Inhibition of metabolism of beta-alanine and D-beta-aminoisobutyric acid by D-cycloserine.

Significant increases in the concentrations of β-aminoisobutyric acid and β-alanine in the urine of patients under D-cycloserine treatment for tuberculosis were found during a study of biochemical changes caused by surgical operation. β-Alanine increased in all cases on the administration of cycloserine at a clinical dose. β-Aminoisobutyric acid excretion was increased by cycloserine treatment only in the genetic low excretors of this amino acid, but not in the high excretors who lack the degradative enzyme, D-β-aminoisobutyrate:pyruvate aminotransferase. Injection of cycloserine increased the concentrations of the amino acids in the liver of rats, and inhibited strongly D-β-aminoisobutyrate: pyruvate and β-alanine:α-ketoglutarate aminotransferases. The increase in the amino acids and the enzyme inhibition occurred after D-cycloserine disappeared from the liver. The inhibition was not caused by D-cycloserine itself, but by its metabolite, D-aminoxyalanine, which was isolated and identified from urine of rats after injection of D-cycloserine. The toxicity of D-aminoxyalanine was also determined using mice, and the relation with clinical toxic effects of D-cycloserine is discussed.     

Homer isoforms differentially regulate cocaine-induced neuroplasticity.

Homer proteins modulate neuroplasticity in excitatory synapses and are dynamically regulated by cocaine. Whereas acute cocaine elevates immediate-early gene (short) isoforms of Homer1 in the nucleus accumbens, withdrawal from repeated cocaine administration downregulates the expression of constitutive Homer1 isoforms. The present study determined whether or not this downregulation in constitutive Homer expression in the accumbens is necessary for enduring alterations in cocaine-induced changes in the brain and behavior. The long vs short Homer isoforms were overexpressed in the rat nucleus accumbens during drug abstinence, and the adaptations elicited by repeated cocaine on glutamate transmission and motor behavior were measured. It was found that both chronic and acute overexpression of constitutive, but not short, Homer isoforms abolished cocaine-induced sensitization of locomotor hyperactivity and prevented the development of glutamate abnormalities in the accumbens, including the reduction in basal extracellular glutamate content and the sensitized glutamate response to a subsequent cocaine challenge injection. Together, these data indicate that the enduring reduction of long Homer isoforms in the nucleus accumbens of cocaine-withdrawn rats is necessary for the expression of cocaine-induced neuroplasticity.     

Modulation of human motor cortex excitability by single doses of amantadine.

Amantadine-sulfate has been used for several decades to treat acute influenza A, Parkinson's disease (PD), and acute or chronic drug-induced dyskinesia. Several mechanisms of actions detected in vivo/in vitro including N-methyl-D-aspartate (NMDA)-receptor antagonism, blockage of potassium channels, dopamine receptor agonism, enhancement of noradrenergic release, and anticholinergic effects have been described. We used transcranial magnetic stimulation (TMS) to evaluate the effect of single doses of amantadine on human motor cortex excitability in normal subjects. Using a double-blind, placebo-controlled, crossover study design, motor thresholds, recruitment curves, cortical stimulation-induced silent period (CSP), short intracortical inhibition (ICI), intracortical facilitation (ICF), and late inhibition (L-ICI) in 14 healthy subjects were investigated after oral doses of 50 and 100 mg amantadine with single and paired pulse TMS paradigms. Spinal cord excitability was investigated by distal latencies and M-amplitudes of the abductor digiti minimi muscle. After intake of amantadine, a significant dose-dependent decrease of ICF was noticed as well as a significant increase of L-ICI as compared to placebo. The effect on ICF and L-ICI significantly correlated with amantadine serum levels. ICI was slightly increased after amantadine intake, but the effect failed to be significant. Furthermore, amantadine had no significant effects on motor thresholds, MEP recruitment curves, CSP, or peripheral excitability. In conclusion, a low dose of amantadine is sufficient in modulating human motor cortex excitability. The decrease of ICF and increase of L-ICI may reflect glutamatergic modulation or a polysynaptic interaction of glutamatergic and GABA-ergic circuits. Although amantadine has several mechanisms of action, the NMDA-receptor antagonism seems to be the most relevant effect on cortical excitability. As L-ICI can be influenced by this type of drug, it may be an interesting parameter for studies of motor learning and use-dependent plasticity.     

Drug addiction as a pathology of staged neuroplasticity.

Using addictive drugs can evolve from controlled social use into the compulsive relapsing disorder that characterizes addiction. This transition to addiction results from genetic, developmental, and sociological vulnerabilities, combined with pharmacologically induced plasticity in brain circuitry that strengthens learned drug-associated behaviors at the expense of adaptive responding for natural rewards. Advances over the last decade have identified the brain circuits most vulnerable to drug-induced changes, as well as many associated molecular and morphological underpinnings. This growing knowledge has contributed to an expanded understanding of how drugs usurp normal learning circuitry to create the pathology of addiction, as evidenced by involuntary activation of reward circuits in response to drug-associated cues and simultaneous reports of drug craving. This new understanding provides unprecedented potential opportunities for novel pharmacotherapeutic targets in treating addiction. There appears to be plasticity associated with the addiction phenomenon in general as well as changes produced by addiction to a specific class of addicting drugs. These findings also provide the basis for the current understanding of addiction as a chronic, relapsing disease of the brain with changes that persist long after the last use of the drug. Here, we describe the neuroplasticity in brain circuits and cell function induced by addictive drugs that is thought to underlie the compulsions to resume drug-taking, and discuss how this knowledge is impelling exploration and testing of novel addiction therapies.     

D-cycloserine transport in human intestinal epithelial (Caco-2) cells: mediation by a H(+)-coupled amino acid transporter.

1. The ability of D-cycloserine to act as a substrate for H+/amino acid symport has been tested in epithelial layers of Caco-2 human intestinal cells. 2. In Na(+)-free media with the apical bathing media held at pH 6.0, D-cycloserine (20 mM) is an effective inhibitor of net transepithelial transport (Jnet) of L-alanine (100 microM) and its accumulation (across the apical membrane) in a similar manner to amino acid substrates (L-alanine, beta-alanine, L-proline and glycine). In contrast L-valine was ineffective as an inhibitor for H+/amino acid symport. Both inhibition of L-alanine Jnet and its accumulation by D-cycloserine were dose-dependent, maximal inhibition being achieved by 5-10 mM. 3. Both D-cycloserine and known substrates for H+/amino acid symport stimulated an inward short circuit current (Isc) when voltage-clamped monolayers of Caco-2 epithelia, mounted in Ussing chambers, were exposed to apical substrate in Na(+)-free media, with apical pH held at 6.0. The D-cycloserine dependent increase in Isc was dose-dependent with an apparent Km = 15.8 +/- 2.0 (mean +/- s.e. mean) mM, and Vmax = 373 +/- 21 nmol cm-2h-1. 4. D-Cycloserine (20 mM) induced a prompt acidification of Caco-2 cell cytosol when superfused at the apical surface in both Na+ and Na(+)-free conditions. Cytosolic acidification in response to D-cycloserine was dependent upon superfusate pH, being attenuated at pH 8 and enhanced in acidic media. 5. The increment in Isc with 20 mM D-cycloserine was non-additive with other amino acid substrates for H+/amino acid symport.     

Modulation of human motor cortex excitability by valproate

Rationale  

Valproate is widely used in the treatment of epilepsy, bipolar disorder, and chronic pain disorders, but its exact mechanisms of action is still incompletely understood.     

Modulation of human motor cortex excitability by quetiapine

RATIONALE: Quetiapine is increasingly used for the treatment of patients with psychosis and bipolar disorder. However, the neurobiological mechanisms, which may account for the favourable risk/benefit profile of this drug, are not entirely understood. OBJECTIVES: Transcranial magnetic stimulation was used to investigate the effects of acute and repeated administration of quetiapine on cortical excitability in healthy volunteers. MATERIALS AND METHODS: Within a double-blind, placebo-controlled, randomized cross-over design motor threshold, intracortical inhibition, intracortical facilitation and cortical silent period were studied in 15 healthy volunteers before and after a single dose of placebo and 100 mg quetiapine. Additional measurements were performed after 5 days of daily intake of 100 mg quetiapine. RESULTS: We observed a significant prolongation of the cortical silent period after a single dose of quetiapine, whereas the placebo had no effects. After repeated administration, there was a trend towards CSP prolongation, which did not reach significance. However, plasma concentrations at this time point were relatively low, as measurements were performed 15 h after the last drug intake. Other parameters of cortical excitability remained unaffected. CONCLUSIONS: By lengthening CSP without affecting MT, ICI and ICF, quetiapine demonstrates a unique neurophysiological profile which differs distinctively from brain excitability profiles of typical antipsychotics such as haloperidol. Provided that the CSP prolongation reflects the antipsychotic potential of quetiapine, TMS may be developed as a tool to monitor neurobiological effects of quetiapine treatment in schizophrenic patients and to explore the efficacy of other antipsychotic drugs with a similar mode of action.     

D-cycloserine Deters Reacquisition of Cocaine Self-Administration by Augmenting Extinction Learning

Augmentation of cue exposure (extinction) therapy with cognitive-enhancing pharmacotherapy may offer an effective strategy to combat cocaine relapse. To investigate this possibility at the preclinical level, rats and squirrel monkeys were trained to self-administer cocaine paired with a brief visual cue. Lever pressing was subsequently extinguished by withholding cocaine injections while maintaining response-contingent presentations of the cue. The glycine partial agonist D-cycloserine (DCS; 15 and 30 mg/kg in rats, 3 and 10 mg/kg in monkeys) was evaluated for its effects on the rate of extinction and subsequent reacquisition of cocaine self-administration. Compared with vehicle, pretreatment with 30 mg/kg DCS 0.5 h before extinction training reduced the number of responses and latency to reach the extinction criterion in rats, but neither dose of DCS altered these measures in monkeys. In both species, pretreatment with the higher dose of DCS before extinction training significantly attenuated reacquisition of cocaine self-administration compared with either extinction training in the absence of DCS or DCS in the absence of explicit extinction. Furthermore, treatment with 30 mg/kg DCS accompanied by brief handling (a stress induction) immediately after but not 6 h after extinction training attenuated reacquisition of cocaine self-administration in rats. No adverse effects of 10 mg/kg DCS were evident in quantitative observational studies in monkeys. The results suggest that DCS augmented consolidation of extinction learning to deter reacquisition of cocaine self-administration in rats and monkeys. The results suggest that DCS combined with exposure therapy may constitute a rational strategy for the clinical management of cocaine relapse.     

Potentiating action of 4-vinylpyridoxal on inhibition of serine transhydroxymethylase by D-cycloserine and its dimer.

The cooperative inhibition of serine transhydroxymethylase (EC 2.1.2.1) in spleen tissue of mice after intraperitoneal injections of various vitamin B₆ antimetabolites was studied. The data obtained reveal that pyridoxal azine, when injected alone in a dose of 75 mg/kg of body weight, produced moderate inhibition of serine transhydroxymethylase, but, when injected in the same dose 1 hr prior to d-cycloserine (500 mg/kg of body weight) injection, exerted a slight potentiating effect on the enzyme inhibition produced by d- cycloserine. In similar experiments, pyridoxal monomethylhydrazone in a dose of 7.5 mg/kg of body weight did not inhibit the activity of serine transhydroxymethylase and did not produce a potentiating effect on inhibition of the enzyme by d-cycloserine. 4-Vinylpyridoxal (4-vinyl-4-deformylpyridoxal), injected into mice in a dose of 0.5 to 1.0 mg/kg of body weight, does not decrease the activity of serine transhydroxymethylase in spleen tissue, but when injected 1 hr prior to injective of d-cycloserine or its dimer, it potentiates (unlike pyridoxal monomethylhydrazone) the inhibitory effects of both d-cycloserine and its dimer, producing more extensive and more prolonged inhibition of the enzyme. If d-cycloserine or its dimer is injected into mice in doses of 500 mg/kg of body weight, the potentiating effect of 4-vinylpyridoxal approaches 200–250 per cent or more, depending on the time after the injection of the antimetabolite. Thus, it is of interest to study further the chemotherapeutic action of moderate doses of d-cycloserine or its dimer in combination with 4-vinylpyridoxal.     

Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycine receptor.

Glycine has been shown to modulate N-methyl-D-aspartate (NMDA) subclass of acidic amino acid receptors which have been implicated in learning and memory. We report that d-cycloserine (DCS) which has a high affinity for the glycine modulatory site in the NMDA receptor complex modulated memory processing in a dose-dependent manner. Mice were trained on a footshock avoidance task. Immediately after training DCS was administered (2.5 to 50 mg/kg s.c.). When retention was tested a week later, 20 mg/kg facilitated retention the best with lower and higher doses be less effective in weakly trained young mice. DCS also facilitated retention in 'senescence-accelerated mice' in which impairment of learning and memory increases with age. DCS had to be administered at higher doses to improve retention as impairment of learning and memory increased.     

RS 67333 and D-cycloserine accelerate learning acquisition in the rat.

Various 5-hydroxytryptamine (5-HT) central receptor subtypes have been implicated in cognitive performances. In the present investigation, we studied the effects of the selective 5-HT(4) receptor agonist RS 67333 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone; 1 mg/kg, i.p.) on spatial learning in the rat, and compared them to those of a reference drug, the partial NMDA receptor agonist D-cycloserine (10 mg/kg, i.p.). The effects of these two drugs were evaluated in four protocols which employed the Morris water maze task with various numbers of daily trials and inter-trial intervals (ITI; 4 trials with 30 s ITI; 2 trials with 2 h or 12 h ITI; or one daily trial). In the 2 trial-2 h ITI protocol, rats treated with RS 67333 or D-cycloserine exhibit a reduced mean swim distance during the first days of training when compared to controls. Neither RS 67333 nor D-cycloserine modified the acquisition performances in the 2 trial-12 h ITI or the one daily trial tests or the retention score measured in each protocol. These data suggest that RS 67333 and D-cycloserine can improve the learning rate in a high demand memory task and confirm that selective 5-HT(4) receptor ligands may provide novel approaches for the development of cognitive enhancers.     

Actions of D-cycloserine at the N-methyl-D-aspartate-associated glycine receptor site in vivo.

The antibiotic, D-cycloserine has been shown to be a partial agonist at the N-methyl-D-aspartate (NMDA)-coupled, strychnine-insensitive glycine receptor by in vitro receptor binding. This partial agonism was further investigated in an in vivo system, by monitoring changes in levels of cyclic guanosine-monophosphate (cGMP), a well characterized second messenger response, mediated by the NMDA receptor complex, in the cerebellum of the mouse. Parenteral injections of D-cycloserine produced a biphasic dose-response curve which suggested partial agonism. In support of this contention, when intracerebellar injections were made together with D-serine, a glycine agonist, D-cycloserine attenuated the N-methyl-D-aspartate receptor-mediated increase in levels of cGMP. Likewise, systemic administration of D-cycloserine attenuated increases in cGMP induced by pentylenetetrazol. These data are relevant to the study of N-methyl-D-aspartate-mediated neurotransmission, since D-cycloserine is a parenterally bioavailable compound, with both agonist and depressant properties at the N-methyl-D-aspartate-associated glycine receptor.     

Stress, depression, and neuroplasticity: a convergence of mechanisms.

Increasing evidence demonstrates that neuroplasticity, a fundamental mechanism of neuronal adaptation, is disrupted in mood disorders and in animal models of stress. Here we provide an overview of the evidence that chronic stress, which can precipitate or exacerbate depression, disrupts neuroplasticity, while antidepressant treatment produces opposing effects and can enhance neuroplasticity. We discuss neuroplasticity at different levels: structural plasticity (such as plastic changes in spine and dendrite morphology as well as adult neurogenesis), functional synaptic plasticity, and the molecular and cellular mechanisms accompanying such changes. Together, these studies elucidate mechanisms that may contribute to the pathophysiology of depression. Greater appreciation of the convergence of mechanisms between stress, depression, and neuroplasticity is likely to lead to the identification of novel targets for more efficacious treatments.     

Augmentation treatment of psychotherapy for anxiety disorders with D-cycloserine

Anxiety disorders are among the most common mental disorders. One of the most effective strategies to treat anxiety disorders is exposure therapy with or without cognitive intervention. Fear reduction in exposure therapy is similar to extinction learning. Preclinical studies suggest that extinction learning can be blocked by antagonists at the glutamatergic N-methyl-D-aspartate (NMDA) receptor, and facilitated with D-cycloserine (DCS), a partial agonist at the glycine recognition site of the NMDA receptor in the amygdala. DCS is an established antibiotic drug for the chronic treatment of tuberculosis in humans, but has only recently been investigated as an augmentation therapy for psychological treatment procedures. The review of the literature provides preliminary support for the use of acute dosing of DCS as an adjunctive intervention to exposure therapy for anxiety disorders, including specific phobia and social anxiety disorder. Negative results have recently been reported in the treatment of subclinical fears of animals. These studies suggest that DCS needs to be administered on an acute rather than a chronic dosing schedule, include sufficient time for memory consolidation, and be administered together with psychological treatment that leaves sufficient room for further improvement. It remains to be seen whether these highly promising findings represent reliable pharmacological strategies to enhance exposure therapy of anxiety disorders.