Comparative study of the behavioral, neurophysiological, and motor effects of psychotropic drugs in the dog

The purpose of this study was to present a comparative and detailed picture of behavioral, physiological, and motor effects of some barbiturates, benzodiazepines, and neuroleptics, using an operant procedure of differential reinforcement of response duration (DRRD) in the dog. An increase in response rate with low doses of barbiturates and benzodiazepines is interpreted in terms of behavioral disinhibition, anxiolytic effect, and enhancement of motivation. The depressive effects noted with higher doses of benzodiazepines and barbiturates, as well as with all doses of neuroleptics, can be explained in different ways. For benzodiazepines and barbiturates, ataxic effects more than sedative or motivational effects are implicated. However, for neuroleptics, loss of motivation or "anhedonia" better explains the decrease in operant responding. Differences between the main classes of psychotropic drugs but also within a class between 1,4 benzodiazepines or 1,5 benzodiazepines, hypnotic or nonhypnotic benzodiazepines, and typical or atypical neuroleptics are highlighted and correlated with human observations.     

海洛因成瘾大鼠伏隔核毁损术前后觅药行为及多巴胺神经递质的变化

目的研究海洛因成瘾大鼠毁损伏隔核前后觅药行为及多巴胺神经递质的变化。方法建立海洛因成瘾大鼠模型，毁损大鼠双侧伏隔核，利用条件性位置偏好实验测定成瘾前、后，术前、术后成瘾大鼠觅药行为的变化，利用高效液相方法测定边缘系统多巴胺神经递质的变化。结果毁损大鼠双侧伏隔核能够完全消除条件性地点偏好。成瘾大鼠边缘系统多巴胺含量较对照组明显增高。毁损前后大鼠边缘系统多巴胺含量无明显变化。结论伏隔核是调节强化作用的重要位置，长期使用海洛因可使大鼠边缘系统多巴胺含量明显增高，但毁损前后无明显变化，与条件性位置偏好表现不同步。     

Neurophysiologic and neurochemical principles of the effect of anticonvulsants

This article surveys neurophysiological and neurochemical findings on the mechanism of action of clinically useful antiepileptics. Two mechanisms appear to be particularly important: reducing the hyperexcitability of the cell membranes by a direct action at ion channels; changes in synaptic transmission by means of an intervention in neurotransmitter systems; it seems that in this regard an important neurotransmitter is the inhibitory gamma-aminobutyric acid GABA. With these mechanisms as basis, antiepileptics can be classified into several groups. In anticonvulsively effective concentrations, phenytoin and carbamazepine will stabilise the cell membranes and thus inhibit their hyperexcitability. This effect seems to be due to a blocking effect on Na+ permeability. If administered in anticonvulsively effective concentrations, phenobarbital and benzodiazepines enhance the GABAerg inhibition by direct attachment to the GABA receptor chloride ionophore complex of the postsynaptic neuronal membrane. In addition, phenobarbital produces a reduction of the postsynaptic effect of glutamic acid which is an excitatory neurotransmitter. In higher concentrations, barbiturates and benzodiazepines produce direct changes in ion conductivity, and this seems to be an important factor determining the sedative/hypnotic effects of these substances. Primidone seems to act mainly (in long-term treatment) via its active metabolite phenobarbital. Valproic acid will lead both to a stabilisation of the membranes and to an amplification of the GABAerg transmission; in this connection, both presynaptic and postsynaptic sites of action are discussed. On the other hand, ethosuximide, given in anticonvulsively effective concentrations, does not affect membrane excitability and synaptic transmission. It can be expected that clarification of the mechanisms of action of clinically effective antiepileptics results in a stricter on-target search for new active substances.     

Restless legs syndrome and periodic limb movements in sleep: pathophysiology and treatment

The paper presents current views on the pathophysiology and treatment options in the restless legs syndrome (RLS) and periodic limb movements in sleep (PLMS). Moreover, concepts are outlined concerning possible involvement of various cerebral structures as well as neurotransmitter and metabolic systems in the RLS pathophysiology, with the focus on the role of dopamine and iron deficiency. Dopaminergic agents (i.e. L-dopa and dopamine agonists), currently regarded as the best therapeutic option in the treatment of RLS, are discussed in detail. Favorable outcomes attained in the treatment of RLS with the opioid receptor agonists, anticonvulsants, benzodiazepines, and adrenolytic agents are also reported.     

Genetic and neurobiological aspects of attention deficit hyperactive disorder: a review.

This paper reviews key studies that have addressed genetic and neurobiological aspects in attention deficit hyperactive disorder. Genetic studies can be divided into three distinct types: twin, adoption, and family studies. Evidence for a particular mode of inheritance and the possible specific genetic abnormalities are also explored. There is strong evidence of genetic involvement in this condition, although a clear-cut mode of inheritance and specific genetic abnormalities are yet to be determined. Neurobiological aspects such as the neuroanatomical and neurochemical evidence of various neurotransmitter system involvement is explored. Frontal lobe and dopamine and norepinephrine neurotransmitter systems appear to be involved in attention deficit hyperactive disorder.     

Cholinergic mechanisms in schizophrenia: Current concepts

Although the neurotransmitter dopamine plays a prominent role in the treatment of schizophrenia, the dopamine hypothesis fails to explain several aspects of the disorder. It is evident that the pathophysiology of schizophrenia involves other neurotransmitter systems as well. In this review, we discuss the increasing data implicating the cholinergic system in its pathogenesis. Cholinergic neurotransmission plays a crucial role in various central nervous system functions. The cholinergic system consists of two families of receptors, the muscarinic cholinergic and the nicotinic cholinergic, that use acetylcholine as a neurotransmitter. Data from clinical pharmacology, neuroimaging, and postmortem studies suggest an alteration of the muscarinic cholinergic system in schizophrenia. Muscarinic agonists are being evaluated as new treatment options with putative antipsychotic and cognition enhancing properties. Smoking is highly prevalent among schizophrenic subjects. Nicotine improves attention in schizophrenia. Nicotinic receptors, in particular the α7 nicotinic receptor, are candidates for the development of new medications to treat cognitive and perceptual deficits in schizophrenia. This review summarizes the evidence in support of a role for the muscarinic cholinergic system and the nicotinic cholinergic system in the pathophysiology of schizophrenia. As current treatments fail to sufficiently address all aspects of schizophrenia, promising new pharmacologic approaches that focus on the cholinergic system are currently under development.     

Insights into the structure and function of GABA-benzodiazepine receptors: ion channels and psychiatry.

OBJECTIVE: As a result of combined biophysical and molecular biological studies, important insights into the structure and function of gamma-aminobutyric acid (GABA) receptors have been achieved. These insights have helped to define the role of GABA receptors in synaptic inhibition and the ion channel mechanisms by which different neuropsychiatric drugs work. The authors' goal is to describe the actions of GABA as a neurotransmitter and discuss the modulation of receptor function by different drugs. DATA COLLECTION: The authors focus on more recent studies of the structure and physiology of the receptor-ion channel complex and the relevance of these studies to psychiatry. FINDINGS: The CNS effects of benzodiazepines, barbiturates, and alcohol have been linked to the GABA-chloride channel receptor complex. Multiple subunits of this complex have been cloned, sequenced, and expressed in heterologous systems. The results of cloning studies, coupled with membrane biophysics, have provided important insights into the structure and function of GABA receptors and their modulation by psychopharmacological agents. CONCLUSIONS: Future understanding of disease states, drug effects, and therapeutic successes and failures may be expressed in terms of differences in the structure and function of specific receptors and their associated ion channels. Furthermore, the ability to describe the molecular function of receptor subtypes offers the ability to tailor drug specificity by developing agents directed against a given receptor subtype. The current GABA studies also have important implications for the understanding of how neurotransmitter systems may be involved in illness.     

Timing, space and ADHD: the dopamine theory revisited

OBJECTIVE: The objective of this study was to review the dopamine theory of attention deficit hyperactivity disorder (ADHD) in terms of advances made over the last decade. METHOD: 'Hyper' and 'hypo' dopaminergic theories are discussed, as well as noradrenergic and neuropsychological findings in ADHD. A model incorporating both anterior and posterior attention systems, involved in orienting, inhibition, vigilance and working memory, is described. Neuropsychological studies of covert orienting are reviewed. RESULTS: The dopamine theory is supported by neuroimaging, genetic and stimulant medication studies, which confirm an inhibitory dopaminergic effect at striatal/prefrontal level. Work in rodents and primates, as well as humans has shown that noradrenergic systems are also important in prefrontal regulation, in particular alpha(2A) noradrenergic agonists have a beneficial effect on cognitive tasks. Neuropsychological studies implicate posterior parietal mechanisms in the orienting of attention. Working memory may require integration of spatial and temporal information, involving anterior and posterior systems. CONCLUSIONS: Anterior and posterior attention systems are involved in inhibition, working memory and orientation. Attention deficit hyperactivity disorder symptoms and subtypes are likely to reflect deficits in both inhibition and working memory, and may be heterogeneous. While the dopamine theory is supported by genetic and stimulant medication studies, the work of Arnsten and colleagues suggests a potential role for alpha(2) noradrenergic agonists such as guanfacine.     

An empirical analysis of two forms of extinction to treat aggression.

We compared the effectiveness of two extinction interventions, extinction by omission and noncontingent delivery of reinforcement, to treat aggressive behavior with a 10-year-old boy. Before the intervention, a functional analysis revealed that aggression was maintained by positive reinforcement in the form of attention. The extinction by omission intervention consisted of ignoring aggressive behavior. Noncontingent reinforcement involved delivering attention to the boy on a fixed-time schedule. Both treatments were compared using a multielement research design. Noncontingent reinforcement produced a more rapid elimination of aggression. Additionally, the schedule of noncontingent reinforcement was gradually thinned during the intervention. Finally, both parents successfully implemented the noncontingent schedule of reinforcement independently for up to 5 weeks after treatment.     

Dopamine: 50 years in perspective

The discovery of dopamine as a neurotransmitter in brain by Arvid Carlsson approximately 50 years ago, and the subsequent insight provided by Paul Greengard into the cellular signalling mechanisms triggered by dopamine, gained these researchers the Nobel Prize for Medicine in 2000. Dopamine research has had a greater impact on the development of biological psychiatry and psychopharmacology than work on any other neurotransmitter. Neuropsychological views of the role of dopamine in the CNS have evolved from that of a simple reward signal to a more complex situation in which dopamine encodes the importance or 'salience' of events in the external world. Hypofunctional dopamine states underlie Parkinson's disease and attention deficit hyperactivity disorder, and there is increasing evidence for dopamine hyperactivity in schizophrenia. Some of the medicines that are most widely used in psychiatry, such as L-DOPA, methylphenidate and neuroleptic drugs, act on dopaminergic mechanisms.     

The neurotensin receptor agonist NT69L suppresses sucrose-reinforced operant behavior in the rat

NT69L is a neurotensin analog that can be administered peripherally. It blocks amphetamine- and cocaine-induced hyperactivity in rats. It also blocks nicotine-induced locomotor activity and has shown sustained efficacy in a rat model of nicotine-induced sensitization. The present study tested the effect of NT69L on responding for sucrose reinforcement on a continuous reinforcement schedule (CRF) and incrementing (FR1-FR5) discrimination schedule. Male Sprague-Dawley rats, on restricted food intake, were trained to press a lever for sucrose pellets on a CRF and incrementing discrimination schedule of reinforcement. On the following day, the testing session was followed by an extinction session, where lever pressing was not reinforced. Immediately after extinction, a reversal to CRF was implemented to test for relapse. Trained rats were injected with NT69L (1 mg/kg) or saline 30 min before each testing session. Dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels were determined. NT69L significantly suppressed the lever pressing behavior for sucrose reinforcement on CRF which measures the "hedonic" value of the reward. NT69L also suppressed sucrose self-administration on the incrementing discrimination schedule of reinforcement (FR3-FR5) that is analogous to the motivational incentive. Reversal to CRF was significantly reduced by pretreatment with NT69L. The suppression of sucrose self-administration behavior by pretreatment with NT69L had a pattern similar to that for extinction. The effect of NT69L on dopamine, tyrosine 3-hydroxylase, and dopamine receptor mRNA levels is discussed relative to changes occurring during extinction.     

Bedeutung von Lernen und Gedächtnis in der Pathogenese von Suchterkrankungen

The persistance of addiction-associated cognitions and behavior is caused, in least part, by long-lasting drug-associated memories. Relapses, triggered by exposure to drug-associated cues, contribute considerably to the maintenance of addiction and are, even after drug-free periods for years, a major challenge in the treatment of addiction. An important advance in understanding the underlying pathophysiology derives from recent research results showing similarities between the process of drug addiction and physiological neural plasticity in learning and memory. In the focus of attention are basic mechanisms involving dopamine, glutamate, and their cellular and molecular targets leading to drug-induced synaptic alterations in the mesolimbic reward system. There is growing evidence from preclinical and clinical studies that specific treatments such as extinction training and cue-exposure therapy are effective. The challenge of future research is to determine which drug-induced adaptations are relevant to the pathophysiology of addiction and to generate more efficient therapies for extinction of addiction-associated cognitions and behavior.     

The role of gamma-aminobutyric acid in the mechanism of action of anticonvulsant drugs

Decreased activity of gamma-aminobutyric acid, the major inhibitory neurotransmitter in CNS can be epileptogenic. Manipulation of the GABA system has been a target for development of antiepileptic drugs. The different ways for augmenting gabaergic inhibition by conventional and new AEDs are presented in this paper. Among the I generation, barbiturates and benzodiazepines are potent anticonvulsants that act as GABA modulators in postsynaptic GABA-A receptor complex but their usefulness is limited by dependence and tolerance to antiseizure activity. The II generation drugs vigabatrin and tiagabine, and to some extent gabapentin have been developed by a rationale strategy and none of them exert direct action in GABA receptors. Only two former drugs exhibit selective, strictly defined activity: vigabatrine is an irreversible inhibitor of GABA-aminotransferase and tiagabine acts as a GABA-uptake inhibitor from synaptic cleft into neurons and glia. Gabapentin binds to a novel receptors in epileptogenic areas in CNS and enhances GABA turnover. Drugs with multiple mechanisms of action, felbamate and topiramate not only potentiate gabaergic inhibition in several ways but also diminish the activity of excitatory amino acids at their NMDA or AMPA receptors; the later mechanism seems to be essential for their potential neuroprotective activity in epileptogenesis. None of gabamimetic drugs provide optimal seizure control but better tolerability of newer ones and well-established mechanisms of action provide possible harmless therapy.     

The effect of early‐life stress on memory systems supporting instrumental behavior

People experiencing early‐life stress (ELS) exhibit increased incidence of behaviors that lead to addiction and obesity as adults. Many of these behaviors may be viewed as resulting from an overreliance on habits as opposed to goal‐directed instrumental behavior. This increased habitization may result from alterations in the interactions between dorsolateral striatum‐dependent and hippocampus‐dependent learning systems. As an initial examination of this idea, we investigated the effect of ELS on instrumental learning and extinction. In Experiment 1, we examined the effect of ELS in two groups of people, one trained on a continuous reinforcement schedule and one trained on a partial reinforcement schedule. We found that people who experienced ELS had a diminished effect of the partial reinforcement schedule on extinction. In Experiment 2, we again manipulated reinforcement schedule and also challenged declarative memory by requiring subjects to perform a concurrent task. We found that the declarative challenge did not affect extinction responding in the non‐ELS group. In a moderate‐ELS group, we observed a diminished sensitivity to the reinforcement schedule during extinction only under divided attention. In the high‐ELS group, we observed a reduced sensitivity to reinforcement schedule even in the absence of the declarative memory challenge, consistent with Experiment 1. Our results suggest that ELS reduces the tendency to use declarative, hippocampus‐dependent memory in instrumental tasks in favor of habits. ELS may affect hippocampal development, thus altering the interaction between memory systems and potentially contributing to poor health outcomes. © 2013 Wiley Periodicals, Inc.     

Comparison of the effects of cocaine and other inhibitors of dopamine uptake in rat striatum, nucleus accumbens, olfactory tubercle, and medial prefrontal cortex

It is thought that inhibition of dopamine reuptake into neurons may play a major role in the mechanisms by which cocaine produces its reinforcing effects. The striatum, while rich in dopamine terminals, is not implicated in drug reinforcement, whereas the mesolimbic dopamine pathway appears to play a primary role. It is therefore possible that the properties and drug sensitivities of the dopamine uptake systems in the nigrostriatal, mesolimbic, and mesocortical tracts differ. The effects of cocaine, GBR 12909, amfonelic acid, and methylphenidate on dopamine uptake in the striatum, nucleus accumbens, olfactory tubercle, and medial prefrontal cortex were examined. Over 80% of the dopamine uptake in each of the 4 regions was sodium-dependent and exhibited K_m values of approximately 100 nM. Cocaine, GBR 12909, amfonelic acid, and methylphenidate each biphasically inhibited uptake in the striatum, nucleus accumbens and olfactory tubercle with GBR 12909 and amfonelic acid being approximately 50-fold more potent than cocaine or methylphenidate. In the medial prefrontal cortex, cocaine and GBR 12909 could inhibit only about 40% of the [³H]dopamine uptake. There are similarities in the properties and drug sensitivities of the dopamine uptake systems in brain areas which are implicated in drug reinforcement and those which are not.     

CNS depressant effects of volatile organic solvents

Volatile chemicals used widely as solvents can produce acute effects on the nervous system and behavior after inhalation exposure, and many are subject to abuse. This review considers the nature of the acute effects of volatile organic solvents by comparing their actions to those of classical CNS depressant drugs such as the barbiturates, benzodiazepines and ethanol. Like CNS depressant drugs, selected inhalants have been shown to have biphasic effects on motor activity, disrupt psychomotor performance, have anticonvulsant effects, produce biphasic drug-like effects on rates of schedule-controlled operant behavior, increase rates of punished responding, enhance the effects of depressant drugs, serve as reinforcers in self-administration studies and share discriminative stimulus effects with barbiturates and ethanol. Toluene and 1,1,1-trichloroethane, as well as subanesthetic concentrations of halothane, have been the most extensively studied; however, it is unclear whether important differences may exist among solvents in their ability to produce a depressant profile of acute effects. The possibility that selected solvents can have acute effects similar to those of depressant drugs may shed light on the nature of their acute behavioral toxicology and on their abuse.     

Nigrostriatal collaterals to thalamus degenerate in parkinsonian animal models

Movement, cognition, emotion, and positive reinforcement are influenced by mesostriatal, mesocortical, and mesolimbic dopamine systems. We describe a fourth major pathway originating from mesencephalic dopamine neurons: a mesothalamic system. The dopamine transporter, specific to dopamine containing axons, was histochemically visualized in thalamic motor and limbic-related nuclei and regions that modulate behavioral state as opposed to sensory nuclei in rats, nonhuman primates, and humans. Anatomical tracing established this innervation's origin via axon collaterals from the mesostriatal pathway. These findings implicate the thalamus as a novel site for disease specific alterations in dopamine neurotransmission, such as exist with nigral degeneration attending Parkinson's disease. This was confirmed in hemiparkinsonian animals where reduction of thalamic dopamine innervation occurred coincident with signs of active axonal degeneration. Individual mesencephalic dopamine neurons therefore have the potential to modulate normal and pathologic behavior not only through traditional nigrostriatal pathways but also by way of axon collaterals that innervate the thalamus.     

Attention-deficit/hyperactivity disorder (ADHD) behaviour explained by dysfunctioning reinforcement and extinction processes

Inattentiveness, overactivity and impulsiveness are presently regarded as the main clinical symptoms of attention-deficit/hyperactivity disorder (ADHD). Inattention is, however, a characteristic of most psychiatric disorders. It is argued that the ADHD Inattentive subtype may have heterogeneous origins and be qualitatively different from the ADHD Hyperactive/Impulsive subtype. At the neurobiological level, ADHD symptoms may to a large extent be caused by a dysfunctioning dopamine system: A dysfunctioning meso-limbo-cortical dopamine branch will produce altered reinforcement and extinction processes, on a behavioural level giving rise to deficient sustained attention, hyperactivity, motor and cognitive impulsiveness. A dysfunctioning nigro-striatal dopamine branch will cause ‘extrapyramidal’ symptoms. Our model disentangles the behaviours usually explained by ‘executive functions’ into cognitive impulsiveness, motor impulsiveness and deficient motor control. The various dopaminergic branches may not be equally dysfunctional in all individuals with ADHD. Etiologically, dopamine dysfunctioning will probably mainly be genetically determined while sometimes be induced by environmental factors like drugs of abuse or pollutants, which may explain geographical differences in prevalence rates.     

Gabaergic mechanisms and anxiety: an overview and a new neurophysiological model

GABA is one of the principal inhibitory neurotransmitters in the mammalian brain and an ever increasing wealth of information suggests that GABAergic mechanisms have a special role in the neurophysiology of anxiety. All of the most commonly used antianxiety drugs (the benzodiazepines, the barbiturates, ethanol) selectively enhance only GABA-mediated synaptic transmission. Furthermore, the relative affinities of pharmacologically active benzodiazepines for the benzodiazepine receptor correlate well with their ability to antagonize GABA-modulin (the endogenous inhibitor of GABA receptors) in vitro, as well as with their ability to potentiate GABA-mediated electrically evoked cortical inhibition in vivo. Finally, it is of interest for the neurophysiology of anxiety that repetitive stimulation of the recurrent inhibitory GABAergic pathway in the rat hippocampus leads to a remarkable reduction of the effectiveness of GABA; this elimination of GABAergic "inhibition" is counteracted by antianxiety drugs. On the basis of the above a neurophysiological model of anxiety is proposed.