The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

While the monoamine deficiency hypothesis of depression is still most commonly used to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that is not adequately explained by the hypothesis. This article draws attention to contributions from another apparently common pharmacological property of antidepressant medications-the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence is presented suggesting the hypercholinergic neurotransmission, which is associated with depressed mood states, may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. In support of this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder. If this hypothesis is supported by further preclinical and clinical research, nicotinic acetylcholine receptor antagonists may represent a novel class of therapeutic agents for treating mood disorders.

Bupropion is an atypical antidepressant that also has usefulness as a smoking-cessation aid. Because hydroxybupropion, a major metabolite of bupropion, is believed to contribute to its antidepressant activity, this metabolite may also contribute to the smoking-cessation properties of bupropion. This study investigated the effects of hydrobupropion enantiomers on monoamine transporters and nicotinic acetylcholine receptor (nAChR) subtypes. Racemic bupropion and hydroxybupropion inhibit [3 H]norepinephrine (NE) uptake with similar potency (IC 50 values of 1.9 and 1.7 M, respectively), but most of the latter activity resides in the (2S,3S)-hydroxy isomer (IC 50 ϭ 520 nM) rather than (2S,3R)-hydroxybupropion (IC 50 Ͼ 10,000 nM). Similar results were found with [ 3 H]dopamine (DA) uptake. The effects of bupropion and enantiomers of hydroxybupropion on human nAChR subtypes indicate that the (2S,3S) isomer is more potent than the (2S,3R) isomer or racemic bupropion as an antagonist of ␣ 4 ␤ 2 (functional IC 50 ϭ 3.3 M). In addition, (2S,3S)-hyroxybupropion and bupropion were considerably more potent than (2R, Ϫ3R)-hydroxybupropion in a mouse depression model (forced swimming test) and in antagonism of acute nicotine effects in mice. Together, our results suggest that clinical and behavioral effects of bupropion arise from actions at nAChR as well as DA and NE transporters. Furthermore, our data suggest that the (2S,3S)-hydroxybupropion isomer may be a better drug candidate for smoking cessation than bupropion because of its higher potency at the relevant targets.Tobacco use is the leading cause of premature death in the United States. The vast majority of smokers (70%) report a desire to quit smoking, but poor smoking-cessation results indicate a need to explore innovative approaches to treating nicotine addiction. In addition to nicotine-replacement therapy, the atypical antidepressant bupropion is now recognized as an effective aid to smoking cessation. The efficacy of bupropion in the treatment of nicotine dependence was believed to involve the modulation of dopaminergic (dopamine, DA) and noradrenergic (norepinephrine, NE) systems. Indeed, bupropion is a relatively weak DA-reuptake inhibitor and inhibits the firing of locus coeruleus NE neurons at high concentrations (Cooper et al., 1994). Its inhibition of transporter function is associated with increases in extracellular DA and NE concentrations, which may substitute for nicotine-evoked neurotransmitter release during smoking, mimicking nicotine reinforcement and alleviating withdrawal symptoms stemming from the absence of nicotine. No other neuronal sites were believed to play a role in bupropion's because of its lack of binding affinity for almost all of the major classes of neuronal receptors (Ascher et al., 1995).However, findings from our laboratories that bupropion acted as a relatively potent, noncompetitive nAChR antagonist suggested that actions of bupropion at nAChR were of possible relevance for smoking cessation, especially given the ABBREVIAT...

Nicotinic acetylcholine receptors (nAChRs) containing ␣7 subunits are thought to assemble as homomers. ␣7-nAChR function has been implicated in learning and memory, and alterations of ␣7-nAChR have been found in patients with Alzheimer's disease (AD). Here we report findings consistent with a novel, naturally occurring nAChR subtype in rodent, basal forebrain cholinergic neurons. In these cells, ␣7 subunits are coexpressed, colocalize, and coassemble with ␤2 subunit(s). Compared with homomeric ␣7-nAChRs from ventral tegmental area neurons, functional, presumably heteromeric ␣7␤2-nAChRs on cholinergic neurons freshly dissociated from medial septum/diagonal band (MS/DB) exhibit relatively slow kinetics of whole-cell current responses to nicotinic agonists and are more sensitive to the ␤2 subunit-containing nAChR-selective antagonist, dihydro-␤-erythroidine (DH␤E). Interestingly, presumed, heteromeric ␣7␤2-nAChRs are highly sensitive to functional inhibition by pathologically relevant concentrations of oligomeric, but not monomeric or fibrillar, forms of amyloid ␤ 1-42 (A␤ 1-42 ). Slow whole-cell current kinetics, sensitivity to DH␤E, and specific antagonism by oligomeric A␤ 1-42 also are characteristics of heteromeric ␣7␤2-nAChRs, but not of homomeric ␣7-nAChRs, heterologously expressed in Xenopus oocytes. Moreover, choline-induced currents have faster kinetics and less sensitivity to A␤ when elicited from MS/DB neurons derived from nAChR ␤2 subunit knock-out mice rather than from wild-type mice. The presence of novel, functional, heteromeric ␣7␤2-nAChRs on basal forebrain cholinergic neurons and their high sensitivity to blockade by low concentrations of oligomeric A␤ 1-42 suggests possible mechanisms for deficits in cholinergic signaling that could occur early in the etiopathogenesis of AD and might be targeted by disease therapies.

Recent advances concerning effects of chronic nicotine exposure on nicotinic acetylcholine receptor (nAChR) expression are reviewed. Implications are assessed of these findings for roles of nAChR in health and disease and for design of drugs for treatment of neurological and psychiatric disorders. Most studies continue to show that chronic nicotine exposure induces increases in numbers of nAChR-like binding or antigenic sites ("upregulation") across all nAChR subtypes investigated, but with time- and dose-dependencies and magnitudes for these effects that are unique to subsets of nAChR subtypes. These effects appear to be post-transcriptionally based, but mechanisms involved remain obscure. With notable exceptions, most studies also show that chronic nicotine exposure induces several phases of nAChR functional loss ("desensitization" and longer-lasting "persistent inactivation") assessed in response to acute nicotinic agonist challenges. Times for onset and recovery and dose-dependencies for nicotine-induced functional loss also are nAChR subtype-specific. Some findings suggest that upregulation and functional loss are not causally- or mechanistically-related. It is suggested that upregulation is not as physiologically significant in vivo as functional effects of chronic nicotine exposure. By contrast, brain levels of nicotine in tobacco users, and perhaps levels of acetylcholine in the extracellular space, clearly are in the range that would alter the balance between nAChR in functionally ready or inactivated states. Further work is warranted to illuminate how effects of chronic nicotinic ligand exposure are integrated across nAChR subtypes and the neuronal circuits and chemical signaling pathways that they service to produce nicotine dependence and/or therapeutic benefit.

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In women, medroxyprogesterone acetate (MPA) is the most commonly used progestin component of HT. In vitro, MPA negatively impacts markers of neuronal health and exacerbates experimentally-induced neurotoxicity. There is in vitro evidence that these factors are driven by GABAergic and neurotrophic systems. Whether these effects translate to a negative impact on brain function has not been tested in vivo, clinically or preclinically. Here we evaluate the mnemonic and neurobiological effects of MPA in the surgically menopausal rat. Aged ovariectomized (OVX) rats were given subcutaneous vehicle, natural progesterone, low-dose MPA or high-dose MPA. Multiple cognitive domains were analyzed via the water radial-arm maze (WRAM), and Morris maze (MM). Cognitive brain regions were assayed for changes in the GABAergic system by evaluating GAD protein, the synthesizing enzyme for GABA, and neurotrophins. On the WRAM, both progestin types impaired learning. Further, high-dose MPA impaired delayed memory retention on the WRAM, and exacerbated overnight forgetting on the MM. While neurotrophins were not affected by progesterone or MPA treatment, both progestin types altered GAD levels. MPA significantly and progesterone marginally decreased GAD levels in the hippocampus, and both MPA and progesterone significantly increased GAD levels in the entorhinal cortex. These findings suggest that MPA, the most commonly used progestin in HT, is detrimental to learning and two types of memory, and modulates the GABAergic system in cognitive brain regions, in aged menopausal rats. These findings, combined with in vitro evidence that MPA is detrimental to neuronal health, indicates that MPA has negative effects for brain health and function.

The expression of nicotinic acetylcholine receptors by neurons, microglia, and astrocytes suggests possibly diverse mechanisms by which natural nicotinic cholinergic signaling and exposure to nicotine could modulate immune responses within the CNS. In this study, we show that nicotine exposure significantly delays and attenuates inflammatory and autoimmune responses to myelin Ags in the mouse experimental autoimmune encephalomyelitis model. In the periphery, nicotine exposure inhibits the proliferation of autoreactive T cells and alters the cytokine profile of helper T cells. In the CNS, nicotine exposure selectively reduces numbers of CD11c+ dendritic and CD11b+ infiltrating monocytes and resident microglial cells and down-regulates the expression of MHC class II, CD80, and CD86 molecules on these cells. The results underscore roles of nicotinic acetylcholine receptors and nicotinic cholinergic signaling in inflammatory and immune responses and suggest novel therapeutic options for the treatment of inflammatory and autoimmune disorders, including those that affect the CNS.