Stimulation of eating by the second messenger cAMP in the perifornical and lateral hypothalamus.

Despite intense study of neurotransmitters mediating hypothalamic controls of food intake, little is known about which second messengers are critical for these mechanisms. To determine whether adenosine 3',5'-cyclic monophosphate (cAMP) might participate in these mechanisms, we injected the membrane-permeant cAMP analog 8-bromo-cAMP (8-BrcAMP) hypothalamically in satiated rats. Injection of 8-BrcAMP (10-100 nmol) into the perifornical (PFH) and lateral hypothalamus (LH) dose dependently stimulated food intake of up to 15.7 g in 2 h. Significantly smaller responses were obtained with thalamic injections. In contrast to the strong stimulatory effects of PFH and LH 8-BrcAMP, cAMP and 8-bromo-guanosine 3',5'-cyclic monophosphate (100 nmol) were ineffective, suggesting a chemically specific, intracellular action. Consistent with this, combined PFH injection of 7-deacetyl-7-O-(N-methylpiperazino)-tau-butyryl-forskolin dihydrochloride and 3-isobutyl-1-methylxanthine, agents that increase endogeneous cAMP, stimulated eating of up to 9.9 g in 2 h. These results demonstrate that increases in PFH/LH cAMP can elicit complex, goal-oriented behavior, suggesting an important role for cAMP in hypothalamic mechanisms stimulating food intake.

Behavioral and electrical correlates of absence seizures induced by thalamic stimulation in juvenile rhesus monkeys with frontal aluminum hydroxide implants: a pharmacologic evaluation.

A new method for producing electro-clinical correlates of absence seizures (petit mal epilepsy) in conscious juvenile rhesus monkeys is described. A behavioral arrest reaction associated with concomitant 2 1/2 to 3 Hz spike and wave electroencephalograph (EEG) after discharge pattern, was obtained by thalamic stimulation in monkeys with bilaterally symmetric aluminum hydroxide (Al(OH)3) lesions in anterior premotor cortical areas. The characteristic behavioral and EEG features associated with absence seizures appeared reproducibly, 63 +/- 5 days after aluminum hydroxide cortical implantation. This test system distinguishes between anticonvulsants that are effective in generalized seizures of the absence type and anticonvulsant drugs that are effective in focal seizures. Clinically useful anti-absence drugs, such as ethosuximide, sodium valproate, clonazepam, and trimethadione, are effective in this model. Diphenylhydantoin, which is contraindicated in absence states, increases the spike and wave after-discharge pattern. The limitations, advantages, and potential usefulness of this model in predicting anti-absence activity as well as the incidence of side effects of new drugs is discussed.

Experimental spike and wave EEG pattern from thalamic stimulation in anaesthetized juvenile monkeys.

A bilaterally synchronous 3/sec spike and wave pattern in the EEG can be obtained during stimulation of the nucleus medialis dorsalis (nMD) and nucleus paracentralis (nPC) of the thalamus, in lightly anaesthetized juvenile monkeys. The spike and wave EEG patterns have a frequency of 2 1/2 to 3Hz and occur during low frequency stimulation, without continuing into the post-stimulatory phase. Stimulation of the mesencephalic reticular formation (MRF) at higher voltages inhibits the thalamic-induced spike and wave response. This finding has heuristic significance, as activating stimuli arrest the wave and spike EEG pattern of human absence (petit mal epilepsy) seizures. The study also demonstrates the morphological similarity of the 3/sec spike and wave thalamic induced response in experimental and clinical absence states as well as similarities in their alterations with different levels of activation.

Arrest reaction with concomitant spike and wave afterdischarge following thalamic stimulation in conscious juvenile monkeys with Al (OH)3 focal premotor lesions.

The behavioural and electroencephalographic responses resulting from stimulation of a specific area in the nucleus medialis dorsalis (nMD) of unanaesthetized juvenile Rhesus monkeys is described. A behavioural arrest reaction, lack of awareness and motor inhibition with concomitant 2 1/2 to 3Hz spike and wave EEG afterdischarge patterns were obtained by stimulation of the nMD in monkeys with bilaterally symmetrical aluminium hydroxide Al (OH)3 lesions in anterior premotor cortical areas.