Biomedical subjects

D Cyril D'Souza

Publications and source records attributed to D Cyril D'Souza.

9 recordsLinked to original sources

PubMed2006

The vulnerability to alcohol and substance abuse in individuals diagnosed with schizophrenia.

Individuals with schizophrenia are at increased risk for developing substance abuse disorders. Here, we consider factors that might elevate their risk for substance abuse. The tendency among schizophrenic individuals to overvalue drug-like rewards and to devalue the potential negative consequences of substance abuse may be a contributing factor to their substance abuse risk. This bias, which may partly reflect the convergence of glutamatergic and dopaminergic input to the limbic striatum, also may contribute to disadvantageous decision-making and other impulsive behavior. This propensity to seek drug-like rewards is augmented by alterations in nicotinic cholinergic, GABAergic, glutamatergic, and cannabinnoid receptor function associated with schizophrenia that increase the abuse liability of low doses of nicotine, ethanol, and perhaps cannabis, and augment the dysphoric effects of higher doses of ethanol and cannabis. The distortions in reward processing and altered response to substances of abuse also increase the likelihood that individuals with schizophrenia will self-medicate their subjective distress with abused substances. The focus on distinctions between motivation and reward with respect to substance abuse risk by schizophrenic patients suggests a need for a reconsideration of the construct of "negative symptoms" for this dually-diagnosed patient group.

Alcoholism↗

PubMed2005

Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function.

BACKGROUND: In healthy individuals, ketamine hydrochloride and amphetamine sulfate produce cognitive, behavioral, and subjective effects resembling endogenous psychoses. Studying the comparative and interactive effects of these agents may provide insights into the roles of the glutamate and monoamine systems in psychosis and cognition. OBJECTIVES: To directly compare the effects of ketamine and amphetamine and to explore their interactive effects within individuals. DESIGN: Placebo-controlled, randomized, double-blind psychopharmacologic trial. SETTING AND PARTICIPANTS: Forty-one healthy individuals recruited from the community who completed up to 4 test days. MAIN OUTCOME MEASURES: On each test day, participants received amphetamine (a 1-minute infusion of amphetamine sulfate, 0.25 mg/kg, or saline) and ketamine (a 1-minute intravenous infusion of ketamine, 0.23 mg/kg, followed by a 1-hour infusion of 0.5 mg/kg or an identical saline bolus and infusion). The order of amphetamine and ketamine infusions was randomized. RESULTS: At the doses studied, ketamine and amphetamine produced positive symptoms and euphoria. However, perceptual changes were produced only by ketamine, and hostility, grandiosity, and somatic concern were stimulated only by amphetamine. Amphetamine and ketamine produced conceptual disorganization, but only ketamine produced concrete ideation and unusual mannerisms. Ketamine produced negative symptoms and disrupted delayed recall. Ketamine and amphetamine showed 3 types of interactive effects: (1) amphetamine attenuated the impairment of working memory produced by ketamine; (2) amphetamine and ketamine had additive effects on thought disorder, arousal, and euphoria; and (3) amphetamine and ketamine had less-than-additive effects on psychosis. CONCLUSIONS: These findings implicate N-methyl-D-aspartate glutamate receptors and dopamine systems in psychosis. However, glutamate and dopamine may differentially contribute to psychosis, thought disorder, and euphoria. Regarding medication development for cognitive dysfunction, the pattern of the interactive effects of ketamine and amphetamine is consistent with the hypothesis that facilitation of prefrontal cortical dopamine levels would attenuate some cognitive impairments associated with deficits in N-methyl-D-aspartate receptor function.

Amphetamine↗

PubMed2004

Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects.

RATIONALE: Some of the behavioral consequences of deficits in N-methyl-D-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry. OBJECTIVE: This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects. METHODS: Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions. RESULTS: Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion. CONCLUSIONS: These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.

Adult↗

PubMed2004

Nicotine effects on brain function and functional connectivity in schizophrenia.

BACKGROUND: Nicotine in tobacco smoke can improve functioning in multiple cognitive domains. High rates of smoking among schizophrenic patients may reflect an effort to remediate cognitive dysfunction. Our primary aim was to determine whether nicotine improves cognitive function by facilitating activation of brain regions mediating task performance or by facilitating functional connectivity. METHODS: Thirteen smokers with schizophrenia and 13 smokers with no mental illness were withdrawn from tobacco and underwent functional magnetic resonance imaging (fMRI) scanning twice, once after placement of a placebo patch and once after placement of a nicotine patch. During scanning, subjects performed an n-back task with two levels of working memory load and of selective attention load. RESULTS: During the most difficult (dichotic 2-back) task condition, nicotine improved performance of schizophrenic subjects and worsened performance of control subjects. Nicotine also enhanced activation of a network of regions, including anterior cingulate cortex and bilateral thalamus, and modulated thalamocortical functional connectivity to a greater degree in schizophrenic than in control subjects during dichotic 2-back task performance. CONCLUSIONS: In tasks that tax working memory and selective attention, nicotine may improve performance in schizophrenia patients by enhancing activation of and functional connectivity between brain regions that mediate task performance.

Adult↗

PubMed2003

NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development.

There is an urgent need to improve the pharmacotherapy of schizophrenia despite the introduction of important new medications. New treatment insights may come from appreciating the therapeutic implications of model psychoses. In particular, basic and clinical studies have employed the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, as a probe of NMDA receptor contributions to cognition and behavior. These studies illustrate a translational neuroscience approach for probing mechanistic hypotheses related to the neurobiology and treatment of schizophrenia and other disorders. Two particular pathophysiologic themes associated with schizophrenia, the disturbance of cortical connectivity and the disinhibition of glutamatergic activity may be modeled by the administration of NMDA receptor antagonists. The purpose of this review is to consider the possibility that agents that attenuate these two components of NMDA receptor antagonist response may play complementary roles in the treatment of schizophrenia.

Animals↗

PubMed2003

N-methyl-D-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability.

This review takes a translational neuroscience perspective on the role of glutamate systems in human ethanol abuse and dependence. Ethanol is a simple molecule with profound effects on many chemical systems in the brain. Glutamate is the primary excitatory neurotransmitter in the brain. Glutamatergic systems are targets for the actions of ethanol via its antagonism of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor and other mechanisms. The modulation of glutamatergic function by ethanol contributes to both euphoric and dysphoric consequences of ethanol intoxication. Adaptations within glutamatergic systems appear to contribute to ethanol tolerance and dependence and to both acute and protracted features of ethanol withdrawal. Perhaps because of the important glutamatergic mediation of the behavioral effects of ethanol, glutamatergic systems appear to contribute to the vulnerability to alcoholism, and novel glutamatergic agents may play a role in the treatment of ethanol abuse and dependence.

Alcohol Drinking↗

PubMed2003

Altered NMDA glutamate receptor antagonist response in recovering ethanol-dependent patients.

Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine. In this double-blind study, 34 recently detoxified alcohol-dependent patients and 26 healthy comparison subjects completed 3 test days involving a 40-min infusion of saline, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg in a randomized order. Recovering ethanol-dependent patients showed reduced perceptual alterations, dysphoric mood, and impairments in executive cognitive functions during ketamine infusion relative to the healthy comparison group. No attenuation of ketamine-induced amnestic effects, euphoria, or activation was observed. The alterations in NMDA receptor function observed in recovering ethanol-dependent patients may have important implications for ethanol tolerance, ethanol dependence, and the treatment of alcoholism.

Adult↗

PubMed2003

NMDA receptor antagonism and the ethanol intoxication signal: from alcoholism risk to pharmacotherapy.

This paper reviews clinical evidence suggesting that antagonism of the N-methyl-D-aspartate subtype of glutamate receptors by ethanol may convey an important component of the ethanol intoxication signal, that is, subjective and objective responses associated with the consumption of a large amount of ethanol. It will then review recent evidence that two phenotypes associated with increased risk for heavy alcohol consumption, recovering ethanol-dependent patients, and healthy individuals with a family history of alcohol dependence, exhibit reduced sensitivity to the dysphoric consequences of administration of the NMDA receptor antagonist, ketamine. Each of these groups displays reduced sensitivity to a potentially important response that might normally trigger the cessation of ethanol consumption. These data raise the possibility that alterations in NMDA receptor function that reduce the response to the NMDA antagonist component of ethanol may increase the risk for heavy drinking. This hypothesis is consistent with growing evidence that NMDA receptor antagonists may play a role in the treatment of alcoholism by suppressing alcohol withdrawal, reducing the development or expression of alcohol tolerance, or preventing or reversing the sensitiziation to ethanol effects.

Alcoholic Intoxication↗

PubMed2002

Ritanserin antagonism of m-chlorophenylpiperazine effects in neuroleptic-free schizophrenics patients: support for serotonin-2 receptor modulation of schizophrenia symptoms.

RATIONALE: Serotonin-2 (5-HT(2)) receptor antagonism has been hypothesized to have antipsychotic activity. However, there has been limited evidence directly linking 5-HT(2) receptor antagonism to symptom control in schizophrenic patients. OBJECTIVES: In order to test this hypothesis this study evaluated the capacity of pretreatment with the 5-HT(2) receptor antagonist ritanserin to attenuate the effects of the 5-HT agonist, m-chlorophenylpiperazine (mCPP). METHODS: Twenty-two male inpatients who met DSM-III-R criteria for schizophrenia or schizoaffective disorder completed 4 test days during which 10 mg ritanserin or matched placebo was administered orally 50 min prior to the intravenous infusion of 0.1 mg/kg mCPP or saline. The test days were conducted in a randomized order under double-blind conditions. RESULTS: mCPP mildly and transiently increased positive symptoms and behavioral activation but not negative symptoms, as assessed by the Brief Psychiatric Rating Scale. mCPP also raised plasma prolactin and cortisol levels. All of these effects were attenuated by ritanserin pretreatment. CONCLUSIONS: These data support a contribution of 5-HT(2) receptor stimulation to symptom exacerbation in schizophrenic patients and a role for 5-HT(2) receptor antagonism in the prevention of this effect.

Adult↗