Hypothalamic sites for cardiovascular and sympathetic modulation by prostaglandin E2

Prostaglandin E₂ (PGE₂, 0.5–5 nmol/kg) injected into the lateral cerebral ventricle of the rat increased the systemic blood pressure and heart rate in a dose dependent manner. These effects were accompanied by increases in plasma norepinephrine and epinephrine concentration. Injection of the low dose of prostaglandin E₂ into discrete hypothalamic nuclei induced a marked increase in heart rate, a moderate increase in the arterial blood pressure and a significant elevation of plasma norepinephrine level. This study suggests a possible central role for PGE₂ in modulation of cardiovascular dynamics and sympathetic nervous activity.     

Interactions of norepinephrine with Purkinje cell responses to putative amino acid neurotransmitters applied by microiontophoresis

In cerebellum, the evoked responses of the Purkinje neuron to both excitatory and inhibitory afferent input are enhanced by local norepinephrine (NE) administration. To determine the nature of this synergistic interaction between NE and the synaptic inputs, Purkinje cell responses to microiontophoretically applied amino acid neurotransmitters were examined before, during, and after NE iontophoresis. NE was found to preferentially augment GABA-induced inhibition, whereas it antagonized inhibition produced by glycine. This enhancement of GABA inhibition was seen at NE doses which caused minimal change in spontaneous activity, and at times after spontaneous discharge returned to control levels following NE application. Dopamine did not facilitate the response to GABA even at doses having direct depressant effects on spontaneous discharge. Glutamate-evoked excitations and subsquent depressions were also augmented during NE administration, relative to the level of background activity. Thus, NE selectively enhanced responses of Purkinje neurons produced by microiontophoretic application of amino acids postulated to be cerebellar neurotransmitters, supporting the hypothesis that NE acts on postsynaptic processes to increase the responsiveness of the Purkinje cell to afferent input. These data also provide evidence supporting the concept that a primary effect of noradrenergic input to cerebellum may be to modulate the action of other transmitters.     

Modulation of sensory responsiveness of single somatosensory cortical cells during movement and arousal behaviors

This study tested the hypothesis that the transmission of cutaneous sensory information to single somatosensory (SI) cortical neurons may be modulated or gated during movement or “arousal” behaviors. The results showed that movement by itself was associated with a powerful suppression of the sensory input to SI cortical cells from their cutaneous receptive fields. Control experiments showed that this sensory suppression during movement could not be due to either(i) an obscuring of the sensory responses by the large increases in the spontaneous discharge rates of these cells generally found during movement, (ii) an occlusion of the sensory response to the test stimuli by the increased activity in parallel sensory channels caused by repetitive foot contact during locomotion, (iii) distraction of the animal's attention or, (iv) differences in the motivational or arousal states associated with various movement states, because sensory suppression was found in both grooming and treadmill locomotion. It was also found that, in the absence of movement, strong arousal was associated with a slight increase in sensory responsiveness and a decrease in spontaneous discharge rate. The finding that movement rather than arousal or attentiveness caused the most potent modulation of the sensory responsiveness and firing rates of SI cortical cells suggests that this cortical area may be closely integrated with central nervous system motor functions.     

The cortisol response to desipramine in endogenous depressives and normal controls: preliminary findings

Plasma cortisol levels were monitored for 2 hours after an intramuscular injection of 75 mg desipramine in 13 endogenous depressives and 20 normal controls. Endogenous depressives had a significantly reduced cortisol response in comparison to normal controls, not explained by sex, age, or baseline cortisol differences between groups. A lack of a cortisol rise of 1.5 micrograms/dl above baseline by 45 minutes discriminated best, with 7 of 13 depressives (55%) being identified in contrast to only 1 of 20 normals (5%). The results suggest that this may be a useful biological test with acceptable sensitivity (55%) and excellent specificity (95%). Furthermore, these data suggest that norepinephrine may be stimulatory to cortisol in man.     

Increased branching of basal dendrites on pyramidal neurons in the occipital cortex of homozygous Brattleboro rats in standard and enriched environmental conditions: A Golgi study

As a continuation of our previous reports in a series of studies on the brain of Brattleboro rats, the branching of basal dendrites of pyramidal neurons in the upper layers of the occipital cortex was quantified in three groups of male heterozygous and homozygous Brattleboro rats. One group raised in standard environmental conditions was killed at 60 days of age, and another from standard conditions was killed at 90 days of age. A third group from enriched environmental conditions was killed at 90 days of age after 30 days of enrichment. Comparing the two types of Brattleboro rats, the homozygous rats showed significantly more total dendritic branching segments per neuron in both the 60-day-old standard condition group and the 90-day-old enriched group. A similar measure (segments per primary branch) was also significantly greater in homozygous than in heterozygous rats at 60 days of age. In the 90-day-old enriched group, the homozygous rats showed a trend toward more segments per primary branch than the heterozygous rats. The results suggest that the complete absence of vasopressin produces metabolic effects which, at certain ages or in certain environmental conditions, increase the branching of basal dendrites of pyramidal neurons in the upper layers of the occipital cortex.     

Norepinephrine release in medial amygdala facilitates activation of the hypothalamic-pituitary-adrenal axis in response to acute immobilisation stress

Activation of the brain noradrenergic system during stress plays an important integrative function in coping and stress adaptation by facilitating transmission in many brain regions involved in regulating behavioural and physiological components of the stress response. The medial amygdala (MeA) has been implicated in modulation of stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, and MeA is a target of innervation from brainstem noradrenergic neurones. However, it is not known whether, and to what extent, activation of the ascending noradrenergic innervation of MeA might modulate stress-induced adrenocorticotropic hormone (ACTH) secretion. In the first experiment in this study, we measured extracellular norepinephrine (NE) levels in MeA using in vivo microdialysis. The concentration of NE in dialysate samples collected in MeA was elevated by more than three-fold over baseline in response to acute immobilisation stress, providing evidence of a possible modulatory role for NE in the MeA during stress. This potential role was then assessed in the second experiment by measuring changes in the elevation of plasma ACTH concentration induced by acute immobilisation stress immediately following bilateral microinjections of alpha1- or beta-adrenergic receptor antagonists directly into MeA. Compared to vehicle-injected controls, the alpha1-receptor antagonist benoxathian dose-dependently and significantly attenuated the ACTH response to acute stress, whereas combined beta1/beta2-receptor blockade in MeA had only a modest effect. These results indicate that MeA does play a role in the stress response, and support the hypothesis that stress-induced activation of NE release in MeA, acting primarily through alpha1 receptors, facilitates activation of the HPA axis in response to acute stress.     

Identification and characterization of a novel allosteric modulator (SoRI-6238) of the serotonin transporter

In the present study we describe a novel agent, SoRI-6238 (ethyl 5-amino-3-(3,4-dichlorophenyl)-1,2-dihydropyrido[3,4-b]pyrazin-7-ylcarbamate) that partially inhibits 5-HT transporter (SERT) binding and allosterically modulates SERT function. Membranes were prepared from rat brain. SoRI-6238 partially inhibited SERT binding to brain membranes with a plateau at about 40% of control. SoRI-6238 fully inhibited norepinephrine transporter (NET) and dopamine transporter (DAT) binding with IC(50) values of 12.1 microM and 5.8 microM, respectively. The apparent K(d) of [(125)I]RTI-55 binding to SERT increased, then reached a plateau with increasing concentrations of SoRI-6238. SoRI-6238 fully inhibited [(3)H]5-HT uptake, acting to decrease the V(max) (noncompetitive inhibition). In kinetic experiments, SoRI-6238 slowed the dissociation of [(125)I]RTI-55 from SERT and slowed the initial association rate. We conclude that SoRI-6238 partially inhibits SERT binding and function, most likely via an allosteric mechanism.     

Genetics of monoamine metabolites in baboons: overlapping sets of genes influence levels of 5-hydroxyindolacetic acid, 3-hydroxy-4-methoxyphenylglycol, and homovanillic acid

Background

Monoamine neurotransmitters (serotonin, dopamine, and norepinephrine) are associated with several psychiatric disorders. Limited evidence suggests that monoamine levels are heritable, but no information concerning genetic relationships among monoamines is available. Further genetic analysis can help explain phenotypic correlations among monoamine levels and might eventually help identify genes involved in response to therapy or risk of psychopathology.

Methods

Levels of the monoamine metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-hydroxy-4-methoxyphenylglycol (MHPG) were measured in cerebrospinal fluid from 271 baboons (Papio hamadryas). Variance components methods were used to estimate heritabilities, and multivariate analyses were used to estimate genetic correlations (pleiotropy) and environmental correlations between metabolites.

Results

Each metabolite exhibited significant heritability in baboons (5-HIAA: h² = .30 ± .17; MHPG: h² = .36 ± .16; HVA: h² = .50 ± .19). Multivariate analyses revealed genetic correlations between 5-HIAA and HVA and between HVA and MHPG. Environmental correlations were found between 5-HIAA and HVA and between 5-HIAA and MHPG.

Conclusions

Overlapping, nonidentical sets of genes influence individual variation in 5-HIAA, MHPG, and HVA levels among baboons. The phenotypic correlation between 5-HIAA and HVA observed in nonhuman primates and humans is likely due to both shared genetic and environmental factors. Genetic analyses of monoamine levels in primates can provide novel information concerning the genetics of variation among humans.     

Blockade of noradrenergic receptors in the basolateral amygdala impairs taste memory

In conditioned taste aversion (CTA), a subject learns to associate a novel taste (conditioned stimulus, CS) with visceral malaise (unconditioned stimulus, US). Considerable evidence indicates that the noradrenergic system in the amygdala plays an important role in memory consolidation for emotionally arousing experiences. The specific aim of the present set of experiments was to determine the involvement of noradrenergic activity in the basolateral amygdala (BLA) during the US presentation and consolidation of CTA as well as during the consolidation of a nonaversive/incidental gustatory memory. Selective bilateral microinfusions of the beta-adrenergic antagonist propranolol administered into the BLA immediately before intraperitoneal (i.p.) lithium chloride (LiCl) injections disrupted CTA memory. Additionally, propranolol infused into the BLA immediately after a pre-exposure to the saccharin (CS) significantly attenuated latent inhibition. The present findings indicating that alterations in noradrenergic function in the BLA affect taste memory formation, provide additional evidence that the BLA plays a critical role in modulating the consolidation of memory and that the influence is mediated by interactions with other brain regions that support memory for different kinds of experiences.     

Modulating effects of posttraining epinephrine on memory: Involvement of the amygdala noradrenergic system

These experiments examined the effects, on retention, of posttraining intra-amygdala administration of norepinephrine (NE), and propranolol. Rats were trained on a one-trial step-through inhibitory avoidance task and tested for retention 24 h later. Injections were administered bilaterally (1.0 microliter/injection) through chronically-implanted cannulae. Low doses of NE (0.1 or 0.3 microgram) administered shortly after training enhanced retention while higher doses (1.0 or 5.0 micrograms) were ineffective. Retention was not affected by NE administered 3 h after training. The effect of intra-amygdala NE on retention is blocked by simultaneous administration of propranolol (0.2 microgram). This finding suggests that the memory-enhancing effect of NE may be mediated by beta-receptors. Posttraining intra-amygdala NE also attenuated the retention deficit produced by adrenal demedullation. Further, intra-amygdala injections of propranolol (0.2 microgram) blocked the enhancing effect, on retention, of posttraining s.c. injections of epinephrine. These findings suggest that activation of noradrenergic receptors in the amygdala may be involved in memory processing and may play a role in the memory-modulating effect of peripheral epinephrine.