Amphetamine and cocaine are stimulant drugs that act on central monoaminergic neurons to produce both acute psychomotor activation and long-lasting behavioral effects including addiction and psychosis. Here we report that single doses ofthese drugs induce rapid expression of the nuclear proto-oncogene c-fos in the forebrain and particularly in the striatum, an extrapyramidal structure implicated in addiction and in long-term drug-induced changes in motor function. The two drugs induce strikingly different patterns ofc-fos expression in the striosome-matrix compartments and limbic subdivisions of the striatum, and their effects are pharmacologically distinct, although both are sensitive to dopamine receptor blockade. We propose that differential activation of immediate-early genes by psychostimulants may be an early step in drug-specific molecular cascades contributing to acute and long-lasting psychostimulant-induced changes in behavior.Dramatic changes in behavior occur after exposure to psychomotor stimulant drugs that affect dopaminergic and other monoaminergic systems in the brain. These changes can emerge acutely in response to a single exposure or a few exposures to drugs such as cocaine and amphetamine, and they can evolve into long-lasting behavioral alterations. The molecular mechanisms underlying these extended effects are not understood, but they are thought to involve dopamine receptors and transporters and to bring about modifications in the dopamine-containing nigrostriatal and mesolimbic fiber systems and their neuronal targets in the striatum (1-4).In the experiments reported here, we explored the possibility, suggested by preliminary experiments (5-9), that psychomotor stimulants induce drug-specific molecular responses in striatal neurons by activating expression of immediate-early genes. The induction of several immediateearly genes, whose products influence the transcription of other genes (10), has been linked to stimulus conditions that lead to long-term changes in neuronal responsiveness (11-13). We injected rats with either amphetamine or cocaine and tested for induction of c-fos, a nuclear proto-oncogene whose protein product, the DNA-binding protein Fos, is expressed in a number of neural systems in response to extrinsic signals (14,15). We reasoned that expression of Fos could serve as a sensitive indicator of differential gene activation by psychostimulants in a region of the brain that is directly implicated in the effects of these drugs. MATERIALS AND METHODSDrug-naive adult male Sprague-Dawley rats (250-300 g) were divided into groups receiving (i) no treatment or saline injections, (ii) injections of either amphetamine or cocaine alone, or (iii) injections of amphetamine or cocaine in combination with one of the following: the dopamine-depleting drug reserpine, the dopamine D1 receptor antagonist SCH 23390 (16), the dopamine D2 receptor antagonist YM-09151 (17), the serotonin antagonist metergoline (18), or the serotonin synthesis inhibitor p-chlorophenylalanine (18). All ...

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Postmortem analysis of five subjects with Parkinson's disease9-14 years after transplantation of fetal midbrain cell suspensions revealed surviving grafts that included dopamine and serotonin neurons without pathology. These findings are important for the understanding of the etiopathogenesis of midbrain dopamine neuron degeneration and future use of cell replacement therapies.Despite indirect evidence of long-term survival of fetal midbrain dopamine cell suspensions in people with Parkinson's disease 1 , the question remains whether grafted neurons are affected by pathogenic factors intrinsic to the parkinsonian brain.Prominent neuropathological features of Parkinson's disease include dopaminergic neuron loss in the substantia nigra, the presence of dystrophic neurites (Lewy neurites) 2 and the presence of Lewy bodies 3,4 . Ultimately, the durability of transplanted fetal ventral midbrain neurons in therapeutic approaches relies on their resistance to these neurodegenerative processes. Because many aspects of these processes remain unknown, it is important to understand the effects of neurodegeneration in the parkinsonian striatum upon transplanted fetal dopamine neurons. We report histopathological findings in the brains of three subjects (referred to as subjects 4, 5 and 6) with advanced idiopathic Parkinson's disease who had received intracerebral transplantation

Lighting cycles synchronize (entrain) mammalian circadian rhythms by altering activity of cells in the suprachiasmatic nucleus (SCN) of the hypothalamus, a circadian pacemaker. Exposure of hamsters and rats to light pulses at those phases of the circadian rhythm during which light can shift the rhythm caused increased immunoreactivity for the product of the immediate-early gene c-fos in cells in the region of the SCN that receives retinal fibers. Light pulses also increased messenger RNA for the Fos protein and for the immediate-early protein NGFI-A in the rat SCN. Similar increases in mRNA for NGFI-A were seen in the SCN of hamsters. Thus cells in this portion of the SCN undergo alterations in gene expression in response to retinal illumination, but only at times in the circadian cycle when light is capable of influencing entrainment.