Effects of local anesthetics on experiential, physiologic and endocrine measures in healthy humans and on rat hypothalamic corticotropin-releasing hormone release in vitro: clinical and psychobiologic implications.

Local anesthetics, given i.v. to treat cardiac arrhythmias and for regional anesthesia, exert prominent central nervous system side effects, such as sensory distortions and mood changes. In experimental animals, these drugs activate limbic structures, such as the amygdala, that may coordinately regulate sensory processing, mood and pituitary hormone secretion during stress. Clinically relevant i.v. doses of the short-acting local anesthetic procaine were administered to 17 healthy volunteers and topographic electroencephalographic (EEG) spectra, stress-responsive neuroendocrine and cardiovascular parameters and sensory-cognitive and mood changes were examined. Because corticotropin-releasing hormone (CRH) mimics the behavioral and physiologic responses to stress and activates limbic structures in experimental animals, the effects of procaine and lidocaine on immunoreactive CRH release from rat hypothalami in vitro were also explored. Procaine administration produced a dose-related increase in fast (21-50 Hz) EEG activity, a significant decrease in alpha EEG activity and dose-dependent increases in heart rate, systolic blood pressure and plasma adrenocorticotropic hormone, cortisol and prolactin secretion. Dose-dependent increases in sensory distortions involved virtually all modalities, particularly auditory, visual and somatosensory. Mood changes occurred in most subjects, including anxiety, euphoria and arousal. In vitro, procaine and lidocaine both produced significant dose-related increases in immunoreactive CRH release from rat hypothalami, maximal at 10(-6) M, that were blocked by carbamazepine, a limbic anticonvulsant used in the management of mood disorders. The electrophysiologic effects of procaine in these volunteers were analogous to local anesthetic effects in experimental animals and consistent with the activation of subcortical structures localized within the temporal lobe, such as the amygdala. The effects of procaine on stress-responsive neurohormones were similar to those of amygdala stimulation both in experimental animals and human subjects. The in vitro data suggested that procaine-induced pituitary-adrenal activation involves stimulation of hypothalamic CRH, although additional (e.g., limbic-hypothalamic) mechanisms may contribute in vivo. These data were compatible with a direct action of local anesthetics on limbic structures that might account for many of the central effects seen with the systemic use of these agents in clinical practice.

Quantitative electroencephalographic effects of caffeine in panic disorder.

It has been demonstrated that patients with panic disorder are more sensitive than normal control subjects to the anxiogenic effects of caffeine. The underlying physiologic basis for this difference is unclear. We examined the electroencephalographic (EEG) activity of seven patients with panic disorder and seven normal control subjects during the randomized double-blind, placebo-controlled administration of oral caffeine (7 mg/kg). EEG data were collected on-line from 28 electrodes; artifact-free epochs were selected manually for off-line Fourier transformation. Caffeine was associated with a significant increase in peak occipital alpha frequency and significant decreases in occipital alpha amplitude, central beta amplitude, and central theta amplitude. Despite the observation that caffeine increased anxiety more in the patients with panic disorder than in the normal control subjects, the two groups did not differ in their EEG responses to caffeine.

Intravenous procaine as a probe of limbic system activity in psychiatric patients and normal controls.

Evidence from animal and human studies suggests that procaine hydrochloride may selectively activate limbic system structures and suppress neocortical structures. We administered a series of intravenous bolus doses of procaine hydrochloride to 31 subjects (7 with affective disorders, 17 with borderline personality disorder, and 7 healthy normal volunteers). Dose-related cognitive and sensory distortions and illusions were observed; affective experiences ranged widely from euphoric to dysphoric. Topographic electroencephalogram (EEG) analysis indicated selective increases in fast activity (26-45 Hz) over the temporal lobes; the degree of increase in this activity correlated with degree of dysphoria experienced. Procaine was associated with increases in secretion of cortisol, adrenocorticotrophic hormone (ACTH), and prolactin, but not with growth hormone. These preliminary data are consistent with the possibility that procaine might serve as a clinically useful probe of psychosensory, affective, electrophysiological, and endocrine effects referable to the limbic system.