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Drugs of Abuse and Brain Gene Expression

From the Behavioral Neuroscience Program, Department of Psychology, State University of New York at Buffalo (G.T.), and Department of Social Sciences, Medaille College (J.M.H.), Buffalo, NY.

View larger version (23K): [in a new window]   Fig. 1. Schematic diagram depicting activation of signal transduction pathways in response to extracellular signals. Exposure to a neurotransmitter leads to stimulation of cell-membrane receptors (R). This stimulation leads to the brief generation of cAMP, allowing the catalytic subunits of PKA to translocate to the cell nucleus, where they can phosphorylate CREB. By means of a process not fully understood, phosphorylated CREB initiates transcription of IEGs. The protein products of these genes interact with one another and bind specifically to DNA sequences (eg, -TGACGTCA-; AP-1 site), modulating gene expression. These (late) genes encode proteins (eg, dynorphin), which then target nearby neural signaling pathways. The diagram is greatly simplified. Alterations in this intracellular signaling cascade by cocaine, ethanol, or morphine may give rise to significant neural plasticity and behavioral change. AC = adenylyl cyclase; ATP = adenosine triphosphate; GI = guanine protein, inhibitory; GS = guanine protein, stimulatory; TATA = ubiquitous sequence bound by a complex of proteins known as TFIIB. Phosphorylated CREB interacts with CBP, which itself interacts with TFIIB and possibly with the TATA-box–binding protein, TBA.

View larger version (19K): [in a new window]   Fig. 2. Schematic representation of the chemical structures of cocaine, ethanol, and morphine. These drugs gain rapid access to rat brain tissue, where they target several neural pathways heavily represented by dopaminergic, opioidergic, and GABAergic systems. There is considerable overlap between these functional neurotransmitter systems, which provides several potential sites at which interactions relevant to the development of drug addiction may occur. AA = amygdala; Acb = nucleus accumbens; Arc = arcuate nucleus; CdP = caudate putamen; Cer = cerebellum; FC = frontal cortex; GP = globus pallidus; H = hypothalamus; Hip = hippocampus; LC = locus ceruleus; NCx = neocortex; PAG = periaquaductal gray area; RN = raphe nucleus; SN = substantia nigra; TH = thalamus; Tu = olfactory tubercle; VTA = ventral tegmental area. Neuroanatomical nomenclature is derived, in part, from the rat atlas of Kruger et al. (213).

View larger version (18K): [in a new window]   Fig. 3. Schematic representation depicting the effects of ethanol (40 mM), cocaine (20 mg/kg), and ethanol-cocaine treatments on Fos-like protein in striatonigral neurons. Ethanol by itself has no effect on the cellular expression of this transcription factor protein. In contrast, cocaine treatment markedly induces the expression of Fos-like protein, particularly in the dorsal caudate putamen. However, concomitant administration of ethanol and cocaine reduces the expected expression of the c-fos gene. Sterile NaCl was used as vehicle.

View larger version (67K): [in a new window]   Fig. 4. Photomicrographs illustrating the striking effects of cocaethylene on brain IEGs. Cocaethylene is derived from the combined ingestion of cocaine and ethanol. This neuroactive metabolite induces the expression of Fos-like protein in dopaminoreceptive neurons of the caudate putamen (cdP). Top, Schematic illustration drawn through a comparable level of the cdP, where induction of Fos-like immunoreactivity is persistently observed after acute cocaethylene treatment. Middle, Representative photomicrograph through the cdP of a rat injected with sterile NaCl. Note the relative absence of Fos-like protein on medium-sized spiny neurons. Bottom, Representative photomicrograph through the cdP of a rat injected with cocaethylene (20 mg/kg). Note the distribution pattern and relative strength of the transcription factor protein. Asterisk indicates unreactive myelinated bundles of corticofugal fibers coursing through the cdP.

View larger version (61K): [in a new window]   Fig. 5. Photomicrograph illustrating the induction of NGFI-ß mRNA molecules in the PVh of the hypothalamus by cocaethylene (cocaeth). Top, Schematic coronal view depicting the topographical organization of the PVh with an emphasis on parvocellular neurosecretory neurons. Middle, Photomicrograph through a common level of the PVh of a rat injected with NaCl. Hybridized neurons are rare in parvocellular aspects of this hypothalamic nucleus. Bottom, Representative photomicrograph of the PVh of a rat injected with cocaethylene. A reliable increase in the number of positively hybridized neurons in the parvocellular (and magnocellular) aspects of the PVh is apparent 30 minutes after cocaethylene treatment. * = third ventricle; pv = periventricular. Reprinted with permission from Ref. 159.