Caffeine self-administration, withdrawal, and adverse effects among coffee drinkers.

Twenty-two coffee drinkers (three to seven cups per day) underwent repeated double-blind trials to test for caffeine self-administration, withdrawal, and adverse effects. Each trial consisted first of a randomized crossover period of 1 day of decaffeinated coffee and 1 day of caffeinated coffee (100 mg) to assess withdrawal and adverse effects of caffeine. Next, subjects were given 2 days of concurrent access to the two coffees. The relative use of the two coffees was used to assess caffeine self-administration. Reliable caffeine self-administration occurred in three of 10 subjects in study 1 and seven of 12 subjects in study 2. Withdrawal symptoms were headaches, drowsiness, and fatigue. The major adverse effect from self-administration was tremulousness. The occurrence of headaches on substitution of decaffeinated coffee prospectively predicted subsequent self-administration of caffeine. These results indicate that some coffee drinkers exhibit signs of a caffeine dependence, ie, they self-administer coffee for the effects of caffeine, have withdrawal symptoms on cessation, and experience adverse effects.

Elicited pontogeniculooccipital waves and phasic suppression of diaphragm activity in sleep and wakefulness.

Fractionations are 20- to 100-ms pauses in diaphragm activity that occur spontaneously during rapid-eye-movement (REM) sleep, sometimes in association with pontogeniculooccipital (PGO) waves. Auditory stimuli can elicit fractionations or PGO waves during REM sleep, non-REM (NREM) sleep, and waking; however, their interrelationship has not been investigated. To determine whether the two phenomena are produced by a common phasic-event generator in REM sleep, we examined PGO waves and fractionations that were elicited by auditory stimuli (tones) presented to freely behaving cats across states. Tones elicited PGO waves and two types of fractionations: short-latency fractionation responses (SFRs; 10- to 60-ms latencies) and long-latency fractionation responses (LFRs; 60- to 120-ms latencies). Both a PGO wave and a SFR were elicited in 60-70% of trials across states, but each could be elicited alone. The latencies and durations of elicited SFRs were similar across states, but the latencies of elicited PGO waves in REM sleep (mean 62.5 ms) were significantly longer than in waking or NREM sleep. Elicited SFRs consistently occur with shorter latencies than do PGO waves, in contrast to spontaneous fractionations, which have a variable relationship to PGO waves and usually occur 10-40 ms after the onset of the PGO wave. The LFR then, elicited most frequently during REM sleep, resembles a spontaneous fractionation in its temporal relationship to the PGO wave and may reflect the bias toward motoneuronal inhibition characterizing REM sleep but not NREM sleep or waking. We conclude that, although PGO waves and SFRs share some features, like LFRs they probably are generated by different neuronal populations. In three cats there was no correlation between PGO waves and fractionations, whereas in one cat they were associated in REM sleep (LFRs and SFRs) and waking (SFRs only). Thus the majority of evidence argues against the existence of a common phasic-event generator in REM sleep.

Effect of dose on the ability of caffeine to serve as a reinforcer in humans.

This study tested the effects of dose on the reinforcing effects of caffeine in humans. Eight moderate coffee drinkers were given concurrent access to decaffeinated coffee vs. decaffeinated coffee to which different doses of caffeine (25, 50, 150 and 200mg/cup) were added. Subjects were tested across several independent double-blind trials. The coffees with 25mg of caffeine were repeatedly self-administered at a rate greater than that of decaffeinated coffee in two of six subjects, the 50mg dose in four of eight subjects, the 150mg dose in three of six subjects, and the 200mg dose in none of the three subjects tested. Headaches, drowsiness and fatigue occurred with use of decaffeinated coffee in five subjects. When these symptoms occurred, there was a greater probability of self-administration of the caffeinated coffee. We conclude that doses of caffeine similar to those in tea or soda can serve as reinforcers.

Microinjections into the pedunculopontine tegmentum: effects of the GABAA antagonist, bicuculline, on sleep, PGO waves and behavior.

Neurons in the peribrachial region (PB) at the pontine border are implicated in the generation of ponto-geniculo-occipital (PGO) waves, which appear spontaneously during rapid eye movement sleep (REM) and in association with alerting behaviors during waking, as well as in the regulation of REM itself. It has been hypothesized that PGO-related bursting in a subpopulation of these neurons results from low threshold spikes triggered by phasic hyperpolarizations or by excitatory inputs reaching a steadily hyperpolarized neuron. The hyperpolarization necessary for triggering the low threshold spikes may come from local GABA neurons or from GABAergic input into PB. To test the hypothesis that antagonizing GABA would alter PGO wave generation and/or behavioral state, we microinfused, in cats, the GABAA antagonist, bicuculline, locally into PB and monitored behavior, behavioral state and PGO waves recorded in the lateral geniculate bodies. Bicuculline produced no significant alteration in PGO wave activity. In 3 cats, bicuculline produced behaviors ranging from spontaneous orienting and startle (4 cats) to flight behaviors (2 cats) and aggressiveness (2 cats), an effect probably due to diffusion into the central gray region. Thus, the results do not support a GABAA-ergic role in PB in the generation of PGO waves.

Central administration of a 5-HT2 receptor agonist and antagonist: lack of effect on rapid eye movement sleep and pgo waves.

Serotonin (5-HT) has a role in regulating behavioral state and controlling the production of ponto-geniculo-occipital (PGO) waves, though the exact mechanism of action is not known. The most prevailing explanation is that 5-HT exerts its influence on behavioral state and PGO waves by inhibiting and disinhibiting cholinergic cells in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT), which have been implicated in their generation. Recent work in rats has demonstrated 5-HT2 receptors on most cholinergic cells in PPT/LDT. We microinfused the relatively specific 5-HT2 agonist, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), the relatively specific 5-HT2 antagonist, ketanserin, and the nonspecific 5-HT antagonist, methysergide, locally into the peribrachial region of PPT in cats and monitored behavioral state and PGO waves. Neither drug significantly affected behavioral state or PGO wave activity. These results suggest that 5-HT2 receptors associated with cholinergic cells are minimally involved in the control of behavioral state and, together with the recent findings of others, suggest that 5-HT may not modulate PGO wave generation via direct action on cholinergic neurons in PPT/LDT, a departure from the long-held but minimally-tested view.