Eating induced by perifornical cAMP is behaviorally selective and involves protein kinase activity.

It has previously been shown that agents that increase endogenous cAMP elicit robust eating when injected into the perifornical hypothalamus (PFH) but not when injected into surrounding brain sites, suggesting that PFH cAMP may play a role in eating control. We report here that bilateral microinjection of the adenylyl cyclase activator 7-deacetyl-7-O-(N-methylpiperazino)-gamma-butyryl-forskolin dihydrochloride (MPB forskolin; 300 nmol/0.3 microl) into the PFH is sufficient to elicit intense eating (up to 15.7 +/- 2.3 g in 2 h) in satiated rats, without concomitant effects on other behaviors, including gnawing and drinking. In contrast, the inactive analog 1, 9-dideoxyforskolin is ineffective, suggesting that the effects of MPB forskolin are behaviorally selective and pharmacologically specific. We also show that injection of the protein kinase A inhibitor H-89 (100 nmol) into the PFH reduced MPB forskolin-induced eating by up to 50%. Collectively, these results suggest that increased cAMP production in a single brain area may be sufficient to selectively generate a patterned, goal-oriented behavior by activating cAMP-dependent protein kinase.

The second messenger cAMP elicits eating by an anatomically specific action in the perifornical hypothalamus.

We have previously shown that a membrane-permeant analog of cAMP, 8-bromo-cAMP (8-br-cAMP), elicits a vigorous eating response when microinjected into the perifornical hypothalamus (PFH) or lateral hypothalamus (LH) of satiated rats, suggesting that increases in cAMP in these areas may be important in the neural control of eating. To determine the locus of this effect, we compared the ability of 8-br-cAMP (1-100 nmol/0.3 microl) to elicit eating after microinjection into the PFH, LH, or the following bracketing areas: the anterior and posterior LH, paraventricular nucleus of the hypothalamus, thalamus, and amygdala. 8-br-cAMP at 50 nmol elicited eating (>/=3.4 gm in 2 hr) exclusively in the PFH and LH. At 100 nmol, 8-br-cAMP elicited a larger response in these areas and elicited a smaller, more variable response in the thalamus. We similarly mapped the feeding-stimulatory effects of compounds that increase endogenous cellular cAMP in naive rats. Combined microinjection of matched doses (300 nmol) of 3-isobutyl-1-methylxanthine and 7-deacetyl-7-O-(N-methylpiperazino)-gamma-butyryl-forskolin was effective exclusively in the PFH, eliciting an average 2 hr food intake of 8.4 +/- 2.0 gm. Collectively, these results suggest that increases in cellular cAMP within a specific brain site, the PFH, may play a role in the neural stimulation of eating.

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.