Timing performance is sensitive to fluctuations in time and motivation, thus interval timing and motivation are either inseparable or conflated processes. A behavioral systems model (e.g., Timberlake, 2000) of timing performance (Chapter 1) suggests that timing performance in externally-initiated (EI) procedures conflates behavioral modes differentially sensitive to motivation, but that response-initiated (RI) procedures potentially dissociate these behavioral modes. That is, timing performance in RI procedures is expected to not conflate these behavioral modes. According to the discriminative RI hypothesis, as initiating-responses become progressively discriminable from target responses, initiating-responses increasingly dissociate interval timing and motivation. Rats were trained in timing procedures in which a switch from a Short to a Long interval indexes timing performance (a latency-to-switch, LTS), and were then challenged with pre-feeding and extinction probes. In experiments 1 (Chapter 2) and 2 (Chapter 3), discriminability of initiating-responses was varied as a function of time, location, and form for rats trained in a switch-timing procedure. In experiment 3 (Chapter 4), the generalizability of the discriminative RI hypothesis was evaluated in rats trained in a temporal bisection procedure. In experiment 3, but not 1 and 2, RI enhanced temporal control of LTSs relative to EI. In experiments 1 and 2, the robustness of LTS medians to pre-feeding but not extinction increased with the discriminability of initiating-responses from target responses. In experiment 3, the mean LTS was robust to pre-feeding in EI and RI. In all three experiments, pre-feeding increased LTS variability in EI and RI. These results provide moderate support for the discriminative RI hypothesis, indicating that initiating-responses selectively and partially dissociate interval timing and motivation processes. Implications for the study of cognition and motivation processes are discussed (Chapter 5).

Intermittent social defeat stress produces vulnerability to drugs of abuse, a phenomena known as cross-sensitization, which is proceeded by a corresponding upregulation of ventral tegmental area (VTA) mu-opioid receptors (MORs). Since VTA MORs are implicated in the expression of psychostimulant sensitization, they may also mediate social stress-induced vulnerability to drugs of abuse. Social stress and drugs of abuse increase mesolimbic brain-derived neurotrophic factor (BDNF) signaling with its receptor, tropomyosin-related kinase B (TrkB). These studies examined whether VTA MOR signaling is important for the behavioral and cellular consequences of social stress. First, the function of VTA MORs in the behavioral consequences of intermittent social defeat stress was investigated. Lentivirus-mediated knockdown of VTA MORs prevented social stress-induced cross-sensitization, as well as stress-induced social avoidance and weight gain deficits. Next it was examined whether VTA MOR expression is critical for stress-induced alterations in the mesocorticolimbic circuit. At the time cross-sensitization was known to occur, lentivirus-mediated knockdown of VTA MORs prevented stress-induced increases in VTA BDNF and its receptor, TrkB in the nucleus accumbens (NAc), and attenuated NAc expression of delta FosB. There was no effect of either stress or virus on BDNF expression in the prefrontal cortex. Since social stress-induced upregulation of VTA MORs is necessary for consequences of social stress, next activity dependent changes in AKT, a downstream target of MOR stimulation associated with sensitization to psychostimulant drugs, were investigated. Using fluorescent immunohistochemical double labeling for the active form of AKT (pAKT) and markers of either GABA or dopamine neurons in the VTA, it was determined that social stress significantly increased the expression of pAKT in GABA, but not dopamine neurons, and that this effect was dependent on VTA MOR expression. Moreover, intra-VTA inhibition of pAKT during stress prevented stress-induced weight gain deficits, while acute inhibition of VTA pAKT blocked the expression of cross-sensitization in subjects that had previously exhibited sensitized locomotor activity. Together these results suggest that social stress upregulates MORs on VTA GABA neurons, resulting in AKT phosphorylation, and that increased VTA MOR-pAKT signaling may represent a novel therapeutic target for the intervention of substance abuse disorders.

Ethinyl estradiol, (EE) a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives (Shively, C., 1998), and is found in at least 30 different contraceptive formulations currently prescribed to women (Curtis et al., 2005). EE is also used in hormone therapies prescribed to menopausal women, such as FemhrtTM (Simon et al., 2003). Thus, EE is prescribed clinically to women at ages ranging from puberty through reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young, female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection. For these studies, the low and medium doses correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to the range of doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. For each study, cognition was evaluated with a battery of maze tasks tapping several domains of spatial learning and memory. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; this was seen for both cyclic and tonic regimens. Cyclic and tonic delivery of low EE, a dose that corresponds to doses used in the clinic today, resulted in transient and null impairments, respectively, on cognition.