Schultz, Wolfram. Predictive reward signal of dopamine neurons. J. Neurophysiol. 80: 1–27, 1998. The effects of lesions, receptor blocking, electrical self-stimulation, and drugs of abuse suggest t...

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Predictive Reward Signal of Dopamine Neurons

https://lsa.umich.edu/psych/research&labs/berridge/publications/Berridge&RobinsonBrResRev1998.pdf

What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?

• Recent research on schizophrenia has demonstrated that in this disorder the brain is not, strictly speaking, normal. The findings suggest that nonspecific histopathology exists in the limbic system, diencephalon, and prefrontal cortex, that the pathology occurs early in development, and that the causative process is inactive long before the diagnosis is made. If these findings are valid and not epiphenomena, then the pathogenesis of schizophrenia does not appear to fit either traditional metabolic, posttraumatic, or neurodegenerative models of adult mental illness. The data are more consistent with a neurodevelopmental model in which a fixed "lesion" from early in life interacts with normal brain maturational events that occur much later. Based on neuro-ontological principles and insights from animal research about normal brain development, it is proposed that the appearance of diagnostic symptoms is linked to the normal maturation of brain areas affected by the early developmental pathology, particularly the dorsolateral prefrontal cortex. The course of the illness and the importance of stress may be related to normal maturational aspects of dopaminergic neural systems, particularly those innervating prefrontal cortex. Some implications for future research and treatment are considered.

Implications of normal brain development for the pathogenesis of schizophrenia

Background: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N -methyl-D-aspartate subtype of excitatory amino acid receptor. Methods: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. Results: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. Conclusions: These data indicate that N -methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.

https://jamanetwork.com/journals/PSYCH/articlepdf/496531/archpsyc_51_3_004.pdf

Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses.

http://www.columbia.edu/itc/gsas/g9600/2003/JavitchReadings/Schultz(Sulzer).pdf

Getting Formal with Dopamine and Reward

The selective activation of the prefrontal cortical dopamine system by mild stress can be mimicked by anxiogenic beta-carbolines such as FG7142. To investigate the functional relevance of elevated levels of dopamine turnover in the prefrontal cortex, the current study examined the effects of FG7142 on the performance of spatial working memory tasks in the rat and monkey. FG7142 selectively increased prefrontal cortical dopamine turnover in rats and significantly impaired performance on spatial working memory tasks in both rats and monkeys. Spatial discrimination, a task with similar motor and motivational demands (rats), or delayed response performance following zero-second delays (monkeys) was unaffected by FG7142. Further, biochemical analysis in rats revealed a significant positive correlation between dopamine turnover in the prefrontal cortex and cognitive impairment on the delayed alternation task. The cognitive deficits in both rats and monkeys were prevented by pretreatment with the benzodiazepine receptor antagonist, RO15-1788, which blocked the increase in dopamine turnover and by the dopamine receptor antagonists, haloperidol, clozapine, and SCH23390. These findings indicate that excessive dopamine activity in the prefrontal cortex is detrimental to cognitive functions mediated by the prefrontal cortex.

https://www.pnas.org/content/pnas/93/3/1325.full.pdf

Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys.

Cocaethylene: A neuropharmacologically active metabolite assciated with concurrent cocaine-ethanol ingestion

Fetal neuronal grafts in monkeys given methylphenyltetrahydropyridine

The anxiogenic benzodiazepine inverse agonist FG7142 increases dopamine turnover in rodent prefrontal cortex but not in other dopamine terminal field areas. FG7142-induced increases in prefrontal cortical dopamine receptor stimulation impair prefrontal-dependent, but not nonprefrontal-dependent, cognitive tasks in rats and monkeys. The degree of impairment correlates with levels of prefrontal cortical dopamine turnover in rats and can be blocked in rats and monkeys with dopamine receptor antagonists, suggesting that increased dopamine turnover is directly related to the cognitive deficits. The current study examined nondopaminergic drug effects on FG7142-perturbed biochemistry and cognition. Both the noradrenergic alpha-2 agonist clonidine and the glycine/NMDA antagonist (+)HA966 prevented the FG7142-induced increase in dopamine turnover in rodent prefrontal cortex. Infusion of (+)HA966 into the ventral tegmental area (VTA) also blocked this increase in dopamine turnover, indicating that critical modulatory effects of (+)HA966 on FG7142-induced changes in dopamine turnover are occurring at the level of mesoprefrontal dopamine neuron cell bodies. Systemic (+)HA966 and clonidine, but not propranolol or D-cycloserine, prevented FG7142-associated spatial working memory deficits in rats and monkeys. These results support the idea of a critical range of dopamine turnover for optimal prefrontal cortical cognitive functioning, with excessive dopamine turnover leading to cognitive impairment. These studies also provide evidence for the regulation of prefrontal cortical dopamine turnover and cognition by multiple neurotransmitter systems and suggest that the VTA is an important regulatory site for these effects.

https://www.jneurosci.org/content/jneuro/16/23/7768.full.pdf

R. H. Roth

Papers

Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys.

Cocaethylene: A neuropharmacologically active metabolite assciated with concurrent cocaine-ethanol ingestion

Fetal neuronal grafts in monkeys given methylphenyltetrahydropyridine

Dopamine and Spatial Working Memory in Rats and Monkeys: Pharmacological Reversal of Stress-Induced Impairment

Serotonin-containing neuronal perikarya and terminals: differential effects of P-chlorophenylalanine.