GABA receptor subtype antagonists in the nucleus accumbens shell and ventral tegmental area differentially alter feeding responses induced by deprivation, glucoprivation and lipoprivation in rats.

GABA(A) and GABA(B) receptor agonists stimulate feeding following microinjection into the nucleus accumbens shell and ventral tegmental area, effects blocked selectively and respectively by GABA(A) and GABA(B) receptor antagonists. GABA antagonists also differentially alter opioid-induced feeding responses elicited from these sites. Although GABA agonists and antagonists have been shown to modulate feeding elicited by deprivation or glucoprivation, there has been no systematic examination of feeding elicited by homeostatic challenges following GABA antagonists in these sites. Therefore, the present study examined the dose-dependent ability of GABA(A) (bicuculline, 75-150 ng) and GABA(B) (saclofen, 1.5-3 microg) antagonists administered into the nucleus accumbens shell or ventral tegmental area upon feeding responses elicited by food deprivation (24 h), 2-deoxy-D-glucose-induced glucoprivation (500 mg/kg) or mercaptoacetate-induced lipoprivation (70 mg/kg). A site-specific effect of GABA receptor antagonism was observed for deprivation-induced feeding in that both bicuculline and saclofen administered into the nucleus accumbens shell, but not the ventral tegmental area, produced short-term (1-4 h), but not long-term (24-48 h) effects upon deprivation-induced intake without meaningfully altering body weight recovery. In contrast to the relative inability of GABA receptor antagonism in both sites to alter 2-deoxy-D-glucose-induced intake, mercaptoacetate-induced intake was eliminated by saclofen and significantly reduced by bicuculline in the nucleus accumbens shell and eliminated by both bicuculline and saclofen in the ventral tegmental area. These data reinforce the findings that GABA(A) and GABA(B) receptors in the nucleus accumbens shell and ventral tegmental area are not only important in the modulation of pharmacologically induced feeding responses, but also participate in differentially mediating the short-term feeding response to food deprivation in the nucleus accumbens shell as well strongly modulating lipoprivic, but not glucoprivic feeding responses in both sites.

NPY-induced feeding: pharmacological characterization using selective opioid antagonists and antisense probes in rats.

The ability of neuropeptide Y to potently stimulate food intake is dependent in part upon the functioning of mu and kappa opioid receptors. The combined use of selective opioid antagonists directed against mu, delta or kappa receptors and antisense probes directed against specific exons of the MOR-1, DOR-1, KOR-1 and KOR-3/ORL-1 opioid receptor genes has been successful in characterizing the precise receptor subpopulations mediating feeding elicited by opioid peptides and agonists as well as homeostatic challenges. The present study examined the dose-dependent (5-80 nmol) cerebroventricular actions of general and selective mu, delta, and kappa1 opioid receptor antagonists together with antisense probes directed against each of the four exons of the MOR-1 opioid receptor gene and each of the three exons of the DOR-1, KOR-1, and KOR-3/ORL-1 opioid receptor genes upon feeding elicited by cerebroventricular NPY (0.47 nmol, 2 ug). NPY-induced feeding was dose-dependently decreased and sometimes eliminated following pretreatment with general, mu, delta, and kappa1 opioid receptor antagonists. Moreover, NPY-induced feeding was significantly and markedly reduced by antisense probes directed against exons 1, 2, and 3 of the MOR-1 gene, exons 1 and 2 of the DOR-1 gene, exons 1, 2, and 3 of the KOR-1 gene, and exon 3 of the KOR-3/ORL-1 gene. Thus, whereas the opioid peptides, beta-endorphin and dynorphin A(1-17) elicit feeding responses that are respectively more dependent upon mu and kappa opioid receptors and their genes, the opioid mediation of NPY-induced feeding appears to involve all three major opioid receptor subtypes in a manner similar to that observed for feeding responses following glucoprivation or lipoprivation.

Opioid receptor involvement in food deprivation-induced feeding: evaluation of selective antagonist and antisense oligodeoxynucleotide probe effects in mice and rats.

Central administration of general and selective opioid receptor subtype antagonists in the rat has revealed a substantial role for mu, a moderate role for kappa, and a minimal role for delta receptors in the mediation of deprivation-induced feeding. Antisense probes directed against the kappa opioid receptor (KOP), nociceptin opioid receptor (NOP), and delta opioid receptor (DOP) genes in rats result in reductions similar to kappa and delta antagonists, whereas antisense probes directed against the mu opioid receptor (MOP) gene produced modest reductions relative to mu antagonists, suggesting that isoforms of the MOP gene may mediate deprivation-induced feeding. Since these isoforms were initially identified in mice, the present study compared the effects of general and selective opioid receptor antagonists on deprivation-induced feeding in rats and mice and antisense probes directed against exons of the MOP, DOP, KOP, and NOP genes on deprivation-induced feeding in the mouse. Food-deprived (12 and 24 h) rats and mice displayed similar profiles of reductions in deprivation-induced feeding following general, mu, and kappa opioid antagonists. In contrast, mice, but not rats, displayed reductions in deprivation-induced intake following delta antagonism as well as DOP antisense probes, suggesting a species-specific role for the delta receptor. Antisense probes directed against the KOP and NOP genes also reduced deprivation-induced intake in mice in a manner similar to kappa antagonism. However, the significant reductions in deprivation-induced feeding following antisense probes directed against either exons 2, 4, 7, 8, or 13 of the MOP gene were modest compared with mu antagonism, suggesting a role for multiple mu-mediated mechanisms.