Jason M. White

Behavioural effects of histamine and its antagonists: a review

This review focusses on the behavioural effects of histamine and drugs which affect histaminergic function, particularly the H1- and H2-receptors antagonists. Research in this area has assumed considerable importance with increasing interest in the role of brain histamine, the clinical use of both H1 and H2 antagonists and evidence of nonmedical use of H1 antagonists. Results from a number of studies show that H1 and H2 antagonists have clear, but distinct subjective effects and that H1 antagonists have discriminative effects in animals. While H1 antagonists are reinforcers in certain conditions, histamine itself is a punisher. Moderate doses of H1 antagonists affect psychomotor performance in some situations, but the results are variable. The exceptions are terfenadine and astemizole, which do not seem to penetrate the blood-brain barrier readily. In studies of schedule-controlled behaviour, marked changes in response rate have been observed following administration of H1 antagonists, with the magnitude and direction dependent on the dose and the baseline behaviour. Histamine reduces avoidance responding, an effect mediated via H1-receptors. Changes in drinking and aggressive behaviour have also been observed following histamine administration and distinct roles for H1- and H2-receptors have been delineated. Separate H1- and H2-receptor mechanisms have also been suggested to account for changes in activity level. While the H2 antagonists do not always have strong behavioural effects when administered peripherally, there is evidence that cimetidine has a depressant effect on sexual function. These and other findings reveal an important role for histaminergic systems in a wide range of behaviour.

Conditioned alcohol-like and alcohol-opposite responses in humans

Conditioned heart rate and skin temperature responses of 12 social drinkers were observed following repeated exposure to alcohol. Each subject received alcohol for four sessions in one room and a non-alcoholic drink for four sessions in a room of quite different appearance. Alcoholic and non-alcoholic drinks were distinctive and the alcoholic content could not be determined on the basis of taste. In the final three testing sessions, placebos were presented in order to test the influence of room and drink cues separately and in combination. A conditioned heart rate response opposite in direction to the alcohol effect was elicited by room and drink cues in combination and by the room cue in isolation. These results were in accordance with the predictions of the conditioning model of tolerance. A conditioned heart rate response in the same direction as the drug effect was elicited by the drink cue presented in isolation. Similar, but non-significant changes were also obtained with skin temperature. In addition, conditioned responses occurred independently of any expectancy. The results demonstrated that the direction of conditioned drug responses may depend on the type of stimulus presented.

Acute tolerance to alcohol: changes in subjective effects among social drinkers

The development of acute of acute tolerance to the subjective effects of alcohol was examined in 32 social drinkers. Measures were made of self-reported level of intoxication and responses to questions from the alcohol scale of the Addiction Research Centre Inventory. The time to peak self-reported intoxication level was found to be 20 min earlier than the time to peak blood alcohol concentration. Changes from the ascending to the descending limb of the blood alcohol curve were found with five of the ARCI questions. In all cases the proportion of alcohol-typical responses was lower on the descending portion of the curve. even though blood alcohol levels were equivalent. Further analyses examined the effects of prior drinking history on the development of acute tolerance. Peak self-reported intoxication levels were significantly lower and occurred earlier for heavier drinkers. Furthermore, for four of the five ARCI questions heavier drinkers were less likely to give analcohol-typical response than lighter drinkers on the ascending portion of the curve.

The effects of amphetamine and scopolamine on adjunctive drinking and wheel-running in rats.

Two groups of rats were exposed to a fixed-interval 90 s schedule of food reinforcement. One group had access to a drinking tube containing water and the second had access to a running wheel. Amphetamine (0.3–10.0 mg/kg) and scopolamine (0.1–3.0 mg/kg) were assessed for their effects on lever-pressing, adjunctive drinking and adjunctive wheel-running. Low to moderate doses of amphetamine increased overall rates of lever-pressing, whereas the highest dose decreased them. Scopolamine decreased overall lever-pressing rates in a dose-dependent manner. Both drugs changed the within-interval pattern of lever-pressing from one of increasing probability through the interval to almost constant probability throughout. Overall rates of adjunctive drinking and adjunctive wheel-running were decreased by amphetamine and scopolamine. Amphetamine failed to alter the within-interval patterns of either drinking or wheel-running in any substantial manner. The effect of scopolamine was to make the probabilities of each adjunctive behaviour more even through the interval. Although the two drugs had different actions, there was little difference in the way drinking and wheel-running were affected by each.

Behavioral interactions between nicotene and caffeine

Nicotine (0.01-1.0 mg/kg) was administered alone and together with three doses of caffeine (3.0, 10.0 and 30.0 mg/kg) to rats responding on a fixed-interval 2-min schedule of food reinforcement. The effects on overall response rate depended on dose: with the 3.0 mg/kg dose of caffeine response rate was increased by an amount approximately equal to the effect of the caffeine alone, while 10.0 mg/kg of caffeine reduced and 30.0 mg/kg completely abolished the increases in response rate produced by nicotine. The within-interval pattern of responding was affected in a similar, dose-related manner by both nicotine and caffeine alone. These effects added to produce large changes in the pattern when high doses of the two drugs were co-administered. The changes comprised increases in lower response rates in the early and middle parts of the interval and proportionally smaller increases or decreases in the higher rates occurring later in the interval. The interaction between nicotine and caffeine cannot be characterized simply, but depends on the particular aspect of behavior under examination.

Response to alcohol cues as a function of consumption level

The response to consumption of placebo beer was studied in male social drinkers whose normal alcohol intake consisted of at least 80% beer. There was a significant correlation between change in heart rate and normal level of beer intake with heavier drinkers showing more marked declines. Similarly, heavier drinkers reported greater desire to drink following consumption of the placebo beer. Skin temperature and withdrawal scale scores showed little change and did not correlate with intake. These results suggest that the amount of experience of alcohol paired with alcohol-related cues may be an important determinant of the magnitude of the conditioned responses to those cues.

Acquisition and extinction of an alcohol-opposite conditioned response in humans

Twelve social drinkers were given a 0.7 g/kg dose of alcohol mixed with a distinctively flavoured drink in each of five sessions, and the same drink with no alcohol in a further three sessions. All sessions were conducted in the same room. The alcohol increased heart rate, but with repeated administration change was slower to begin. In the first placebo session the change in heart rate was a decrease below baseline level, particularly in the early part of the session. Repeated administration of the placebo resulted in a diminution of this alcohol-opposite conditioned response.

Schedule-induced wheel-running: Effects of exposure to the schedule

Rats were given access to a running wheel from a chamber where milk was delivered according to a fixed-time 1-min schedule. For most animals the effect of the schedule was to decrease wheel-running rate below that during massed reinforcement control sessions. With further exposure to the schedule wheel-running rate tended to increase and a well-defined temporal pattern developed. Subsequent exposure to the control condition caused an initial increase and then, in most cases, a decline in wheel-running rate. Re-exposure to the schedule increased wheel-running rates in three out of four subjects and the temporal pattern developed more rapidly. Judgement as to whether a particular behavior pattern is schedule-induced or not can only be reliably made when there is strong evidence that the overall rate and temporal pattern of the behavior are stable. Wheel-running appears to be a schedule-induced behavior under some experimental conditions.

Behavioral interactions between nicotine and diazepam

Graded doses of nicotine (0.01-1.0 mg/kg) were administered alone and together with three doses of diazepam (0.3, 1.0 and 3.0 mg/kg) to rats responding on a fixed-interval 2-min schedule of liquid food reinforcement. Nicotine (0.03-1.0 mg/kg) increased overall rate, but diazepam had little effect. Both nicotine and the two highest doses of diazepam attenuated the change in response rate through the interval. When combined with nicotine the lowest dose of diazepam increased overall rates above those produced by nicotine alone. However, it appeared to diminish the effects of nicotine on the within-interval pattern of responding. These changes appeared to be due to an elevation in the high rates at the end of the interval. In contrast, the highest diazepam dose increased overall response rates when combined with low doses of nicotine, but decreased the high rates observed after larger nicotine doses. This dose of diazepam combined in an additive manner with nicotine to reduce the degree of response rate change within the interval. The interaction between nicotine and diazepam depends on the aspect of behavior under investigation and the particular doses of the two drugs.

Effects of repeated alcohol administration on human operant behaviour

Nine human subjects were exposed to a multiple fixed-ratio (FR) differential-reinforcement-of-low-rate (DRL) schedule of monetary reinforcement. Presses on a manipulandum requiring relatively high force were occasionally followed by an increased money total displayed on a computer screen. Subjects were exposed to the schedule until their behaviour had stabilized. Prior to each of the next three sessions they were administered 0.85 g/kg alcohol. In eight of the nine subjects the initial effect of alcohol was to increase FR response rate and, consequently, reinforcement rate. Subsequent alcohol administration resulted in sensitization: even greater rate-increasing effects. In two further control sessions behaviour returned towards baseline level. DRL response rate was slightly increased by alcohol, but reinforcement rate remained unchanged. There was no consistent change in DRL response or reinforcement rates from the first to the third alcohol sessions. The effects of alcohol on human behaviour were similar to the effects found in studies with animals. The results were also consistent with the view that the changes in behaviour which occur with repeated drug administration depend in part on whether the initial effect of the drug is to increase, decrease or produce no change in reinforcement rate.