C. David Wise

Possible Etiology of Schizophrenia: Progressive Damage to the Noradrenergic Reward System by 6-Hydroxydopamine

Single or repeated intraventricular injections of 6-hydroxydopamine caused marked and long-lasting deficits in brain self-stimulation and other rewarded behaviors in the rat. The behavioral deficits, as well as the depletion of brain norepinephrine induced by 6-hydroxydopamine, were prevented by prior treatment with chlorpromazine. Episodic or continuous formation of endogenous 6-hydroxydopamine in man as a result of a genetically determined enzymatic error could selectively damage the binding capacity and, eventually, the structural integrity of the noradrenergic reward mechanism. Such damage might cause the fundamental symptoms and long-term downhill course of schizophrenia.

Benzodiazepines: Anxiety-Reducing Activity by Reduction of Serotonin Turnover in the Brain

The anxiety-reducing effects of minor tranquilizers in the rat conflict test were mimicked by serotonin antagonists and by p-chlorophenylalanine, an inhibitor of serotonin synthesis; the depressant effects of the minor tranquilizers were mimicked by norepinephrine antagonists. Intraventricular injections of serotonin led to a suppression of behavior, and also antagonized the anxiety-reducing action of benzodiazeprines. Intraventricular injections of norepinephrine led to a release of punished behavior from suppression, and also antagonized the depressant action of benzodiazepines. The anxiety-reducing activity, and the decrease in serotonin turnover induced by benzodiazepines, were maintained over repeated doses, whereas depressant activity, and the decrease induced in norepinephrine turnover, both rapidly underwent tolerance. Tranquilizers may exert their anxiety-reducing effects by a reduction of serotonin activity in a behaviorally suppressive punishment system, and they may exert their depressant effects by a reduction of norepinephrine activity in a behaviorally facilitatory reward system.

Facilitation of Brain Self-Stimulation by Central Administration of Norepinephrine

Rats with electrodes implanted in the medial forebrain bundle stimulated their own brains at sharply reduced rates after systemic administration of disulfiram or intraventricular administration of diethyldithiocarbamate. Both drugs inhibit dopamine-β-hydroxylase, the enzyme responsible for the final step in the biosynthesis of norepinephrine. The suppressed behavior was reinstated by intraventricular injections of 1-norepinephrine, but not by injection of its biologically inactive isomer, d-norepinephrine. Intraventricular administration of dopamine and serotonin did not restore self-stimulation. The rewarding effect of medial forebrain bundle stimulation may depend on the availability of norepinephrine as a transmitter, but not on dopamine or serotonin.

Norepinephrine: Reversal of Anorexia in Rats with Lateral Hypothalamic Damage

Injection of norepinephrine in the lateral ventricles of rats recovering from lateral hypothalamic anorexia caused immediate feeding and, frequently, overeating. Intraventricular administration of the α-noradrenergic blocker, phentolamine, suppressed feeding in both normal rats and rats that had recovered from lateral hypothalamic lesions. Feeding is reinforced by ascending medial forebrain bundle fibers that form α-noradrenergic synapses in the hypothalamus and forebrain. Damage to these fibers suppresses feeding by reducing noradrenergic transmission and, hence, the rewarding value of food. Recovery of feeding after hypothalamic lesions coincides with the recovery of noradrenergic reward function.

Nerve growth factor: enhanced recovery of feeding after hypothalamic damage.

A single intraventricular injection of nerve growth factor (NGF). given at the time of brain damage, facilitated the course of recovery from the lateral hypothalamic anorexic syndrome in male rats. In the second and third weeks after the trauma, NGF-treated rats ate more food, regained body weight more rapidly, and fed more vigorously in response to intraventricular administration of norepinephrine than untreated controls. After full recovery, rats that had been treated with NGF were resistant to reinstatement of the hypothalamic syndrome by 6-hydroxydopamine. NGF may facilitate behavioral recovery by promoting the development of supersensitivity to norepinephrine and possibly also by stimulating the growth of regenerating noradrenergic neurons in the brain.

Post-mortem measurement of enzymes in human brain: Evidence of a central noradrenergic deficit in schizophrenia

Abstract Postmortem brain specimens from 18 schizophrenic patients and 12 normal controls were assayed for dopamine-β-hydroxylase (DBH), the enzyme responsible for the final step in norepinephrine biosynthesis. There was a significant reduction in the DBH activity of the schizophrenic group in all brain regions examined. Enzyme deficits in hippocampus and diencephalon were somewhat larger than that in pons-medulla. Since various extraneous factors, such as non-specific deterioration, drug treatment, duration of hospitalization, cause of death, sex, and age could be ruled out, the deficits in DBH may be associated with the schizophrenic disease process. These findings are consistent with the hypothesis that noradrenergic “reward” pathways are damaged in schizophrenia.

Neuropharmacology of Reward and Punishment

A hungry pigeon is easily trained to peck at a target to obtain food. A frightened rat, periodically subjected to electrical foot shock, learns equally well to avoid the painful stimulation by pressing a pedal. These demonstration experiments illustrate a high form of behavioral adaptation which Skinner (1938) has termed operant reinforcement. The term operant emphasizes the fact that the behavior operates on the environment to generate consequences. The term reinforcement refers to the fact that the behavior is strengthened when its consequences are favorable or rewarding.

Self-stimulation reward pathways: Norepinephrine vs dopamine

Abstract Anatomical and pharmacological studies of brain self-stimulation are reviewed. The evidence clearly indicates that central noradrenergic neurons, particularly those in the locus coeruleus, mediate self-stimulation reward. The role of dopaminergic neurons is still unclear. Although electrodes in the dopamine cell groups of the substantia nigra support high rates of self-stimulation, the behaviour is abolished after mechanical or chemical damage to ipsilateral noradrenergic pathways, or after pharmacological inhibition of norepinephrine synthesis.

AMPHETAMINE AND NORADRENERGIC REWARD PATHWAYS

Publisher Summary This chapter reviews amphetamine and noradrenergic reward pathways. The effects of norepinephrine, and dopamine on self-stimulation were directly examined by injecting these agents in the lateral ventricle through permanently-indwelling cannulas. l-Norepinephrine facilitated medial forebrain bundle self-stimulation over a wide range of doses. Similar doses of dopamine are much less effective, or may even suppress self-stimulation. The mild facilitating effects of dopamine are sometimes observed after a delay of several minutes, and thus may reflect conversion of the dopamine to norepinephrine. It is found that to further evaluate the hypothesis that dopamine mediates rewarding effects, rostally-projecting dopamine pathways were mapped for self-stimulation at points in the brain where a somewhat better separation of noradrenergic, and dopaminergic systems than that in the substantia nigra is described. Self-stimulation was obtained from some electrodes in the dopamine tracts of the internal capsule, particularly from sites surrounding the tip of the crus cerebri, but maximal rates were only about 20% of the maximal rates obtained from medial forebrain bundle electrodes.

Noradrenergic Reward Mechanisms, Recovery of Function, and Schizophrenia

Over the past two decades, research findings in many different fields have resulted in the identification of central monoamine systems tentatively associated with reward and punishment. While the reward system has been characterized as mainly noradrenergic (Stein, 1967, 1968; Wise and Stein, 1969), the punishment system appears to be at least partially serotonergic (Wise, Berger and Stein, 1970, in press, a). Recent histochemical work suggests that noradrenergic neurons may be organized into two ascending systems: a dorsal pathway originating in the locus coeruleus which mainly innervates the cerebral cortex and hippocampus, and a ventral pathway originating in the reticular formation of the lower brain stem which mainly innervates the hypothalamus and ventral parts of the limbic system (Fuxe, Hokfelt and Ungerstedt, 1970). Both pathways appear to mediate rewarding effects (Ritter and Stein, 1972; Arbuthnott, Fuxe and Ungerstedt, 1971), but their differential distribution suggests different functions: the ventral branch may mainly regulate motivational activities, whereas the dorsal branch may mainly regulate cognitive activities (Stein and Wise, 1971).