarized. The importance of pharmacokinetics for the proper clinical use of acamprosate is highlighted. The anti-relapse as well as the well-known effects of acamprosate on ethanol intake are discussed. The recent experiments in animal models of conditioned withdrawal are reviewed. These experiments, explored for the first time the anticraving effect of the drug. Finally, the proposed hypotheses on the neuropharmacological mechanism of action of acamprosate are discussed. The discussion deals with the relative importance of various hypotheses as well as with the recent experiments that support them. It is pointed out that further research is necessary in order to clearly understand the mode of action of acamprosate as well as the neurobiological mechanisms involved in alcohol dependence.

Functional magnetic resonance imaging of psychopharmacological brain effects: an update

Functional magnetic resonance imaging (fMRI) is well established for the examination of functional activity in the living brain. The method permits the development of functional activation maps during perceptual, cognitive and emotional efforts with a high temporal and spatial resolution. As of late there has been growing interest in using this technique to investigate regionally specific brain activity following the administration of drugs such as nicotine, cocaine, lorazepam, scopolamine, antipsychotics or antidepressants. Studies in experimental animals investigate signal changes associated with the administration of psychopharmacological substances in different brain areas using a high magnetising field (> 4 Tesla). FMRI-studies in healthy human volunteers and psychiatric patients focus on cerebral activity following acute drug administration (single challenge) and on adaptive effects of the CNS due to long- term medication. Their results provide insights into brain physiology and neuropharmacological mechanisms which are in turn relevant for preclinical pharmacological studies, responder analyses and for the investigation of pathogenetic models in psychiatric diseases. However, with these new opportunities, additional methodological considerations and limitations emerge. Besides the need of controlling motion artefacts, the influence of interfering psychological variables, an exact specification of the experimental design, a standardised analysis for data adjustment and technical limitations have to be considered. This article provides an overview of the underlying model of brain function, present applications, future possibilities and methodological limitations of fMRI for the understanding of human psychopharmacology.

Effects of dopamine receptor antagonists on nicotine-induced attentional enhancement.

An understanding of the neuropharmacological mechanisms mediating attentional enhancement by nicotine would indicate whether these effects could be dissociated pharmacologically from other behavioural effects of nicotine. The aim of the present study was to examine the involvement of dopamine neurotransmission in the effects of nicotine on different response indices of an attentional paradigm. The effects of the D2-type dopamine receptor antagonist raclopride (0.025-0.1 mg/kg) and the D1-type receptor antagonist SCH23390 (0.006-0.024 mg/kg) were tested, in both the presence and absence of nicotine (0.1 mg/kg), in rats trained in a modified version of the five-choice serial reaction time task (5-CSRTT). Nicotine robustly enhanced the accuracy of signal detection, reduced omission errors and shortened response latencies. Neither raclopride nor SCH23390 altered the effects of nicotine on accuracy and omissions, but raclopride augmented accuracy and SCH23390 increased omissions when given alone. By contrast, raclopride, but not SCH23390, reversed the nicotine-induced reductions in response latencies, at doses that had no effect on their own. In the presence of nicotine, both antagonists had rate-disruptive effects at the highest dose. Both antagonists also reduced responding in the intertrial interval, and this effect was additive to the nicotine-induced decrease in this measure. The data indicate that D2-type dopamine receptors may be involved in the effects of nicotine on response speed. Neither the D1- nor the D2-type dopamine receptor antagonist affected nicotine-induced improvements in signal detection, at doses that reversed dependence-related behavioural effects of nicotine in previous studies. Thus these effects may be pharmacologically dissociable.

Effect of repeated nicotine exposure on core temperature and motor activity in male and female rats

Comparatively little is known about the thermoregulatory effects of single and repeated administration of nicotine. Nicotine is a relatively fast acting drug that induces transient changes in core temperature (Tc) of rodents. The development of radio telemetry allows one to detect subtle and rapid changes in Tc that otherwise are difficult to measure with conventional colonic probe techniques. To this end, Tc and motor activity (MA) were monitored by radio telemetry in male and female Sprague-Dawley rats following five daily injections of saline or nicotine tartrate (0.5mg/kg; sc). The first injection of saline led to a transient increase in Tc that was attributed to the handling and injection procedures. Rats dosed with nicotine for the first time were hypothermic for approximately 2h after injection. The hypothermia was attributed to an impaired increase in Tc from handling and injection. A transient hyperthermic response began to develop with each successive injection of nicotine. After the fourth injection of nicotine, Tc of male rats increased by 0.5°C above controls; Tc of females increased by 0.25°C above controls after the fifth injection. MA also increased transiently with each injection of saline and nicotine. The MA response of females was significantly greater than the males for the second through fifth injections of nicotine. Overall, the thermoregulatory system develops sensitization with 4–5 repeated injections of nicotine. The mediation of a hyperthermic response to a systemically administered cholinergic agonist is a novel effect. It may aid in understanding the delayed hyperthermic response to organophosphate pesticides. The sensitization of the thermoregulatory system to nicotine may shed light on the neuropharmacological mechanisms of this drug.

Effects of the atypical antipsychotic risperidone on hostility and aggression in schizophrenia: a meta-analysis of controlled trials

Atypical antipsychotics have been hypothesized to be more effective than classical antipsychotics in the treatment of hostility and aggression, due to their characteristic pharmacological profile, involving serotonergic as well as dopaminergic systems. In the present quantitative review the published evidence regarding the effects of risperidone on hostility and aggression in schizophrenia is evaluated. Meta-analysis of seven controlled trials revealed significant differences between risperidone and classical antipsychotics and between risperidone and placebo, although the effect size was small. Additional analyses in which only methodological rigorous studies were included showed highly significant differences (risperidone versus classical antipsychotics) and the effect size approached the ‘medium’ range. We conclude that risperidone is superior to classical antipsychotics and placebo in the treatment of hostility and aggression in schizophrenia. Neuropharmacological mechanisms that might account for this effect are discussed, and directions for future research are outlined.

FMRI: a new tool for the in vivo localization of drug actions in the brain.

Functional magnetic resonance imaging (fMRI), a still-emerging, non-invasive neuroimaging tool, has been applied to a wide range of questions in sensory, motor control, and cognitive psychology. Only more recently has it been applied to understand the sites and mechanisms of action of pharmacological agents within the human CNS. However, in so doing, a new set of problems and concerns surrounding the technique must be addressed because of the unique transduction mechanisms (both physiological and biophysical) that exist to produce the fMRI signal from the underlying neuronal activity. Experimental design and control issues become paramount in performing fMRI pharmacological protocols and in signal interpretation. With these caveats, the use of pharmacological agents with fMRI is likely to greatly increase in the near term as new questions about both brain physiology and neuropharmacological mechanisms become addressable for the first time. Examples are given using nicotine and cocaine as a prototypical agents.

The psychopharmacology of sex, part 2: effects of drugs and disease on the 3 phases of human sexual response.

Issue: Many drugs can uniquely affect the phases of human sexual response, both positively and negatively, according to their neuropharmacologic mechanisms of action. Various diseases and disorders can also impact the different phases of the human sexual response, according to their pathophysiologies. Understanding these issues will assist clinicians in determining whether sexual dysfunction is due to a disease or to a drug, which will allow rational management of sexual disorders by targeting the specific dysfunctional phase of the sexual response with a drug that has an appropriate and compensatory neuropharmacologic mechanism of action.

Dopamine D 2-like receptor binding in the brain of male Japanese quail ( Coturnix japonica)

Japanese quail ( Coturnix japonica) have been used extensively to study appetitive behaviors. However, little is known about the appetitive-relevant neurochemical systems in this species. The present investigation examined the distribution of D 2-like dopamine receptors in the quail brain. [ 3H]Spiperone was incubated in brain tissue homogenates and non-specific binding was defined using (−)-sulpiride. Scatchard analysis of whole brain without cerebellum and forebrain alone indicated approximate K d's of 0.08 and 0.04 nM, respectively. In addition, the preferential D 3 agonist (±)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (7-OH-DPAT) did not displace [ 3H]spiperone binding in quail forebrain. Finally, regional analysis showed that the highest densities of D 2-like receptors were located in the forebrain. Overall, these results indicate that there is some conservation of dopaminergic mechanisms between aves and mammals. Thus, Japanese quail may be useful for examining the neuropharmacological mechanisms of dopaminergic stimulant drugs that work via D 2-like receptor activation.

Neuronal mechanisms mediating the integration of respiratory responses to hypoxia.

The activation of peripheral chemoreceptors by hypoxia or electrical stimulation of the carotid sinus nerve elicited a hypoxic respiratory response consisting of both stimulatory and subsequent or simultaneous inhibitory components (hypoxic respiratory stimulation and depression). Both components have different time domains of responses (time-dependent response), providing an integrated respiratory response to hypoxia. This review has focused on the neuroanatomical and neurophysiological correlations responsible for these responses and their neuropharmacological mechanisms. Hypoxic respiratory depression is characterized by the initial activation of respiration followed by a progressive and gradual decline in ventilation during prolonged and/or severe hypoxic exposure (biphasic response). The responsible mechanisms for the depression are located within the central nervous system and may be dependent upon activity from peripheral chemoreceptor. Two underlying mechanisms contributing to the depression have been advocated. (1) Change in synaptic transmission: Within the neuronal network controlling the hypoxic respiratory response, hypoxia might induce the enhancement of inhibitory neurotransmission (modulation), disfacilitation of excitatory neruotransmission or both. (2) Change in the membrane property of respiratory neurons: Hypoxia might suppress the membrane excitability of respiratory neurons composing the hypoxic respiratory response via modulating ion channels, leading to hyperpolarization or depolarization blocking of the neurons. However, the quantitative aspects of Pao(2) (degree and duration of hypoxic exposure) to induce these changes and the susceptibility of both mechanisms to the Pao(2) level have not yet been clearly elucidated.

１１．前庭代償の薬理

Vestibular compensation, the behavioral recovery that occurs following the removal of afferent input from one vestibular organ or nerve, is a useful experimental model of lesion-induced plasticity in the central nervous system. While the recovery of resting activity in the vestibular nuclei ipsilateral to the lesioned side is involved in the process of vestibular compensation, the neuropharmacological mechanisms underlying neuronal recovery are unknown.This review focuses on the pharmacological basis of vestibular compensation to clarify the changes in the neurochemical or synaptic organization of the vestibular nuclei and discusses the neurochemical mechanisms underlying the development of vestibular compensation.

Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration

The psychostimulants, d-amphetamine ( d-AMP) and methylphenidate (MPH), are widely used to treat attention-deficit hyperactivity disorder (ADHD) in both children and adults. The purpose of this paper is to integrate results of basic and clinical research with stimulants in order to enhance understanding of the neuropharmacological mechanisms of therapeutic action of these drugs. Neurochemical, neurophysiological and neuroimaging studies in animals reveal that the facilitative effects of stimulants on locomotor activity, reinforcement processes, and rate-dependency are mediated by dopaminergic effects at the nucleus accumbens, whereas effects on delayed responding and working memory are mediated by noradrenergic afferents from the locus coeruleus (LC) to prefrontal cortex (PFC). Enhancing effects of the stimulants on attention and stimulus control of behavior are mediated by both dopaminergic and noradrenergic systems. In humans, stimulants appear to exert rate-dependent effects on activity levels, and primarily enhance the motor output, rather than stimulus evaluation stages of information-processing. Similarity of response of individuals with and without ADHD suggests that the stimulants do not target a specific neurobiological deficit in ADHD, but rather exert compensatory effects. Integration of evidence from pre-clinical and clinical research suggests that these effects may involve stimulation of pre-synaptic inhibitory autoreceptors, resulting in reduced activity in dopaminergic and noradrenergic pathways. The implications of these and other hypotheses for further pre-clinical and clinical research are discussed.

Drugs of abuse and immediate-early genes in the forebrain.

A diverse array of chemical agents have been self administered by humans to alter the psychological state. Such drugs of abuse include both stimulants and depressants of the central nervous system. However, some commonalties must underlie the neurobiological actions of these drugs, since the desire to take the drugs often crosses from one drug to another. Studies have emphasized a role of the ventral striatum, especially the nucleus accumbens, in the actions of all drugs of abuse, although more recent studies have implicated larger regions of the forebrain. Induction of immediate-early genes has been studied extensively as a marker for activation of neurons in the central nervous system. In this review, we survey the literature reporting activation of immediate-early gene expression in the forebrain, in response to administration of drugs of abuse. All drugs of abuse activate immediate-early gene expression in the striatum, although each drug induces a particular neuroanatomical signature of activation. Most drugs of abuse activate immediate-early gene expression in several additional forebrain regions, including portions of the extended amygdala, cerebral cortex, lateral septum, and midline/intralaminar thalamic nuclei, although regional variations are found depending on the particular drug administered. Common neuropharmacological mechanisms responsible for activation of immediate-early gene expression in the forebrain involve dopaminergic and glutamatergic systems. Speculations on the biological significance and clinical relevance of immediate-early gene expression in response to drugs of abuse are presented.

Attempts to Classify Dependence-Liable Drugs by Using a Simple Drug-Discrimination Test in Mice

1. In a simple discrimination test using a two-compartment shuttle box with mice, we examined the action properties of dependence-liable drugs. In mice trained to discriminate morphine from saline, neither methamphetamine (MAP) nor cocaine (COCA) was generalized to the discriminative stimulus effects of morphine. 2. Similarly, in mice trained to discriminate MAP from saline, COCA, which is known to have neuronal mechanisms in common with MAP, was generalized to the stimulus effects of MAP, but morphine was not. 3. Dihydroetorphine (DHE), which has receptor mechanisms in common with morphine, was generalized to the discriminative stimulus effects of morphine, whereas it was not generalized to the effects of MAP. Thus, the present discrimination test might be useful for the first screening of compounds with unknown neuronal mechanisms, particularly for classification into groups having separate neuropharmacological mechanisms in common.

Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens.

Multiple lines of research have implicated the mesolimbic dopamine system in drug reward measured by either the drug self-administration or conditioned place preference paradigm. The present review summarizes recent work that examines the neuropharmacological mechanisms by which drugs impinge on this dopaminergic neural circuitry, as well as other systems that provide input and output circuits to the mesolimbic dopamine system. Studies examining the effect of selective agonist and antagonist drugs administered systemically have indicated that multiple neurotransmitters are involved, including dopamine, serotonin, acetylcholine, glutamate, GABA, and various peptides. Direct microinjection studies have also provided crucial evidence indicating that, in addition to the mesolimbic dopamine system, other structures play a role in drug reward, including the ventral pallidum, amygdala, hippocampus, hypothalamus, and pedunculopontine tegmental nucleus. GABAergic circuitry descending from the nucleus accumbens to the pedunculopontine tegmental nucleus via the ventral pallidum appears to be especially important in directing the behavioral sequelae associated with reward produced by various drugs of abuse. However, activation of the reward circuitry is achieved differently for various drugs of abuse. With amphetamine and cocaine, initiation of reward is controlled within the nucleus accumbens and prefrontal cortex, respectively. With opiates, initiation of reward involves the ventral tegmental area, nucleus accumbens, hippocampus, and hypothalamus. It is not clear presently if these multiple anatomical structures mediate opiate reward by converging on a single output system or multiple output systems.

Neuropharmacological Mechanisms of Nerve Agent-induced Seizure and Neuropathology

McDONAGH, J.H., JR., T.-M. SHIH. Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathy. NEUROSCI BIOBEHAV REV 21(5) 559–579, 1997.—This paper proposes a three phase “model” of the neuropharmacological processes responsible for the seizures and neuropathology produced by nerve agent intoxication. Initiation and early expression of the seizures are cholinergic phenomenon; anticholinergics readily terminate seizures at this stage and no neuropathology is evident. However, if not checked, a transition phase occurs during which the neuronal excitation of the seizure per se perturbs other neurotransmitter systems: excitatory amino acid (EAA) levels increase reinforcing the seizure activity; control with anticholinergics becomes less effective; mild neuropathology is occasionally observed. With prolonged epileptiform activity the seizure enters a predominantly non-cholinergic phase: it becomes refractory to some anticholinergics; benzodiazepines and N-methyl-d-aspartate (NMDA) antagonists remain effective as anticonvulsants, but require anticholinergic co-administration; mild neuropathology is evident in multiple brain regions. Excessive influx of calcium due to repeated seizure-induced depolarization and prolonged stimulation of NMDA receptors is proposed as the ultimate cause of neuropathology. The model and data indicate that rapid and aggressive management of seizures is essential to prevent neuropathology from nerve agent exposure. Published by Elsevier Science Ltd.

Intra-amygdala muscimol decreases operant ethanol self-administration in dependent rats.

Dependence is an important factor motivating continued alcohol use in human alcoholics. Development of a model of ethanol (EtOH) consumption in dependent animals would advance the understanding of reinforcement after chronic EtOH exposure and allow for the investigation of the neuropharmacological mechanisms mediating reinforcement in dependent versus nondependent animals. In the present study, rats were trained to lever press for 10% EtOH, surgically implanted with bilateral guide cannulae in the amygdala, and either made dependent on EtOH by exposure for 2 weeks to EtOH or exposed to air in identical vapor chambers. Upon removal, the rats were placed in operant boxes and allowed to respond on levers for 10% EtOH or water during a 12-hr period. Rats were removed briefly at approximately 6.5 hr for intra-amygdala injections of saline or the GABAA receptor agonist muscimol. After the test period, rats were returned to the vapor chambers for 4 days before retest. EtOH-dependent animals responded more for EtOH across the 12-hr test period than did air control nondependent rats; this difference became more pronounced with repeated test sessions. Intra-amygdala muscimol significantly decreased responding for EtOH in EtOH-dependent rats, but had no effect in nondependent controls. These data suggest that the reinforcing effects of EtOH and neurotransmitter pathways mediating reward are altered after the development of dependence, and they support the use of this paradigm for further investigations into the neuropharmacology of EtOH dependence.

Neuronal mechanisms mediating drug-induced cognition enhancement: cognitive activity as a necessary intervening variable

The conceptual foundations of a research aimed at the determination of potential neuronal, neuropharmacological, and behavioral/cognitive mechanisms mediating drug-induced cognition enhancement are discussed. The available evidence justifies a focus on attentional processes as a target for drug-induced cognition enhancement. Neuropharmacological mechanisms that may mediate drug-induced enhancement of attentional functions are proposed to interact necessarily with attention-associated neuronal activity. The elements of a transsynaptic approach to increase the excitability of basal forebrain cholinergic neurons and hence, attentional functions are discussed. Experimental tests of this hypothesis require the demonstration of interactions between cognition-induced increases in the activity of cortical cholinergic afferents and the effects of putative cognition enhancers. The available data illustrate that the effects of benzodiazepine receptor (BZR) agonists and inverse agonists on cortical acetylcholine (ACh) efflux interact with the state of activity in this system. The feasibility, potential heuristic power, and the experimental and conceptual problems of studies attempting to simulataneously assess drug effects on behavioral/cognitive abilities, ACh efflux, and neuronal activity have been revealed by an experiment intended to correlate performance in a task measuring sustained attention with medial prefrontal ACh efflux and medial prefrontal single-unit activity. The rational development of a psychopharmacology of cognition enhancers requires a union among behavioral/cognitive pharmacology, neuropharmacological and electrophysiological approaches.