The effects of acetaldehyde on nicotine-induced transmitter levels in young and adult brain areas.

The aim of the present study was to examine the effect of acetaldehyde administration on neurotransmitters in the presence of nicotine in brain areas associated with cognition and reward. We assayed these effects via microdialysis in conscious freely moving male Sprague-Dawley rats. It was reported that low doses of acetaldehyde enhance nicotine self-administration in young, but not in adult rats. Since nicotine enhances reward and learning, while acetaldehyde is reported to enhance reward but inhibit learning, acetaldehyde thus would be likely to stimulate reward without stimulating learning. We hoped that examining the effects of acetaldehyde (on nicotine-mediated neurotransmitter changes) would help to distinguish reward mechanisms less influenced by learning mechanisms. To avoid the aversive effect of acetaldehyde, we used a low dose of acetaldehyde (0.16 mg/kg) administered after nicotine (0.3mg/kg). We analyzed six brain regions: nucleus accumbens shell (NAccS), ventral tegmental area (VTA), ventral and dorsal hippocampus (VH and DH), and prefrontal and medial temporal cortex (PFC, MTC), assaying dopamine (DA), norepinephrine (NE) and serotonin (5-HT) and their metabolites in young and adult rats. The effect of acetaldehyde on nicotine-induced transmitter changes was different in young as compared to adult rat brain regions. In the NAccS of the young, DA was not affected while NE and 5-HT were increased. In the adult in this area DA and NE were decreased, while 5-HT was not altered. In other areas also in many cases, the effect of acetaldehyde in the young and in the adult was different. As an example, acetaldehyde administration increased NE in young and decreased NE in adult DH. We found stimulation of nicotine-induced changes by acetaldehyde in seven instances - six of these were observed in areas in young brain, NE in four areas (NAccS, DH, VH, and PFC), and 5-HT in two (NAccS and DH). Only one increase was noted in adult brain (DA in VTA). Inhibition of nicotine-induced changes by acetaldehyde was noticed in four young brain areas (DA in PFC and MTC, 5-HT in VTA, and VH) and in 13 adult brain areas (DA in NAccS, DH, VH, PFC, MTC, NE in NAccS, DH, PFC, MTC, and 5-HT in DH, VH, MTC, and PFC). Thus acetaldehyde was more stimulatory in young and more inhibitory in the adult brain areas tested, which could explain its stimulating nicotine reward only in young animals. That increases in NE were noted only in young, decreases in NE only in adult brain areas further suggest the role of NE in the age-dependent response. In general, six areas showed some increase and four showed decrease in the young versus one showing increase and thirteen showing decrease in the adult. Clearly the effects of acetaldehyde in young animals are different from those in adult animals. Because acetaldehyde did not induce elevated DA levels in the NAccS of the young, we believe that the higher reward in the young caused by acetaldehyde is not likely due to DA changes in the accumbens. The increase of NE and 5-HT in the brain areas of the young only raises the possibility that they may play an important role in reward in some cases when DA in the accumbens does not. Areas involved in cognitive mechanisms and a number of transmitters seem to play a role in reward stimulation.

Nicotine-induced monoamine neurotransmitter changes in the brain of young rats.

A number of studies in various species including man indicated a greater risk of drug preference and addictive behavior in young as compared to adults. Such age dependent preference was also found with nicotine. To examine possible mechanisms for this difference in our continuing study of reward mechanisms, we compared nicotine-induced neurotransmitter changes in the brain regions of adult and young Sprague-Dawley rats, assaying the transmitters via microdialysis in conscious freely moving animals. In general, nicotine-induced changes were significantly less in the regions measured in the young. Nicotine-induced effects on dopamine in the dorsal and ventral hippocampus (VH), prefrontal and medial temporal cortex, and superior cerebral peduncle were lower in the young than in adult, the same in the ventral tegmental area (VTA) and lateral septal nucleus (LS), and somewhat higher in the nucleus accumbens shell (NAccS). Norepinephrine levels in the young were lower in all areas except in the VH where they were the same, and serotonin levels were lower except in the VTA and LS where they remained the same, and higher in the NAccS. Age-dependent differences in the metabolites measured were more mixed. We conclude that the greater nicotine preference in young is not paralleled by a greater effect of nicotine on the release of monoamines at least in most of the brain areas assayed. Thus, increases of nicotine reward are not likely due to increases of monoamines in reward and cognitive areas. The small increase of dopamine (DA) and more significant increase of serotonin (5-HT) only in the NAccS are of significance, and would indicate a more significant role of 5-HT than of DA at least in the age difference in nicotine preference. Developmental changes in receptor composition and distribution involving several transmitter systems and other components such as neuropeptides are also likely to play a role.

The effects of glutamate and GABA receptor antagonists on nicotine-induced neurotransmitter changes in cognitive areas.

In the present study, we tested the effects of glutamate and GABA receptor antagonists on nicotine-induced neurotransmitter changes in the hippocampal (dorsal and ventral) and cortical (medial temporal and prefrontal) brain areas of conscious freely moving rats via microdialysis. Both the antagonists and nicotine were administered intracerebrally. The antagonists tested were NMDA, AMPA-kainate, and metabotropic glutamate receptor subtype antagonists (MK801, CNQX, and LY 341495, respectively) and GABA(A) and GABA(B) receptor subtype antagonists (bicuculline and hydroxysaclofen, respectively). We assayed nicotine-induced changes in dopamine (DA), norepinephrine (NE), serotonin (5-HT), and their metabolites. We found with the antagonists, both decreases and increases in nicotine-induced neurotransmitter responses. In the presence of nicotine all the antagonists (except LY 341495) caused a decrease in DA levels in the regions tested. NE levels were decreased in the cortex by all antagonists. In the hippocampus, GABA antagonists decreased NE levels, as did the metabotropic glutamate antagonist, LY 341495, while the other glutamate antagonists increased NE levels. The results of the 5-HT assay were more variable and dependent on the region and antagonist examined; increases were found slightly more often than decreases. The changes in metabolites were not often parallel with changes in their associated neurotransmitters, indicating that the antagonists also affect the metabolism of the neurotransmitters. The effect of the antagonists in the absence of nicotine was mostly to decrease the level of neurotransmitters, although increases were seen in a few cases. The results suggest that the excitatory glutamatergic- and inhibitory GABAergic-amino acid receptors are both involved in mediating nicotine-induced neurotransmitter responses, and their inhibitory or stimulatory effects are receptor subtype and brain region dependent.

Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study.

Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine and the N-methyl-D-aspartate (NMDA) antagonist, memantine are the medications currently approved for the treatment of Alzheimer's disease (AD). In addition to their beneficial effects on cognitive and functional domains typically disrupted in AD, these agents have also been shown to slow down the emergence of behavioral and psychotic symptoms associated with this disease. However, the underlying mechanisms for these therapeutic effects remain poorly understood and could involve effects of these medications on non-cholinergic or non-glutamatergic neurotransmitter systems respectively. These considerations prompted us to initiate a series of investigations to examine the acute and chronic effects of donepezil (Aricept (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-1 hydrochloride and memantine (1-amino-3,5-dimethyladamantane hydrochloride C12H21N.HCl)). The present study focuses on the acute effects of donepezil and memantine on brain extracellular levels of acetylcholine, dopamine, serotonin, norepinephrine and their metabolites. We assayed changes in the ventral and dorsal hippocampus and the prefrontal and medial temporal cortex by microdialysis. Memantine resulted in significant increases in extracellular dopamine (DA), norepinephrine (NE), and their metabolites, in the cortical regions, and in a reduction of DA in the hippocampus. Donepezil produced an increase in extracellular DA in the cortex and in the dorsal hippocampus. Norepinephrine increased in the cortex; with donepezil it increased in the dorsal hippocampus and the medial temporal cortex, and decreased in the ventral hippocampus. Interestingly both compounds decreased extracellular serotonin (5HT) levels. The metabolites of the neurotransmitters were increased in most areas. We also found an increase in extracellular acetylcholine (ACh) by memantine in the nucleus accumbens and the ventral tegmental area. Our results suggest both region and drug specific neurotransmitter effects of these agents as well as some similarities. We conclude that drugs influencing cognitive mechanisms induce changes in a number of neurotransmitters with the changes being both region and drug specific. Release and metabolism are altered and extracellular neurotransmitter levels can be increased or decreased by the drugs. Other studies are in progress to determine the pharmacological effects associated with chronic treatment with these compounds, which may be more pertinent to the clinical situation in which patients take these medications for months or years.

Locally administered low nicotine-induced neurotransmitter changes in areas of cognitive function.

The present study examined the effect of a low-dose of nicotine; below that one expects to be achieved from a single cigarette, on brain regional heterogeneity and sensitivity of catecholaminergic responses. 1 microM nicotine was infused into six brain areas via a microdialysis probe: the dorsal and ventral hippocampus, the medial temporal and prefrontal cortex, the basolateral amygdala, and the ventral tegmental area (VTA). The nicotine concentration in the brain tissue near the probe site was approximately 0.1 microM. Nicotine-induced increases and decreases could be noted in dopamine (DA), norepinephrine (NE), and serotonin (5HT) levels. In particular, DA and 5HT decreased in both hippocampal areas, while NE increased in the dorsal and decreased in the ventral hippocampus. In the cortical areas, DA and NE increased and 5HT was not significantly altered. In the amygdala all three neurotransmitters increased and in the VTA, all three decreased. Many of the nicotine-induced changes in neurotransmitter concentrations were reversed in the presence of atropine. Where nicotine induced decreases in DA and 5HT in the VTA, increases were observed in the presence of atropine. A similar reversal was seen with NE in the VTA and ventral hippocampus. In contrast, the increases in DA observed in the cortex and amygdala and the increases in NE observed in the cortex, amygdala and dorsal hippocampus were inhibited by the presence of atropine. 5HT was also significantly decreased in the amygdala and both cortical areas in the presence of atropine, where nicotine alone had no significant effect. We conclude, that at low doses, nicotine significantly alters the release of DA, NE, and 5HT--in some areas increasing, in others decreasing endogenous neurotransmitter levels. This data, in conjunction with previous experiments, indicates that the effects of nicotine are regionally heterogeneous and arise from both direct and indirect actions on various receptors and neurotransmitter systems and nicotine's effects at low doses differ from that at higher doses. The changes in effects in the presence of atropine suggest that muscarinic acetylcholine receptors play a major role in nicotine's actions on neurotransmitter systems.

The effects of cholinergic and dopaminergic antagonists on nicotine-induced cerebral neurotransmitter changes.

In a continuing study of nicotine-induced mechanisms in brain areas associated with cognitive processes, the effects of cholinergic and dopaminergic antagonists on nicotine-induced changes in dopamine, norepinephrine, and serotonin were examined. These effects were measured via in vivo microdialysis in the dorsal and ventral hippocampus and in the prefrontal and medial temporal cortex of conscious, freely moving, adult male rats. Nicotine (0.3 mg/kg, free base) was administered subcutaneously and the antagonists were infused locally via the microdialysis probe. Nicotine alone induced an increase of dopamine and its metabolites in all areas, an increase of norepinephrine in the cortex, and an increase of the norepinephrine metabolite 4-hydroxy-3-methoxy-phenylglycol in all areas. Serotonin was decreased in the hippocampus and increased in the cortex. Nicotine-induced dopamine increases were inhibited by nicotinic (mecamylamine 100 microM, methyllycaconitine 500 microM), muscarinic (atropine 100 microM), and dopaminergic D1 (SCH23390 100 microM) and D2 (eticlopride 100 microM) antagonists, in the hippocampal and cortical areas. In the hippocampal areas, these antagonists had less significant effect on norepinephrine and serotonin. However, in the cortical areas, all antagonists inhibited the nicotine-induced increase of serotonin to varying degrees; and some, primarily nicotinic and dopamine D1 antagonists, inhibited the induced increase of norepinephrine. In the hippocampal and cortical areas, the mechanisms of nicotine-induced dopamine increase seem to be similar, but the mechanisms seem to be different for noradrenergic and serotonergic systems, as shown by the fact that nicotine induces no change in norepinephrine and a decrease in serotonin in the hippocampus, while it induces an increase in both in the cortex. Nicotine-induced dopamine release seems to be mediated, in part locally, by nicotinic and muscarinic receptors on dopaminergic cells. In contrast, nicotine's effect on norepinephrine and serotonin is at least partially mediated by initial changes at other than local sites, and through different receptors. Thus, the effects of nicotine and the mechanisms involved differ for different neurotransmitters and in different brain areas.

Regional heterogeneity of nicotine effects on neurotransmitters in rat brains in vivo at low doses.

In our recent studies on nicotine-induced changes in neurotransmitters in brain areas associated with cognitive function using a nicotine dose of 0.5 mg/kg administered subcutaneously to conscious freely moving rats, we found changes in dopamine, norepinephrine, and serotonin, and their metabolites, in the areas examined. For the present report we examined changes in these neurotransmitters following administration of lower nicotine doses, to test regional differences in nicotine response and possible threshold levels for some effects of nicotine. The doses used were 0.15 mg/kg and 0.03 mg/kg nicotine administered subcutaneously. Nicotine levels in the brain reached peak values in less than 10 min and decreased with a half-life of about 60 min (0.15 mg/kg) or 30 min (0.03 mg/kg) to values below detection limits (1 ng/g), by the later time points of the 0.03 mg/kg experiments. Nicotine-induced dopamine (DA) increase (and increase in DA metabolites) and decrease in 5-HT levels at 0.15 mg/kg were significant in the cortex, less so in the hippocampus. Norepinephrine (NE) increase at 0.15 mg/ kg was much less significant than found previously at 0.5 mg/kg. At a low nicotine dose (0.03 mg/kg), the significant changes observed were a decrease in 5-HT in the hippocampus and small increases of DA and NE in the prefrontal cortex and of NE in the medial temporal cortex. In the nucleus accumbens DA, NE, and 5-HT and their metabolites in the ventral tegmental area, mostly DA and metabolites were increased. We conclude that in areas of cognitive function nicotine-induced DA changes are more concentration dependent than changes in NE or 5-HT, and that there are regional differences in neurotransmitter changes induced by nicotine, with NE changes detectable only in the cortex and 5-HT changes only in the hippocampus at a low nicotine dose, indicating significant regional variation in sensitivity to nicotine-induced neurotransmitter changes in brain areas associated with cognitive function. The decrease in 5-HT shows that nicotine also has indirect effects caused by neurotransmitters released by nicotine. The effects of a low nicotine dose are more significant in areas of reward function, indicating differences in sensitivity between cognitive and reward functions.