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Neurotrophins and growth factors not only affect neuronal development, but also maintain neuronal survival and influence neuronal function in the adult brain, and affect various cognitive processes related to learning and memory. Functional tolerance to ethanol represents an adaptive change in the central nervous system that has been hypothesized to have mechanisms in common with those underlying learning or memory. In the present work, the effects of neurotrophins on ethanol tolerance were compared to the effect of the neuropeptide, arginine vasopressin, which maintains (reduces the rate of dissipation of) both ethanol tolerance and memory. Functional tolerance to ethanol was induced in C57BL6J mice by feeding them an ethanol-containing liquid diet, and the effect of neurotrophins on the rate of dissipation of tolerance to the hypnotic effect of ethanol was assessed. Human recombinant brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5, injected intracere-broventricularly once daily following ethanol withdrawal, maintained ethanol tolerance, while tolerance dissipated in ethanol-fed mice injected with vehicle (artificial cerebrospinal fluid) or with basic fibroblast growth factor. The results demonstrate that some neurotrophins can modulate neuroadaptation to ethanol, supporting the hypothesis that these factors can influence the function of postmitotic neurons in the adult brain.

Administration of the neuropeptide, arginine vasopressin, can reduce the rate of dissipation of functional ethanol tolerance in mice that have acquired that tolerance. We previously showed that intracerebroventricular vasopressin administration can also produce an increase in septal c-fos mRNA levels. To evaluate the role of the increased expression of c-fos in the ability of vasopressin to maintain tolerance, ethanol-tolerant mice were given intracerebroventricular injections of vasopressin in the presence or absence of an antisense oligonucleotide to c-fos. The antisense oligonucleotide completely blocked the ability of vasopressin to maintain ethanol tolerance, while a missense oligonucleotide was without effect. The antisense oligonucleotide also attenuated the increase in septal c-fos mRNA levels caused by vasopressin. The results provide evidence for a role of c-fos expression in the maintenance of ethanol tolerance by vasopressin.

Previous work has demonstrated that arginine vasopressin (AVP), acting in the CNS, can maintain functional tolerance to ethanol. We now show that the AVP metabolite peptide, [pGlu4,Cyt6]arginine vasopressin-(4-9), also maintains ethanol tolerance, with a potency similar to that of arginine vasopressin, while nerve growth factor has only a marginal effect. The effects of these peptides on ethanol tolerance correlate with their previously described ability to induce expression of the proto-oncogene, c-fos, in the septum, a putative mechanism underlying peptide effects on neuroadaptive processes.

The effects of sulfated (CCK-8-SE) and non-sulfated (CCK-8-NS) cholecystokinin octapeptide on striatal dopamine (DA) metabolism have been investigated on mice. CCK-8-NS facilitated the disappearance of striatal DA, measured after synthesis inhibition with 350 mg/kg of α-methyl-p-tyrosine. CCK-8-SE, did not affect DA disapperance. In vitro uptake of [3H]DA by striatal slices was affected by neither CCK-8-SE, nor CCK-8-NS (10−5 M). Potassium-induced in vitro release of [3H]DA from striatal slices was significantly increased by 10−5 M CCK-8 NS: however, CCK-8-SE likewise increased DA release in this model system. Apomorphine-induced (1.0 mg/kg) stereotyped cage-climbing behavior was not affected by CCK-8-SE but was enhanced by CCK-8-NS. This effect could be antagonized by haloperidol, but not by naloxone. The data suggest that CCK-8-NS affects striatal DA release, disappearance and receptor sensitivity in the mouse. Dopaminergic mechanisms should therefore be regarded as a possible mode of action of CCK-8-NS on brain functions.