The majority of neurotransmitter systems shows variations in state-dependent cell firing rates that are mechanistically linked to variations in extracellular levels, or tone, of their respective neurotransmitter. Diurnal variation in dopamine tone has also been demonstrated within the striatum, but this neurotransmitter is unique, in that variation in dopamine tone is likely not related to dopamine cell firing; this is largely because of the observation that midbrain dopamine neurons do not display diurnal fluctuations in firing rates. Therefore, we conducted a systematic investigation of possible mechanisms for the variation in extracellular dopamine tone. Using microdialysis and fast-scan cyclic voltammetry in rats, as well as wild-type and dopamine transporter (DAT) knock-out mice, we demonstrate that dopamine uptake through the DAT and the magnitude of subsecond dopamine release is inversely related to the magnitude of extracellular dopamine tone. We investigated dopamine metabolism, uptake, release, D2 autoreceptor sensitivity, and tyrosine hydroxylase expression and activity as mechanisms for this variation. Using this approach, we have pinpointed the DAT as a critical governor of diurnal variation in extracellular dopamine tone and, as a consequence, influencing the magnitude of electrically stimulated dopamine release. Understanding diurnal variation in dopamine tone is critical for understanding and treating the multitude of psychiatric disorders that originate from perturbations of the dopamine system. circadian | caudate-putamen | nucleus accumbens T he dopamine transporter (DAT) is a transmembrane protein that removes dopamine (DA) from the extracellular space to terminate signaling at pre-and postsynaptic receptors. Extensive evidence indicates that aberrant DAT function may be involved in many neuropsychiatric illnesses, including attention deficit hyperactivity disorder (1, 2), depression (3, 4), substance abuse disorders (5, 6), schizophrenia (7-9), and anxiety disorders (10, 11). Our current understanding of the role of the DAT under physiologically normal conditions is that of a homeostatic regulator. This basic hypothesis was confirmed in work using DAT knock-out (KO) mice, where extracellular DA levels ([DA] ext ) and corresponding locomotor activity are substantially higher than in WT animals (12, 13). In addition, up-or down-regulation of the DAT is regarded as a compensatory plasticity to "normalize" [DA] ext in the context of repeated exposure to abused drugs (5,14,15).Despite this progress in understanding DAT function, much less work has been dedicated to understanding the role of the DAT and other presynaptic modulators of [DA] Despite the limited mechanistic understanding of the complex relationship between [DA] ext and nerve terminal function, behaviors known to be governed by DA are strongly influenced by diurnal cycles. For example, behaviors that measure reinforcement and reward, such as psychostimulant self-administration and conditioned place preference, fluctuate markedly a...

Social isolation (SI) rearing, a model of early life stress, results in profound behavioral alterations, including increased anxiety-like behavior, impaired sensorimotor gating and increased self-administration of addictive substances. These changes are accompanied by alterations in mesolimbic dopamine function, such as increased dopamine and metabolite tissue content, increased dopamine responses to cues and psychostimulants, and increased dopamine neuron burst firing. Using voltammetric techniques, we examined the effects of SI rearing on dopamine transporter activity, vesicular release and dopamine D2-type autoreceptor activity in the nucleus accumbens core. Long–Evans rats were housed in group (GH; 4/cage) or SI (1/cage) conditions from weaning into early adulthood [postnatal day (PD) 28–77]. After this initial housing period, rats were assessed on the elevated plus-maze for an anxiety-like phenotype, and then slice voltammetry experiments were performed. To study the enduring effects of SI rearing on anxiety-like behavior and dopamine terminal function, another cohort of similarly reared rats was isolated for an additional 4 months (until PD 174) and then tested. Our findings demonstrate that SI rearing results in lasting increases in anxiety-like behavior, dopamine release and dopamine transporter activity, but not D2 activity. Interestingly, GH-reared rats that were isolated as adults did not develop the anxiety-like behavior or dopamine changes seen in SI-reared rats. Together, our data suggest that early life stress results in an anxiety-like phenotype, with lasting increases in dopamine terminal function.

BACKGROUND Increasing evidence suggests that chronic ethanol exposure decreases dopamine (DA) neurotransmission in the nucleus accumbens (NAc), contributing to a hypodopaminergic state during withdrawal. However, few studies have investigated adaptations in presynaptic DA terminals after chronic intermittent ethanol (CIE) exposure. In monkeys and rats, chronic ethanol exposure paradigms have been shown to increase DA uptake and D2 autoreceptor sensitivity. METHODS The current study examined the effects of ethanol on DA terminals in CIE exposed mice during two time-points after the cessation of CIE exposure. DA release and uptake were measured using fast scan cyclic voltammetry in NAc core slices from C57BL/6J mice, 0 and 72 hours following three weekly cycles (4 days of 16 hrs ethanol vapor/8 hrs room air/day + 3 days withdrawal) of CIE vapor exposure. RESULTS Current results showed that DA release was reduced, uptake rates were increased, and inhibitory D2-type autoreceptor activity was augmented following CIE exposure in mice. CONCLUSIONS Overall, these CIE-induced adaptations in the accumbal DA system reduce DA signaling and therefore reveal several potential mechanisms contributing to a functional hypodopaminergic state during alcohol withdrawal.

The capacity to record from multiple neurons in awake freely moving animals provides a means for characterizing organizational principles of place field encoding within ensembles of hippocampal neurons. In this study, cross‐correlations between pairs of hippocampal place cells and degree of overlap between their respective place fields were analyzed during behavioral performance of delayed matching (DMS) or non‐matching sample (DNMS) tasks, or while the same rats chased pellets in a different environment. The relationship between field overlap and cross‐correlations of neural spike activity within ensembles was shown to be a positive, exponentially increasing, function. Place fields from the same neurons were markedly “remapped” between the Delay and Pellet‐chasing tasks, with respect to physical location and size of fields. However individual pairs of place cells within each ensemble retained nearly the same degree of overlap and cross‐correlation even though the spatial environment and the tasks differed markedly. This suggested that place cells were organized in functional “clusters” which exhibited the same interrelations with respect to place field overlap and cross‐correlations, irrespective of actual field location. When cross‐correlations between place cells were compared to placement of the array recording electrodes within the hippocampus, the strongest correlations were found along previously defined posterior‐projecting fiber gradients between CA3 and CA1 subfields (Ishizuka et al. [1990], J Comp Neurol 295:580–623; Li et al. [1994] (J Comp Neurol 339:181–208). These findings suggest that the functional organization of place fields conforms to anatomical principles suspected to operate within hippocampal ensembles. © 1996 Wiley‐Liss, Inc.