We have examined several neurochemical and behavioural parameters related to the function of the mesolimbic dopamine (DA) pathway in animals treated with nicotine following three modes of drug administration, i.e. systemic intraperitoneal injection, intra-accumbens (Acb) infusion or intraventral tegmental area (intra-VTA) microinjection. The present modes of systemic, intra-Acb and intra-VTA nicotine administration elicited comparable acute increases in dialysate DA levels from the Acb. The increase in extracellular DA levels was paralleled by a significant enhancement of locomotion in a habituated environment in the case of systemic or intra-VTA nicotine administration, whereas unilateral or bilateral intra-Acb nicotine infusion was ineffective, showing that accumbal DA increase is not sufficient to elicit locomotion in this experimental paradigm. Intra-VTA, but not systemic or intra-Acb, nicotine administration caused a long-term (at least 24-h) increase in basal dialysate DA levels from the Acb. In addition, significant increases in tyrosine hydroxylase (TH) and GluR1 (but not dopamine transporter or NR1) mRNA levels in the VTA were detected 24 h after intra-VTA nicotine administration. Systemic nicotine injection caused only an increase in TH mRNA levels while intra-Acb infusion did not modify any of the mRNAs tested. The long-term increase in basal DA levels in the Acb and TH, and GluR1 mRNA levels in the VTA upon intra-VTA nicotine microinjection indicates that even a single nicotine injection can induce plastic changes of the mesolimbic DA pathway.

Adenosine and caffeine modulate locomotor activity and striatal gene expression, partially through the activation and blockade of striatal A 2A receptors, respectively. The elucidation of the roles of these receptors bene®ts from the construction of A 2A receptor-de®cient mice (A 2A -R 2/2 ). These mice presented alterations in locomotor behaviour and striatal expression of genes studied so far, which are unexpected regarding the speci®c expression of A 2A receptor by striatopallidal neurones. To clarify the functions of A 2A receptors in the striatum and to identify the mechanisms leading to these unexpected modi®cations, we studied the basal expression of immediate early and constitutive genes as well as dopamine and glutamate neurotransmission in the striatum. Basal zif268 and arc mRNAs expression was reduced in mutant mice by 60±80%, not only in the striatum but also widespread in the cerebral cortex and hippocampus. Striatal expression of substance P and enkephalin mRNAs was reduced by about 50% and 30%, respectively, whereas the expression of GAD67 and GAD65 mRNAs was slightly increased and unaltered, respectively. In vivo microdialysis in the striatum revealed a 45% decrease in the extracellular dopamine concentration and three-fold increase in extracellular glutamate concentration. This was associated with an up-regulation of D 1 and D 2 dopamine receptors expression but not with changes in ionotropic glutamate receptors. The levels of tyrosine hydroxylase and of striatal and cortical glial glutamate transporters as well as adenosine A 1 receptors expression were indistinguishable between A 2A -R 2/2 and wild-type mice. Altogether these results pointed out that the lack of A 2A receptors leads to a functional hypodopaminergic state and demonstrated that A 2A receptors are necessary to maintain a basal level in immediate early and constitutive genes expression in the striatum and cerebral cortex, possibly via their control of dopamine pathways.

To evaluate the importance of serum anticholinergic activity (SAA) in elderly patients who developed delirium following hospital admission, we performed a cross-sectional study with consecutively referred inpatients in a university geriatric medical ward. Sixty-one patients aged 66 to 95 years (mean age: 79.2+/-11.6; 54% females) were recruited. Delirium was assessed by means of the Confusion Assessment Method, SAA determination, questionnaire for current drug treatment, past medical history and clinical examination, and blood chemistries. Patients were divided into two groups according to the absence (N = 49) or the presence (N = 12) of delirium. Delirious patients showed a significantly higher SAA (23.0 vs 3.9 pmol/mL atropine equivalents, P < .004); they were using antibiotics (P < .05), neuroleptics (P < .002), barbiturates (P < .004), and benzodiazepines (P < .005) more frequently. Subjects with delirium were more likely to have infections and a lower Body Mass Index; they had higher plasma glucose and creatinine. The multivariate analysis identified SAA and use of neuroleptics, and benzodiazepines as the most important features independently associated with delirium. SAA may be a suitable marker for identifying people at risk of developing delirium. Moreover, neuroleptics and benzodiazepines must be carefully used in the elderly because of their relationship with the onset of delirium.

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Enhanced locomotion in a habituated environment is a well documented effect of nicotine mediated by the mesotelencephalic dopaminergic system. The nicotinic receptor subunit alpha6 is, among other subunits, strongly expressed in the dopaminergic neurons of the mesencephalon. To examine the functional role of this subunit, we inhibited its expression in vivo using antisense oligonucleotides. In vitro treatments of embryonic mesencephalic neuron cultures demonstrated that the alpha6 antisense oligonucleotides caused a marked decrease in the level of alpha6 subunit protein. In vivo, 1 week infusion of alpha6 antisense oligonucleotides by osmotic mini-pump reduced the effect of nicotine on locomotor activity in habituated environment by 70%. These data support the notion that the effects of nicotine on the dopaminergic system involve alpha6 subunit containing nAChRs.