Adrenergic pharmacology: focus on the central nervous system

Norepinephrine and epinephrine are involved in the control of several important functions of the central nervous system (CNS), including sleep, arousal, mood, appetite, and autonomic outflow. Catecholamines control these functions through activation of a family of adrenergic receptors (ARs). The ARs are divided into three subfamilies (alpha1, alpha2, and beta) based on their pharmacologic properties, signaling mechanisms, and structure. ARs in the CNS are targets for several therapeutic agents used in the treatment of depression, obesity, hypertension, and other diseases. Not much is known, however, about the role of specific AR subtypes in the actions of these drugs. In this paper, we provide an overview of adrenergic pharmacology in the CNS, focusing on the pharmacologic properties of subtype-selective AR agonists and antagonists, the accessibility of these drugs to the CNS, and the distribution of ARs in different areas of the brain.     

Adrenergic transmission facilitates extinction of conditional fear in mice

Extinction of classically conditioned fear, like its acquisition, is active learning, but little is known about its molecular mechanisms. We recently reported that temporal massing of conditional stimulus (CS) presentations improves extinction memory acquisition, and suggested that temporal spacing was less effective because individual CS exposures trigger two opposing processes: (1) fear extinction, which is favored by CS massing, and (2) fear incubation (increase), which is favored by spacing. We here report the effects of manipulating the adrenergic system during massed or spaced CS presentations in fear-conditioned mice. We administered yohimbine (5 mg/kg), an alpha(2)-receptor antagonist, or propranolol (10 mg/kg), a beta-receptor antagonist, systemically prior to CS presentation sessions and recorded both short- and long-term changes in conditional freezing. Yohimbine treatment facilitated extinction of both cue and context fear with massed protocols. When given before spaced CS presentations, propranolol led to a persistent incubation of cue fear, whereas yohimbine led to persistent extinction, compared with vehicle-treated animals, which showed no change in fear. These results suggest that norepinephrine positively modulates the formation of fear extinction memories in mice. They also provide clear evidence that spaced CS presentations trigger both fear-reducing (extinction) and fear-increasing (incubation) mechanisms.     

Varenicline ameliorates ethanol-induced deficits in learning in C57BL/6 mice

Ethanol is a frequently abused drug that impairs cognitive processes such as learning. Varenicline, an α4β2 nicotinic receptor partial agonist and α7 nicotinic receptor full agonist prescribed for smoking cessation, has been shown to decrease ethanol consumption. The current study investigated whether varenicline could ameliorate ethanol-induced deficits in learning and whether varenicline alters blood alcohol concentration in C57BL/6 mice. Conditioning consisted of two auditory conditioned stimulus (CS; 30 s, 85 dB white noise)—foot shock unconditioned stimulus (US; 2 s, 0.57 mA) pairings. For all studies, saline or ethanol (1.0, 1.5, 2.0 g/kg i.p.) was administered 15 min before training, and saline or varenicline (0.05, 0.1, 0.2 mg/kg i.p.) was administered 60 min before either training or testing. For blood alcohol analysis, saline or varenicline (0.1 mg/kg) was administered 60 min before collection, and saline or ethanol (1.0, 1.5, 2.0 g/kg) was administered 15 min before collection. Varenicline dose-dependently ameliorated ethanol-induced conditioning deficits for all three doses of ethanol when administered before training but not when administered 24 h later, before testing. In addition, varenicline did not alter blood alcohol concentration. The smoking cessation aid varenicline may have therapeutic uses for treating ethanol-associated disruptions in cognitive processes.     

Central and autonomic nervous system integration in emotion

Emotions involve physiological responses that are regulated by the brain. The present paper reviews the empirical literature on central nervous system (CNS) and autonomic nervous system (ANS) concomitants of emotional states, with a focus on studies that simultaneously assessed CNS and ANS activity. The reviewed data support two primary conclusions: (1) numerous cortical and subcortical regions show co-occurring activity with ANS responses in emotion, and (2) there may be reversed asymmetries on cortical and subcortical levels with respect to CNS/ANS interrelations. These observations are interpreted in terms of a model of neurovisceral integration in emotion, and directions for future research are presented.     

Activation and role of the medial prefrontal cortex (mPFC) in extinction of ethanol-induced associative learning in mice

Although the medial prefrontal cortex (mPFC) has been shown to be integrally involved in extinction of a number of associative behaviors, its role in extinction of alcohol (ethanol)-induced associative learning has received little attention. Previous reports have provided evidence supporting a role for the mPFC in acquisition and extinction of amphetamine-induced conditioned place preference (CPP) in rats, however, it remains unknown if this region is necessary for extinction of ethanol (EtOH)-induced associative learning in mice. Using immunohistochemical analysis of phosphorylated and unphosphorylated cAMP response element-binding protein (CREB), the current set of experiments first showed that the prelimbic (PL) and infralimbic (IL) subregions of the mPFC exhibited dynamic responses in phosphorylation of CREB to a Pavlovian-conditioned, EtOH-paired cue. Interestingly, CREB phosphorylation within these regions was sensitive to manipulations of the EtOH-cue contingency-that is, the cue-induced increase of pCREB in both the PL and IL was absent following extinction. In order to confirm a functional role of the mPFC in regulating the extinction process, we then showed that electrolytic lesions of the mPFC following acquisition blocked subsequent extinction of EtOH-CPP. Together, these experiments indicate a role for the PL and IL subregions of the mPFC in processing changes of the EtOH-cue contingency, as well as in regulating extinction of EtOH-induced associative learning in mice.     

Learning disabilities and central nervous system involvement.

The relation of damage to the central nervous system to learning disabilities remains a continuing issue. This study explored how learning disable children fare on the Visual Retention Test. Analysis of correct scores and errors for the 24 children responding to Administration A would ordinarily suggest a primary relationship (t = 2.60, p less than .02; t = 4.01, p less than .001, respectively). However, since extensive medical and case history material yielded no evidence of cerebral injury or disease and since the impact of short-term memory (Administration D) led to no further performance decrement (t less than 1.00), additional research must determine a more precise understanding of perceptual dysfunction and the role of short-term memory in regard to learning disabilities.     

Observation of action and autonomic nervous system responses

Observing somebody performing an action has been shown to elicit neuronal activity in the premotor cortex. This paper investigated physiological effect of observing an effortful action at the peripheral level. As Autonomic Nervous System responses reflect central nervous system processes such as movement planning and programming, it was expected that observing an action would elicit a pattern of ANS responses matching those recorded during actual movement. 12 male subjects, ages 23 to 28 years (M = 25.5, SD = 1.9), were selected as they were experienced in weight lifting. They were asked to observe a squat movement followed by returning to the upright position under 3 different conditions: (i) observation of actual movement performed by somebody else, (ii) observation of a video of the subject himself (first-person video), and (iii) observation of a video of somebody else performing the same movement (third-person video). Moreover, each movement was observed when performed at 50% and 90% of each participant's personal best mark (% of the highest weight which could be lifted). Three ANS parameters were continuously recorded: skin resistance, temperature and heart rate. ANS responses varied as a function of movement intensity: autonomic responses recorded during movement observation at 90% were significantly higher and longer than those recorded during movement observation at 50%. Thus, autonomic responses were linked to the amount of observed effort. Conversely, no difference was found among the three conditions of observation. ANS responses from observation of actual movement were shown to resemble those recorded under the two conditions of video observation.     

Environmental complexity and central nervous system development and function

Environmental restriction or deprivation early in development can induce social, cognitive, affective, and motor abnormalities similar to those associated with autism. Conversely, rearing animals in larger, more complex environments results in enhanced brain structure and function, including increased brain weight, dendritic branching, neurogenesis, gene expression, and improved learning and memory. Moreover, in animal models of CNS insult (e.g., gene deletion), a more complex environment has attenuated or prevented the sequelae of the insult. Of relevance is the prevention of seizures and attenuation of their neuropathological sequelae as a consequence of exposure to a more complex environment. Relatively little attention, however, has been given to the issue of sensitive periods associated with such effects, the relative importance of social versus inanimate stimulation, or the unique contribution of exercise. Our studies have examined the effects of environmental complexity on the development of the restricted, repetitive behavior commonly observed in individuals with autism. In this model, a more complex environment substantially attenuates the development of the spontaneous and persistent stereotypies observed in deer mice reared in standard laboratory cages. Our findings support a sensitive period for such effects and suggest that early enrichment may have persistent neuroprotective effects after the animal is returned to a standard cage environment. Attenuation or prevention of repetitive behavior by environmental complexity was associated with increased neuronal metabolic activity, increased dendritic spine density, and elevated neurotrophin (BDNF) levels in brain regions that are part of cortical-basal ganglia circuitry. These effects were not observed in limbic areas such as the hippocampus.     

Alcoholism and morphologic findings of the nervous system in autopsy cases

154 autopsy cases of alcoholics (120 men and 34 women) were investigated from a neuropathological viewpoint. In only 19 cases could typical diseases of the nervous system caused by alcoholism be found (Wernicke's encephalopathy, central pontine myelinolysis, Marchiafava-Bignami's disease and disorders of the peripheral nerves and muscles). In comparison liver diseases occurred almost five times more frequently in our own material. Diseases caused by alcoholism of the nervous system, the question of brain shrinkage and its partial reversibility, the up to now not completely known effects on the neurophil and cortical cytoarchitectonic are discussed according to the literature.     

Stiff-person syndrome: autoimmunity and the central nervous system

Stiff-person syndrome (SPS) is a rare disease of severe progressive muscle stiffness in the spine and lower extremities with superimposed muscle spasms triggered by external stimuli. Patients with SPS are often referred for psychiatric evaluation and the psychiatrist may be the first to diagnosis SPS. Psychosocial stressors often precede the first manifestations of the disease; depression, anxiety, and alcohol abuse are comorbid illnesses. The identification of an association with antibodies to glutamic acid decarboxylase (GAD) was invaluable for definitively establishing a pathological basis for the disease; antibodies to amphiphysin and gephyrin are also found in cases of SPS but at much lower frequencies. Whether the antibodies inhibit GAD activity in vivo, target GAD-expressing neurons for immune-mediated destruction, are part of a wider immune process, or are merely a marker for destruction of GAD-expressing neurons by an independent neurodegenerative process is not yet clear. Both electromyography and the detection of GAD antibodies are useful in establishing a diagnosis of SPS. Treatment of SPS includes the use of immunomodulating therapies (plasmapheresis and intravenous immunoglobulins) and symptomatic treatment with benzodiazepines and baclofen. The use of tricyclic antidepressants and rapid withdrawal from therapy should be avoided.     

Sympathetic nervous system and pain: a clinical reappraisal

The target article discusses various aspects of the relationship between the sympathetic system and pain. To this end, the patients under study are divided into three groups. In the first group, called "reflex sympathetic dystrophy" (RSD), the syndrome can be characterized by a triad of autonomic, motor, and sensory symptoms, which occur in a distally generalized distribution. The pain is typically felt deeply and diffusely, has an orthostatic component, and is suppressed by the ischemia test. Under those circumstances, the pain is likely to respond to sympatholytic interventions. In a second group, called "sympathetically maintained pain" (SMP) syndrome, the principal symptoms are spontaneous pain, which is felt superficially and has no orthostatic component, and allodynia. These symptoms, typically confined to the zone of a lesioned nerve, may also be relieved by sympathetic blocks. Since the characteristics of the pain differ between RSD and SMP, the underlying kind of sympathetic-sensory coupling may also vary between these cases. A very small third group of patients exhibits symptoms of both RSD and SMP. The dependence or independence of pain on sympathetic function reported in most published studies seems to be questionable because the degree of technical success of the block remains uncertain. Therefore, pain should not be reported as sympathetic function independent until the criteria for a complete sympathetic block have been established and satisfied.     

Aspects of biochemical differentiation in the central nervous system

A demonstration of cell-specific patterns of development in the immature CNS is provided by examples of characteristic, cellspecific time-courses of enzyme development in different classes of brain cells isolated in highly purified form by bulk-separation from the cerebral and cerebellar cortex of the growing rat. The enzymatic analysis was carried out at the level of the nerve and glial cell lysosomes and mitochondria, two subcellular organelles crucial to the economy of all cells. The findings reveal rather similar developmental patterns for the lysosomal hydrolase N-acetyl-β-D-glucosaminidase in neurons and glial cells of the cerebral cortex as well as in two different cerebellar nerve cell types, the Purkinje and the granule cell. However, significant differences in the post-natal chronology of development of the mitochondrial enzyme α-glycerophosphate dehydrogenase were noted between cortical nerve and glial cells, the glial enzyme exhibiting 6-fold higher levels of activity than the neuronal one throughout the first month of postnatal life. The findings emphasize the feasibility as well as the necessity of studies aimed at the elucidation of the cell-specific aspects of the biochemistry of developing nerve and glial cells.     

Studies of nervous system sensitivity in children with learning and attention disorders

Clinically referred children, diagnosed as having learning or attention disorders, with or without hyperactivity, were found to vary widely on a measure of nervous system sensitivity recommended by the Pavlovian investigator Vasilev. That is, the children were contrasted on their mean press and release reaction times (RTs) to four tones, ranging from soft (55 db) to very loud (100 db), with the expectation that some would be able to maintain a parallel separation of press and release RT gradients across all intensity levels (strength), whereas others would show convergence or overlap of the gradients at higher intensities (weakness). Contrary to expectation, girls did not have weaker or more sensitive nervous systems than boys, although the girls rated themselves as less tolerant of intense stimuli. Significantly more of the children diagnosed as hyperactive had weaker nervous systems. The boys also participated in a blind crossover study contrasting placebo and methylphenidate effects; the prescribing physician, who was not informed of the child’s nervous system classification, adjusted the dosage levels so that subjects with weaker nervous systems were titrated at higher dosage levels than those with stronger nervous systems. Gray (1964) suggested an explanation of this paradox, i.e., that the weak nervous system requires a more intense stimulus than the strong to reach the threshold of concentration (or focused attention), whereas for other thresholds the strong requires a more intense stimulus than the weak. Gray’s theory was further supported by the finding that children typed as weak (unmedicated) did not show as great facilitation in RT with reward (moderate stimulus) as did those typed as strong.     

Strength of the nervous system and augmenting-reducing: Paradox lost

Two conflicting viewpoints were identified regarding the relationship between sensation seeking and subjective response to stimulation: (a) that sensory augmenters are high sensation seekers compared with sensory reducers (the view of Zuckerman and Buchsbaum); and (b) that it is the reducer rather than the augmenter who is the high sensation seeker (the view of Petrie and Vando). Proponents of the first approach measure Augmenting-Reducing through the use of the average cortical-evoked response, while advocates of the second position use Petrie's version of the Kinaesthetic Figural Aftereffects Test or Vando's Reducer-Augmenter Scale. It is argued that the disagreement is semantic and results from the differences in method of measurement. It is further argued that most, if not all, of the research findings may be accommodated within the framework of strength-of-the-nervous-system theory which distinguishes between two dimensions,sensitivity andfunctional endurance. The implications for future research are pointed out.     

Conditioned nausea after cancer chemotherapy and autonomic nervous system conditionability

There are marked individual differences in conditioned nausea after cancer chemotherapy. To examine if part of this variation is associated with individual differences in autonomic nervous system conditionability, the present study addressed whether patients with conditioned nausea acquired conditioned heart rate and electrodermal responses at a different rate than patients without conditioned nausea. Of 28 relapse-free patients who had completed cisplatinum treatment for testicular cancer between 1981 and 1986, 10 reported persistent conditioned nausea, 8 extinguished conditioned nausea and 10 no conditioned nausea. These three groups were subjected to a differential conditioning paradigm with 8 sec pictorial stimuli (circles and triangles) serving as conditioned stimuli for an unconditioned electric shock while heart rate and electrodermal activity was monitored. There were 4 habituation, 8 acquisition and 8 extinction trials with each of the two cues. Analyses of variance using nausea status as the independent variable and physiological responses as the dependent lended some support to the notion that conditioned heart rate deceleration developed in response to the reinforced compared to the nonreinforced cue during acquisition in the two groups with persistent or extinguished conditioned nausea but not in the group with no conditioned nausea. In addition, patients that displayed good, as compared to poor heart rate conditionability during acquisition, were more likely to have persistent conditioned nausea, whereas those who showed poor heart rate conditioning mostly were those without conditioned nausea. Electrodermal variables revealed no systematic differences between groups. This tentatively supports that individual differences in parasympathetic but not sympathetic nervous system conditionability may be associated with individual differences in conditioned nausea resulting from cancer chemotherapy.