Neurochemical mechanisms mediating the behavioral and cognitive effects of nicotine

Data are reviewed, largely from experiments in the authors'laboratory, that suggest three modes of action of systemic nicotine in producing three different types of effect upon behavior and cognitive function. (1) Preexposure of a stimulus without consequence makes it harder subsequently to form associations to that stimulus, a form of selective attention known as latent inhibition. Latent inhibition is blocked by nicotine, an effect that is apparently mediated by a nicotine-induced increase in dopamine release in the nucleus accumbens. (2) A single dose of nicotine proactively increases the partial reinforcement extinction effect measured several weeks later: that is, resistance to extinction is decreased by nicotine in animals that have been trained on a continuous reinforcement schedule, and increased in animals trained on a partial reinforcement schedule. This effect appears to be due to increased synthesis of tyrosine hydroxylase in the cell bodies of noradrenergic neurons in the locus coeruleus, followed by axonal transport to the hippocampus and increased synthesis and release of noradrenaline in that structure. (3) Nicotine improves vigilance in animals with cognitive deficits due to destruction of the forebrain cholinergic projection system, either as a consequence of excitotoxic lesions of the nuclei of origin of this system or after prolonged alcohol consumption; and also in human subjects with Alzheimer's disease (in which this system undergoes degeneration). This effect is most likely due to an action at denervated cholinergic synapses in the hippocampus and neocortex. © 1994 Wiley-Liss, Inc.     

Interactions between the effects of propranolol and nicotine on radial maze performance of rats with lesions of the forebrain cholinergic projection system

This experiment investigated the hypothesis that nicotine-induced regional release of noradrenaline contributes to the improvements in radial maze performance following nicotine treatment in rats with lesions to the forebrain cholinergic projection system (FCPS), by examining whether pretreatment with the noradrenergic beta-receptor antagonist propranolol abolished the facilitative effects of nicotine. After S-AMPA (8.0mM) lesions to the nuclei of origin of the FCPS in the nucleus basalis and medial septal areas, rats displayed long-lasting impairment in long-term reference and short-term working memory in both spatial (place) and associative (cue) radial maze tasks. Performance of control and lesioned rats was assessed after administration of nicotine (0.1mg/kg), propranolol (either 0.5 or 5.0mg/kg) and both treatments. Nicotine reduced working memory error rates in lesioned animals, but did not affect the performance of controls. Propranolol dose-relatedly increased error rates in both control and lesioned animals. Adverse effects were more marked in controls, all four types of error being increased under the high dose of propranolol, whereas in lesioned rats significant increases in error rates above baseline were confined to working memory. The low dose of propranolol, in conjunction with nicotine, abolished the improvement in working memory seen with nicotine alone in lesioned rats. However, under joint treatment with the high dose, the substantial increases in working memory error rates seen in lesioned rats after propranolol alone were reduced to baseline level. In controls, reduction in errors to baseline was seen only in the cue task; place task errors remained significantly elevated. These results suggest that both cholinergic depletion and noradrenergic blockade exert disruptive effects on cognition, but that these effects are largely independent, since an additive or interactive mechanism would be predicted to produce greater disruption, following noradrenergic blockade, in lesioned rather than in control animals. Although facilitative effects of nicotine were abolished with the low dose of propranolol, the results further suggest that these effects are independent of release of noradrenaline, since nicotine continued to reduce errors in control and lesioned animals following blockade of beta receptors with the high dose of propranolol.     

Effects of Early Proinflammatory Stress on Anxiety and Depression-Like Behavior in Rats of Different Ages

Neuroscience and Behavioral Physiology - Early proinflammatory stress created by administration of lipopolysaccharide (LPS) (50 μg/kg s.c.) on days 3 and 5 of postnatal life led to decreases...     

Recruitment of medial prefrontal cortex neurons during alcohol withdrawal predicts cognitive impairment and excessive alcohol drinking

Chronic intermittent access to alcohol leads to the escalation of alcohol intake, similar to binge drinking in humans. Converging lines of evidence suggest that impairment of medial prefrontal cortex (mPFC) cognitive function and overactivation of the central nucleus of the amygdala (CeA) are key factors that lead to excessive drinking in dependence. However, the role of the mPFC and CeA in the escalation of alcohol intake in rats with a history of binge drinking without dependence is currently unknown. To address this issue, we examined FBJ murine osteosarcoma viral oncogene homolog (Fos) expression in the mPFC, CeA, hippocampus, and nucleus accumbens and evaluated working memory and anxiety-like behavior in rats given continuous (24 h/d for 7 d/wk) or intermittent (3 d/wk) access to alcohol (20% vol/vol) using a two-bottle choice paradigm. The results showed that abstinence from alcohol in rats with a history of escalation of alcohol intake specifically recruited GABA and corticotropin-releasing factor (CRF) neurons in the mPFC and produced working memory impairments associated with excessive alcohol drinking during acute (24–72 h) but not protracted (16 –68 d) abstinence. Moreover, abstinence from alcohol was associated with a functional disconnection of the mPFC and CeA but not mPFC and nucleus accumbens. These results show that recruitment of a subset of GABA and CRF neurons in the mPFC during withdrawal and disconnection of the PFC–CeA pathway may be critical for impaired executive control over motivated behavior, suggesting that dysregulation of mPFC interneurons may be an early index of neuroadaptation in alcohol dependence.     

New method of <Emphasis Type="Italic">in vitro</Emphasis> culturing of pigment retinal epithelium in the structure of the posterior eye sector of adult rat

We propose a new method of organotypic roller 3D-culturing of the posterior sector of the eye. The method allows maintaining tissue viability in vitro for 14 days (which considerably surpasses the capacities of stationary culturing) and studying of the behavior of pigment retinal epithelial cells and choriocapillary membrane. Using this method we demonstrated phenotypic transformation, migration, and proliferation of pigment retinal epithelial cells under conditions of roller organotypic culture. In the absence of the retina, these cells exhibit properties of scavenger cells (phagocytes) both within and outside the layer. Under conditions of roller culturing in vitro, cells of the pigment retinal epithelium undergo changes similar to those observed in various retinal pathologies in vivo, including age-associated changes. Here we discuss the possibility of using the proposed method for evaluation of the effect of various factors added to the culture medium on the pigment epithelium, for modeling of processes developing in damaged pigment epithelium or under conditions of various pathologies, and for the study of regeneration responses in cells of pigment retinal epithelium in adult vertebrates. __________ Translated from Kletochnye Tehnologii v Biologii i Medicine, No. 4, pp. 207–215, October, 2007     

High Risk of New Episode of Symptomatic Vasospasm in Unaffected Arteries in Subarachnoid Hemorrhage Patients Receiving Targeted Endovascular Treatment for Symptomatic Focal Vasospasm

Background

There is controversy whether asymptomatic vasospasm in other arteries should be concurrently treated (global treatment) in patients receiving targeted endovascular treatment [percutaneous-transluminal-angioplasty (PTA) and/or intra-arterial (IA) vasodilators] for focal symptomatic vasospasm.

Objective

To determine the rates of occurrence of new symptomatic vasospasm in previously asymptomatic arterial distributions among patients with aneurysmal subarachnoid hemorrhage (SAH) who underwent targeted endovascular treatment for focal symptomatic vasospasm.

Methods

We identified all patients with SAH who had received targeted endovascular treatment during a 4-year period. We ascertained any new occurrence of symptomatic vasosopasm requiring endovascular treatment in previously unaffected (and untreated) arterial distributions within the same hospitalization. Blinded reviewers quantitatively graded angiographic vasospasm (<25, 26–49, ≥50 %) in all major arteries for each patient at the time of targeted treatment.

Results

Of the 41 patients who received targeted endovascular treatment (PTA in 41 % and vasodilators in 59 %), 11 (27 %) developed new symptomatic vasospasm in previously asymptomatic vascular distributions requiring endovascular treatment. Moderate severity of angiographic vasospasm in asymptomatic arteries at the time of targeted treatment tended to predict the occurrence of new symptomatic vasospasm. The rate of death and disability at discharge [modified Rankin scale (mRS) of 3–6] was 82 % (9/11) among those who developed a new episode of symptomatic vasospasm compared with 70 % (21/30) in those who did not (P = 0.58).

Conclusions

High risk of new occurrence of ischemic symptoms in previously asymptomatic (and untreated) arterial distributions among patients receiving targeted treatment should be recognized. Further studies should evaluate the benefit of performing global endovascular treatment during the initial targeted endovascular treatment session.