Zalman Amit

The role of endorphins in stress: Evidence and speculations ☆

Several lines of evidence suggest that the endogenous opioid peptides endorphins may play a role in the defensive response of the organism to stress. The present paper summarizes these findings as well as evidence linking endorphins to the anterior pituitary polypeptide hormone adrenocorticotropin (ACTH). Evidence is presented that endorphins may function as trophic hormones in peripheral target organs such as the adrenal medulla and the pancreas. As such they may be part of the physiological mechanisms that mediate adrenaline and glucagon release in response to stress. Endorphins (enkephalins) are also suggested to play a role in the control of the pituitary gland during stress. In such capacity they may act as hormone-releasing or inhibiting factors. Finally, endorphins appear to play a role in the behavioral concomitants of stress. In such capacity endorphins are suggested to function as modulators of neural systems that mediate the elaboration and expression of the reactive/affective components of stress. Speculations on the mode of interaction between endorphins and ACTH in the global response to stress are discussed.

Endogenous opioid ligands may mediate stress-induced changes in the affective properties of pain related behavior in rats.

Abstract The effect of a single or repeated daily sessions of immobilization stress on hot plate-induced paw lick and escape responses was studied in rats. Immobilization prior to testing resulted in increased latency to escape while having no effect on paw lick response. Naloxone pretreatment reversed the effect of immobilization on escape behavior. The data suggest that immobilization-induced changes in pain related behavior may be mediated by an opiate receptor ligand system. Furthermore, they suggest that this endogenous system may be mediating the affective but not the sensory properties of pain related behavior.

Cocaine self-administration in rats influenced by environmental conditions: implications for the etiology of drug abuse

The present study investigated the possibility of environmental factors as an explanation for between-subject differences in cocaine self-administration. Weaning rats (21 days) were housed in isolated or aggregated conditions for 6 weeks and were tested for intravenous cocaine self-administration (0.1-1.0 mg/kg/infusion). Rats housed in groups failed to reliably self-administer this drug whereas isolated rats readily acquired an operant to receive infusions of cocaine. These data suggest that environmental factors play a major role in determining individual differences in the propensity to self-administer cocaine and that, as such, they should be considered more seriously by those interested in the basis and treatment of drug abuse.

The pituitary gland mediates acute and chronic pain responsiveness in stressed and non-stressed rats.

Abstract The effect of hypophysectomy on the responsiveness of rats to acute (hot plate test) and chronic (formalin test) pain was studied. Hypophysectomy did not alter hot plate behavior but increased the duration of the paw withdrawal in the formalin test. Pre-exposure of rats to immobilization stress caused a transient yet significant increase in escape latencies from a hot plate as well as a significant decrease in the duration of paw withdrawal in the formalin test. Hypophysectomy blocked the effect of stress on these behavioral manifestations of acute and chronic pain. The effect of hypophysectomy was not reversed by adrenocorticotropin pretreatment. These results suggest that centrally acting pituitary hormones may have a requisite function in normal and adaptive pain control in mammals.

Ethanol metabolism in rat brain homogenates by a catalase-H2O2 system

Homogenates of perfused rat brains incubated in the presence of ethanol (50-100 mM) and glucose (10 mM) were found to oxidize ethanol to acetaldehyde. The addition of glucose oxidase, a known hydrogen peroxide generator, to the incubation medium, significantly (P less than 0.05) increased the generation of acetaldehyde. The presence in the incubation medium of metyrapone, an inhibitor of cytochrome P450, or pyrazole, an alcohol dehydrogenase inhibitor, did not affect the levels of acetaldehyde obtained. Conversely, the presence of 3-amino-1,2,4-triazole, a known catalase inhibitor, induced a concentration-dependent reduction of the amount of acetaldehyde generated after incubation, even in the presence of glucose oxidase. Homogenates of perfused brains of rats treated with 3-amino-1,2,4-triazole or cyanamide (another H2O2-dependent catalase blocker) also showed a dose-dependent reduction of the acetaldehyde obtained. These findings support the notion that a catalase-mediated oxidation of ethanol is present in rat brain homogenates. It is suggested that this local oxidation of ethanol may have important biological implications. The data of both studies increase support for the notion that acetaldehyde is produced directly in the brain and that it may be the agent mediating some of the psychopharmacological properties of ethanol and be one of the factors determining the propensity of an animal to voluntarily consume ethanol.

Intraventricular self-administration of acetaldehyde, but not ethanol, in naive laboratory rats

For 11 consecutive days, naive rats were maintained in operant chambers where they were given the opportunity to self-administer acetaldehyde (1,2, or 5% v/v), ethanol (2 or 10% v/v), or pH control solutions directly into the cerebral ventricles. Only the animals that had access to the 2 and 5% acetaldehyde solutions showed rates of lever pressing significantly higher than controls. It is suggested that acetaldehyde rather than ethanol itself may mediate the positive reinforcing effects of ethanol in the brain.

Simple flow-thru swivel for infusions into unrestrained animals.

Infusion of fluids into unrestrained animals requires the use of a flow-thru swivel. A method is described for the construction of a simple efficient swivel assembled from disposable plastic syringes and needles.

An investigation of the mechanisms of action of 5-hydroxytryptamine in the suppression of ethanol intake.

The effect of blockage of 5-hydroxytryptamine and norepinephrine uptake on voluntary ethanol consumption in rats was investigated. It was demonstrated that attenuation of ethanol intake occurred only as a result of treatment with specific 5-hydroxytryptamine uptake inhibitors. These results suggested that increasing the availability of central 5-hydroxytryptamine may in some way interfere with the positive reinforcing properties of ethanol. The second phase was designed to determine whether the attenuation of ethanol intake following blockade of 5-hydroxytryptamine uptake may be due to increased post-synaptic activity. Ethanol-preferring animals were pretreated with methergoline, a post-synaptic receptor blocker, followed by treatment with zimelidine, a 5-hydroxytryptamine uptake inhibitor. The results indicate that treatment with methergoline did not alter the zimelidine-induced attenuation of ethanol intake. Based on these results it is suggested that blockade of 5-hydroxytryptamine uptake produces an attenuation of ethanol intake but not as a result of increased post-synaptic activity.

Bidirectional effects of GABAergic agonists and antagonists on maintenance of voluntary ethanol intake in rats

The effects of THIP (GABAA agonist) and picrotoxin (GABA antagonist) on the maintenance of voluntary ethanol ingestion were examined. Thirty-three male Long-Evans rats were initially exposed to a screening procedure in which increasing concentrations of ethanol (from 2% to 9%) were presented in a free choice with water, on an alternate day schedule. Following the screening procedure, the rats were exposed to five ethanol presentations at a concentration of 9%, which constituted the baseline period, and five additional ethanol presentations during which the effects of the GABAergic manipulations were determined (test period). During the test period, the animals received IP injections of either 16 mg/kg of THIP, 2 mg/kg of picrotoxin or saline. The results suggested that the differential GABA manipulations resulted in bidirectional effects on the consumption of ethanol. More specifically, the GABAA agonist THIP increased the intake of ethanol as compared to baseline measures, while the GABA antagonist picrotoxin decreased ethanol intake. Similarly, the administration of THIP increased ethanol preference. In contrast, preference for ethanol over water was decreased following the administration of picrotoxin. It appears that the effects of these GABAergic manipulations are specific to ethanol, since total fluid intake was not influenced by the administration of either drug (i.e., THIP or picrotoxin). In light of the literature suggesting that THIP and picrotoxin are active at different sites within the GABAA chloride-ionophore receptor complex, the present findings would suggest that the GABAA receptor may play a role in regulating the voluntary intake of ethanol.

Zimeldine: a review of its effects on ethanol consumption.

This review evaluates the literature and describes an extensive series of experiments which examined the effects of zimeldine , its metabolite norzimeldine and other serotonin and norepinephrine reuptake inhibitors on voluntary ethanol consumption in rats. The results of these experiments indicate that drugs which specifically inhibit serotonin reuptake are capable of decreasing voluntary ethanol consumption. The behavioral mechanism through which these drugs exert their effects seems to be extinction of the primary reinforcing properties of alcohol. These effects seem to be partially attenuated both by drugs which modulate the norepinephrine system as well as by the serotonin postsynaptic receptor blocker methergoline. The data presented in this review are discussed in terms of the involvement of the serotonin and norepinephrine systems in the mechanism of action of these drugs. In addition, several alternative hypotheses concerning the nature of the phenomenon are offered. Finally, the implications of these data for the possible development of a treatment procedure for problem drinkers is discussed.