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Gamma-Aminobutyric acid (GABA) levels in cerebrospinal fluid were measured in seven patients with tension headache and 12 patients with migraine. GABA was detected only during the migraine attack. The results suggest disordered GABA metabolism in migraine.

Adenosine 3',5'-cycle monophosphate (cyclic AMP) (0.5 mg/kg) was infused into the carotid artery of baboons anesthesized with sodium pentobarbital, causing a biphasic increase in cerebral blood flow (CBF) and reduction in cerebrovascular resistance (CVR) associated in each phase with stimulation of cerebral metabolism evidenced by increased cerebral oxygen consumption (COMRO2) and cerebral glucose consumption (CMRG1). Intracarotid dibutyryl cyclic AMP (0.5 mg/kg) caused a monophasic increase in CBF and reduction of CVR but failed to alter cerebral metabolism. This may be due to its rapid removal from the circulation with ineffective passage across the blood-brain barrier since intracisternal infusion of dibutyryl cyclic AMP caused sustained increase in CBF, CMRO2 and CMRG1 and reduction in CVR. Intracarotid AMP (0.4 mg/kg) and adenosine (0.3 mg/kg) caused an immediate and more marked increase in CBF and decrease in CVR unassociated with cerebral metabolic change making it unlikely that the observed effects of cyclic AMP can be attributed to its breakdown products. Cyclic AMP or its dibutyryl derivative may alter cerebral metabolism secondary to neuronal activation but increase in glucose/oxygen utilization ratio after intracarotid cyclic AMP and intracisternal dibutytyl cyclic AMP also suggests an influence on enzymatic regulation of glucose metabolism.

In a series of 11 dogs, selective stimulation of the carotid body receptors by hypoxic, hypercapnic, acidotic blood produces bradycardia, an increase of coronary flow, and greater release of norepinephrine from the heart; the coronary resistances are decreased. The same stimulation after vagotomy is no longer accompanied by bradycardia; the decrease of coronary resistance is less marked and the release of norephinephrine is increased.

Cerebral hemispheric blood flow and metabolism were measured before and after therapy with intracarotid infusion of combined PBZ and PPL in 15 patients with recent cerebral infarction. HBF was unaltered despite decrease in cerebral perfusion pressure. Cerebral hemispheric oxygen comsumption and carbon dioxide production decreased while cerebral hemispheric lactate production increased. Biphasic cerebral uptake of tyrosine was observed during and immediately after PBZ and PPL infusion. CSF HVA increased, indicating altered DA turnover. CSF 5HIAA levels also increased, suggesting altered 5HT turnover after PBZ and PPL. Release of cyclic AMP from ischemic brain into cerebral venous blood seen in the steady state was abolished after therapy. Cerebral hemodynamic studies suggest a functional balance between monaminergic neurogenic influences in the control of cerebral circulation. Imbalance of such controlling factors in ischemic brain may lead to paradoxical vascular responses to induced hypertension and hypotension. PBZ and PPL enhance such responses perhaps by increasing central neurotransmitter turnover and release. Further shift toward cerebral anaerobic metabolism may occur in ischemic brain following the use of phenoxybenzamine and propranolol. Worsening of neurological deficit occurred in four cases. Combined therapy with PBZ and PPL does not appear beneficial in the therapy of patients with recent stroke.

The effect of ischemia on catecholamine and 5-hydroxytryptamine (5-HT) levels in brain cortex was examined in the gerbil stroke model. Unilateral common carotid artery occlusion produced bilateral decrease in cortical dopamine levels in gerbils both symptomatic and asymptomatic of cerbral ischemia. The 5-HT progressively decreased only in the occluded hemisphere of ischemic animals. In p-chlorophenylalanine (PCPA)-treated gerbisl, dopamine decreased only in the occluded hemisphere of symptomatic animals, but norepinephrine became decreased bilaterally compared with controls. The 5-HT decrease was twice that seen in untreated animals. It is suggested that these results indicate initial release together with reduced synthesis of monoamines in ischemic brain. The incidence of ischemia induced by carotid occlusion decreased from 44% to 26% in PCPA-treated animals, which also suggests that depletion of 5-HT available for neuronal release prior to the induction of ischemia may reduce stroke incidence by limiting impairment of collateral vasocapacitance. PCPA pretreatment did not influence the development of edema in the occluded hemisphere of ischemic animals once ischemia was established.

In a series of 7 dogs, selective stimulation of the carotid body receptors by hypoxic blood produces an increase of coronary flow and greater release of norepinephrine from the heart; the increase of coronary flow is less marked and the release of norepinephrine is increased after vagotomy. Myocardial norepinephrine content is decreased by carotid body stimulation.

In baboons the right cerebral hemisphere was embolised by a shower of microemboli, immediately followed by one large embolus designed to occlude the middle cerebral artery (MCA). One hour after embolism a significant, though small, reduction in blood flow and oxygen consumption of the embolised hemisphere was recorded, at which time the animals were killed and brain monoamines measured. Dopamine was reduced in the ipsilateral caudate nucleus, the reported site of maximal ischaemic damage in this model. Dopamine levels were increased in frontal and occipital grey matter sampled from areas surrounding the occluded MCA territory and in similar brain areas of the opposite non-embolised hemisphere. Noradrenaline was increased in grey matter from both cerebral hemispheres, as well as subcortical structures bilaterally. Brain 5-hydroxytryptamine levels were unaltered, but increased 5-hydroxyindoleacetic acid in cisternal cerebrospinal fluid suggested transient alteration in 5-hydroxytryptamine metabolism after embolism. The effects of cerebral embolism on brain monoamine metabolism appear to be different from the effects of permanent surgical occlusion of major cerebral vessels. The bilaterality of effects after unilateral hemispheric embolism might be related to diaschisis. The mechanisms of the observed changes, as well as their relevance to the progression of cerebral ischaemia and the complications associated with cerebral embolism, still require to be established.

The effect of intravenous infusion of 10 per cent glycerol on regional cerebral blood flow (using hydrogen bolus and Xenon-133 (133Xe) clearance methods) and metabolism was investigated in 57 patients with recent cerebral infarction. Hemispheric blood flow (HBF) increased, together with increase in regional cerebral blood flow (rCBF) and cerebral blood volume (rCBV), in foci of brain ischemia. Hemispheric oxygen consumption (HMIO2) decreased together with hemispheric respiratory quotient. Systemic blood levels of glucose, lactate, pyruvate, and triglycerides also increased after glycerol while free fatty acids (FFA) and inorganic phosphate (Pi) decreased. Hemispheric glucose consumption was unaltered after glycerol so that hemispheric glucose to oxygen ratio tended to rise. Pyruvate and lactate production by brain was unchanged. Glycerol moved across the blood brain barrier into brain and cerebrospinal fluid (CSF). Release of FFA and Pi from infarcted brain was reversed by glycerol. Total phosphate balance was maintained actoss brain both before and after glycerol infusion. Triglycerides increased in CSF after glycerol, originating either from cerebral blood or as a result of lipogenesis in cerebral tissue. The EEG Recording and neurological status of the patients improved despite decreased brain oxygen consumption. Results of this study suggest that after intravenous infusion of 10 per cent glycerol in patients with recent cerebral infarction, glycerol rapidly enters the CSF and brain compartments and favorably affects the stroke process in two ways: first, by redistribution of cerebral blood flow with increase in rCBF and rCBV in ischemic brain secondary to reduction in focal cerebral edema; and second glycerol may become an alternative source of energy either by being directly metabolized by the brain, or indirectly, by enhancing lipogenesis, or by both processes. Involvement of glycerol in lipogenesis with esterification to accumulated FFA might lead to improved coupling of oxidative phosphorylation, a hypothesis that fits the finding of improved neuronal function despite further decrease in cerebral hemispheric oxygen consumption.

Cerebrospinal fluid gamma-aminobutyric acid (CSF GABA) was analyzed in 151 patients who underwent evaluation for central nervous system disease. CSF GABA was not detected in 19 of these patients, who had no evidence of neurologic disease and who served as controls. GABA was most frequently detected in patients with cerebrovascular disease, and was detected only in Parkinson's syndrome of atherosclerotic origin and dementia of multi-infarct type. CSF GABA was not detected in Alzheimer's disease or Huntington's disease. Patients with grand mal seizures exhibited CSF GABA elevation within 24 hours of the ictus. In patients with multiple sclerosis GABA detection was related to the presence or exacerbation of spinal cord lesions. Further study is necessary to evaluate the significance of elevated CSF GABA in central nervous system disease.

Seizure activity as a component of the ischemic process possibly responsible for monoamine changes described in the gerbil stroke model was the subject of this study. Abnormal motor activity suggestive of seizures developed one to three hours after unilateral ligation of the common carotid artery in approximately 50% of gerbils that exhibited signs of stroke. Reduction of cortical levels of dopamine and norepinephrine was observed only when seizures occurred in association with stroke. The levels of 5-hydroxytryptamine were reduced bilaterally in animals with and without signs of stroke and were reduced further in animals with stroke plus seizures. Further study is needed to establish whether the catecholamine changes associated with ischemia-induced seizures are primary and causative or secondary to seizure activity itself. In the ischemic brain, 5-hydroxytryptamine metabolism appears disordered independent of seizure activity. Seizure activity must be taken into account when the mechanisms of disordered monoamine metabolism are being examined in the gerbil stroke model.