Despite great advances in basic neuroscience knowledge, the improved understanding of brain functioning has not yet led to the introduction of truly novel pharmacological approaches to the treatment of central nervous system (CNS) disorders. This situation has been partly attributed to the difficulty of predicting efficacy in patients based on results from preclinical studies. To address these issues, this review critically discusses the traditional role of animal models in drug discovery, the difficulties encountered, and the reasons why this approach has led to suboptimal utilization of the information animal models provide. The discussion focuses on how animal models can contribute most effectively to translational medicine and drug discovery and the changes needed to increase the probability of achieving clinical benefit. Emphasis is placed on the need to improve the flow of information from the clinical/human domain to the preclinical domain and the benefits of using truly translational measures in both preclinical and clinical testing. Few would dispute the need to move away from the concept of modeling CNS diseases in their entirety using animals. However, the current emphasis on specific dimensions of psychopathology that can be objectively assessed in both clinical populations and animal models has not yet provided concrete examples of successful preclinical–clinical translation in CNS drug discovery. The purpose of this review is to strongly encourage ever more intensive clinical and preclinical interactions to ensure that basic science knowledge gained from improved animal models with good predictive and construct validity readily becomes available to the pharmaceutical industry and clinical researchers to benefit patients as quickly as possible.

Regional brain activation was assessed by mapping of Fos-related protein expression in rats trained to self-administration of intravenous nicotine and cocaine. Both drugs produced specific overlapping patterns of activation in the shell and the core of the nucleus accumbens, medial prefrontal cortex, and medial caudate areas, but not in the amygdala. Thus, the reinforcing properties of cocaine and nicotine map on selected structures of the terminal fields of the mesocorticolimbic dopamine system, supporting the idea that common substrates for these addictive drugs exist.

α6* nicotinic acetylcholine receptors (nAChRs) are highly and selectively expressed by mesostriatal dopamine (DA) neurons. These neurons are thought to mediate several behavioral effects of nicotine, including locomotion, habit learning, and reinforcement. Yet the functional role of α6* nAChRs in midbrain DA neurons is mostly unknown. The aim of this study was to determine the composition andin vivofunctional role of α6* nAChR in mesolimbic DA neurons of male rats. Immunoprecipitation and immunopurification techniques coupled with cell-specific lesions showed that the composition of α6* nAChR in the mesostriatal system is heterogeneous, with (non-α4)α6β2* being predominant in the mesolimbic pathway and α4α6β2* in the nigrostriatal pathway. We verified whether α6* receptors mediate the systemic effects of nicotine on the mesolimbic DA pathway by perfusing the selective antagonists α-conotoxin MII (CntxMII) (α3/α6β2* selective) or α-conotoxin PIA (CntxPIA) (α6β2* selective) into ventral tegmental area (VTA). The intra-VTA perfusion of CntxMII or CntxPIA markedly decreased systemic nicotine-elicited DA release in the nucleus accumbens and habituated locomotion; the intra-VTA perfusion of CntxMII also decreased the rate of nicotine infusion in the maintenance phase of nicotine, but not of food, self-administration. Overall, the results of these experiments show that the α6β2* nAChRs expressed in the VTA are necessary for the effects of systemic nicotine on DA neuron activity and DA-dependent behaviors such as locomotion and reinforcement, and suggest that α6β2*-selective compounds capable of crossing the blood–brain barrier may affect the addictive properties of nicotine and therefore be useful in the treatment of tobacco dependence.