P. Marfaing-Jallat

Pain modulating and reward systems: A single brain mechanism?

Abstract The hypothesis that brain rewarding and pain modulating systems could involve a common opiate system, identically blocked by naloxone, has been tested in three experiments. The preferences or aversions for sapid solutions in rats have been employed as reliable measures of responses to rewarding or nociceptive stimulations. In the first experiment, it was shown that the spontaneous aversion to a quinine HCl solution was enhanced when rats were offered the solution 30 min after naloxone at a dose of 1 mg/kg. The same enhanced aversion was observed in the second experiment towards a sweet solution previously made aversive through a conditioned taste aversion paradigm. In the third experiment, by using two different procedures and saccharin or glucose solutions, it was found that naloxone acutely abolished the preference for sweet solutions versus water in rats. It is concluded that: (1) the enhancement by naloxone of the aversion to a sapid solution, similar to the naloxone induced hyperalgesia, allows to assimilate this aversion to other responses to nociceptive stimulations; (2) this suggests that, like other responses to nociceptive stimulations, this aversion is normally attenuated through the release of brain or pituitary opiates; (3) the suppressant effect of naloxone upon both this attenuation of aversion and a preference for a sapid solution supports the notion of a biochemical and functional community between rewarding and pain modulating systems.

Decrease in ethanol consumption by naloxone in naive and dependent rats

Acute effects of the opiate antagonist, naloxone, on alcohol intake have been examined and compared in naive and behaviorally dependent rats. In naive rats the aversion to an 8% alcohol solution exhibited in a 30 min presentation was selectively augmented by an IP administration of naloxone (1 mg/kg) 30 min before a morning drinking session. In other rats, behavioral dependence was established by 15 days of IG administration of intoxicating doses of alcohol. This dependence was exhibited by a sustained preference for ethanol for 6 days. Naloxone (1 mg/kg) abolishes the acquired preference for ethanol tested during an 8 hour day time presentation. These effects of naloxone on alcohol intake in ethanol naive and dependent rats are interpreted in relation to a general non-specific action of naloxone on preferred or aversive flavoured solutions.

Ethanol-induced taste aversion in ethanol-dependent and normal rats

It has previously been shown that the intragastric and parenteral administration of an acutely intoxicating dose of ethanol to naive rats paired with the oral intake of a flavored solution induces a conditioned taste aversion to the solution. Experiments have been designed to examine possible differences in the ethanol-induced aversion between naive rats and rats rendered ethanol dependent by chronic forced administration of alcohol. The classical conditioned taste aversion paradigm was used. Control rats and rats previously fed on an ethanol-containing liquid diet for 15 days were offered a saccharin solution for a 30-min period, 2 hr after the removal of either the control or the intoxicating liquid diet. In four groups of animals, the free intake of the flavored solution was immediately followed by either no injection or an ip administration of 1.5, 3.0 or 4.5 g/kg 20% ethanol solution. Three days later, the acquired aversion was tested with a second 30-min presentation of the saccharin solution. It was shown that in dependent rats, compared to controls, a single association between the oral intake and the withdrawal illness establishes a strong aversion to the flavored solution. In controls, aversion was induced by the three postingestive doses of ethanol. In intoxicated rats, 1.5 g/kg resulted in a maintained or slightly enhanced saccharin intake, whereas higher doses again induced the aversion. Nevertheless, the aversion obtained with the 3 g/kg was significantly lower than in controls. The findings of a withdrawal illness-induced aversion and of a maintained intake of this same solution, induced by the postingestional effect of a small dose of ethanol in dependent rats, are discussed in relation to the problem of the experimental establishment of behavioral ethanol dependence in rats.

The effect of naloxone on intragastric ethanol self-administration ☆

The acute effect of 1.25 and 2.50 mg/kg naloxone was tested in a group of male Wistar rats readily self-administering 10% w/v ethanol intragastrically following 12 days of forced ethanol intoxication. Compared to saline pretreatment, naloxone did not alter 24 hr intakes of food, water or ethanol. However, both does strongly and significantly inhibited lever pressing for ethanol during 2 hr following pretreatment. The results indicate that naloxoness inhibition of ethanol intake does have a transient postabsorptive component, although this component is unlikely to be specific to ethanol.

Non-specific enhancement of ethanol-induced taste aversion by naloxone.

The conditioned taste aversion paradigm (CTA) was used to examine the effects of naloxone on ethanol-induced aversion towards a saccharine solution (3 conditioning and 11 extinction trials). Six groups of rats received conditioning trials consisting of two IP injections after saccharine presentation of different combinations of either ethanol (E: 1.75 g/kg), LiCl (L: 12 mEq/kg, 0.1 M), naloxone (N: 10 mg/kg) or saline (S); S-S, S-N, E-S, E-N, L-S and L-N. Naloxone by itself produced no aversion to the saccharin flavor. Based on the onset and extinction of aversion, naloxone significantly enhanced ethanol but also LiCl-induced CTA. The comparative data argues in favor of different mechanisms of action (1) between the aversive central effects of ethanol and morphine and (2) between ethanols acute behavioral effects and negatively reinforcing properties. Enhancement of ethanol and LiCl-induced CTA by naloxone is compatible with hypernociceptive action of the opiate-antagonist and with the pain-modulating role of opiates in the CNS.

Induction of high voluntary ethanol intake in dependent rats

The experimental conditions under which oral high intake may be induced in previously intoxicated rats have been investigated. Seventeen rats were administered intragastrically with 10 g/kg/day of ethanol for 15 days. At cessation of treatment, they were presented a single bottle of alcoholic solution (10% v/v) during 24 hr. For the following 6 days, they received either an ethyl alcohol solution or water in alternation for 8 hours each. Ethanol treated rats exhibited a high oral intake of ethanol equivalent to the previously injected doses. Controls displayed a significantly lower intake of ethanol. It is concluded that the suppression of the withdrawal state by an initial priming oral intake of ethanol in physically dependent rats is a condition for the development of a conditioned taste preference for ethanol as a basis for the behavioral dependence.

Failure of naloxone to affect initial and acquired tolerance to ethanol in rats

The effects of naloxone on the initial sensitivity to ethanol and the subsequent changes in tolerance induced by prior ethanol treatment were studied in rats by using the drinking test for assessing behavioral effects. Naloxone (N) was administered concurrently with ethanol (E) in either 5 successive single doses spaced at 2-day intervals (Experiment 1) or during 4 days of chronic i.v. infusion (E: 9 g/kg, N: 9 mg/kg in 6 injections per day, Experiment 2). Both treatments produced an increase in nervous tolerance toward ethanol. However naloxone was found to exert no effect on either initial or acquired tolerance toward ethanol. The results are discussed in terms of possible relations between the CNS mechanisms involved in tolerance to morphine and ethanol.

Ethanol prefernce following hypothalamic stimulation: Relation to stimulation parameters and energy balance ☆

Abstract Rats were given 5, 10, 20 and 30 min daily sessions of lateral hypothalamic stimulation. Approximately half of the rats showed a large and highly significant increase in their total intake of and preference for 10% v/v ethanol which was continously available in their home cages. In terms of latency, total consumption and preference for ethanol, 10 min of daily stimulation produced a much greater enhancement than did 30 min. The ethanol drinking rats used more energy per unit of body weight which suggests that the stimulation and/or the ethanol itself may have increased energy expenditure. Simply changing the diet from powdered chow to identical composition pellets produced a large reduction in both total ethanol intake and preference. Reinstating the powdered diet produced a rapid reinstatement of ethanol drinking. These data are discussed in terms of ethanols role in modulating stimulation induced changes in energy balance.

Alcohol intake in hypothalamic hyperphagic rats

Abstract The free 24 hr intake of alcohol has been tested after VM hypothalamic lesion in rats given ad lib. or limited access to the solid food and single or two-bottles presentation of an ethyl alcohol solution. Contrary to the classically observed overresponsiveness toward oro-sensory aversive stimuli of hyperphagic hypothalamic rats, a majority of rats in these various experimental conditions increased their intake of the ethanol solution. Through this overdrinking of ethyl alcohol treated as supply of calories, rats developed partially or exclusively their hyperphagia and became obese. This alcohol hyperphagia was very persistent. However it remained moderate compared to that developed on solid food. The maximal 24 hr intake of pure alcohol did not exceed the maximal rate of the oxydative capacity.

Relationship between initial sensitivity to ethanol and the high alcohol intake in dependent rats

The high spontaneous intake of ethanol, which can be induced in rats after a period of forced administration, may be used to study the altered state created in the C.N.S. by the chronic exposure to ethanol. The relationship between the initial acute sensitivity to ethanol and this induced high oral intake has been examined in rats. Initial sensitivity was determined in two groups of rats either by a test of motor impairment or by alcohol induced hypothermia. After 15 days of daily IG administration of 10 g/kg, rats were submitted to the ethanol presentations which display the high voluntary intake. Two groups of controls were initially tested for their motor impairment or hypothermia respectively under ethanol and then treated for 15 days with saline injections. The results indicate a highly significant negative correlation between initial sensitivity and the level of dependence induced by a chronic treatment and manifested by a voluntary high intake. In control groups, the low intake of ethanol observed in the final test was not correlated to the initial sensitivity to ethanol as tested by hypothermia but weakly correlated to sensitivity measured by motor impairment. The results are discussed in terms of mechanisms which determine the voluntary intake of ethanol in ethanol naive and dependent rats.