Intracerebral administration of protein kinase A or cAMP response element-binding protein antisense oligonucleotide can modulate amphetamine-mediated appetite suppression in free-moving rats

Abstract

. Intracerebral administration of protein kinase A or cAMP response element-binding protein antisense oligonucleotide can modulate amphetamine-mediated appetite suppression in free-moving rats. Am J Physiol Endocrinol Metab 292: E123-E131, 2007. First published August 8, 2006; doi:10.1152/ajpendo.00195.2006.-Although amphetamine (AMPH)-induced appetite suppression has been attributed to its inhibitory action on neuropeptide Y (NPY), an appetite neurotransmitter abundant in the brain, molecular mechanisms underlying this effect are not well known. This study examined the possible role of protein kinase A (PKA) and cAMP response element-binding protein (CREB) signaling in this anorectic effect, and the results showed that both PKA and CREB mRNA levels in hypothalamus were increased following AMPH treatment, which was relevant to a reduction of NPY mRNA level. To determine whether PKA or CREB was involved in the anorectic response, intracerebroventricular infusions of antisense oligonucleotide (or missense control) were performed 60 min before daily AMPH treatment in conscious rats, and results showed that either PKA or CREB knockdown could block AMPH-induced anorexia as well as restore NPY mRNA level, indicating the respective involvement of PKA and CREB signaling in the regulation of NPY gene expression. It is suggested that hypothalamic PKA and CREB signaling may involve the central regulation of AMPH-mediated feeding suppression via the modulation of NPY gene expression. amphetamine; neuropeptide Y; feeding behavior; signaling transduction AMPHETAMINE (AMPH) is a well-known appetite suppressant. After the approval in the 1940s and 1950s of AMPH and AMPH-like compounds for the treatment of obesity, AMPH has served as a prototype for the development of subsequent anorectic drugs such as phentermine and phenylpropanolamine (11,38). AMPH derivatives, such as 3,4-methylenedioxymethamphetamine (MDMA, Adam), have emerged over the last two decades as common recreational psychostimulants or "club drugs" because of their hallucinogenic effect with relatively low toxicity (51). In humans, AMPH can be used to treat attention-deficit/hyperactivity disorder (ADHD) because of its psychomotor effects, such as increased attention, restlessness, and feelings of confidence (5, 6). Because of these effects of AMPH, the mechanisms behind AMPH-induced anorexia, weight loss, and psychomotor effects have been investigated extensively.AMPH is regarded as an indirect dopamine agonist. The anorectic action of AMPH is relevant to the central release of biogenic amines (33, 53) that in turn may lead to an inhibitory action on hypothalamic neuropeptide Y (NPY) (28). Acute treatment with AMPH markedly decreases food intake, followed by a gradual return of normal food intake with subsequent daily treatment (27,30,46). NPY, an orexigenic neurotransmitter in the brain, appears to play an essential role in the regulation of feeding behavior (7, 61) and is postulated to control the energy balance by stimulating feeding behavior and inhibiting th...

Knockdown of the transcript of ERK in the brain modulates hypothalamic neuropeptide‐mediated appetite control in amphetamine‐treated rats

“…a tolerant effect) due to hunger or a negative energy balance (Kuo et al, ). The present results confirm that POMC (or MC 3 receptors) might function reciprocally with that of NPY during amphetamine treatment (Hsieh et al, ).…”

ORIGINAL ARTICLE: The approach to the mechanism of calcitonin gene-related peptide-inducing inhibition of food intake

“…These findings suggest that cAMP acting as the second messenger may play a crucial role in the neural circuit(s) controlling eating. Besides the role in integrating multiple neuropeptides or neurotransmitters in the hypothalamus, cAMP may also contribute to the modulation of synthesis and release of peripheral hormones Hsieh et al. (2007).…”

Involvement of hypothalamic PI3K–STAT3 signalling in regulating appetite suppression mediated by amphetamine

“…This result implies that PI3K-STAT3 signalling might not be the only pathway regulating NPY and POMC expression in amphetamine-treated rats. Several other signal pathways, such as c-fos/c-jun signalling , PKA signalling (Hsieh et al, 2007) and PKCλ signalling (Hsieh et al, 2011), are also involved in regulating NPY and POMC gene expression.…”