Cocaine induces fast dopamine increases in brain striatal regions, which are recognized to underlie its rewarding effects. Both dopamine D1 and D2 receptors are involved in cocaine’s reward but the dynamic downstream consequences of cocaine effects in striatum are not fully understood. Here we used transgenic mice expressing EGFP under the control of either the D1 receptor (D1R) or the D2 receptor (D2R) gene and microprobe optical imaging to assess the dynamic changes in intracellular calcium ([Ca2+]i) responses (used as marker of neuronal activation) to acute cocaine in vivo separately for D1R versus D2R expressing neurons in striatum. Acute cocaine (8 mg/kg ip) rapidly increased [Ca2+]i in D1R expressing neurons (10.6±3.2%) in striatum within 8.3±2.3min after cocaine administration after which the increases plateaued; these fast [Ca2+]i increases were blocked by pretreatment with a D1R antagonist (SCH 23390). In contrast cocaine induced progressive decreases in [Ca2+]i in D2R expressing neurons (10.4±5.8%) continuously throughout the 30min that followed cocaine administration; these slower [Ca2+]i decreases were blocked by pretreatment with a D2R antagonist (raclopride). Since activation of striatal D1R expressing neurons (direct-pathway) enhances cocaine reward whereas activation of D2R expressing neurons suppresses it (indirect-pathway) (Lobo et al., 2010), this suggests that cocaine’s rewarding effects entail both its fast stimulation of D1R (resulting in abrupt activation of direct-pathway neurons) and a slower stimulation of D2R (resulting in longer lasting deactivation of indirect-pathway neurons). We also provide direct in-vivo evidence of D2R and D1R interactions in the striatal responses to acute cocaine administration.

A dual-wavelength laser speckle contrast imaging technique (DW-LSCI) is presented for simultaneous imaging of cerebral blood flow and hemoglobin oxygenation changes at high spatiotemporal resolutions. Experimental validation was performed using a rat transient forebrain ischemia model. The results showed that DW-LSCI was able to track detailed hemodynamic and metabolic changes induced by ischemia, i.e., decreased oxy- and total hemoglobin concentrations and blood flow as well as increased deoxy-hemoglobin concentration in the downstream regions, thus allowing us to distinguish cerebral arterial and venous flows. Simultaneous cerebral blood flow and oxygenation imaging at high spatiotemporal resolutions is crucial to the understanding of neural process and brain functions.

MRI techniques to study brain function assume coupling between neuronal activity, metabolism and flow. However, recent evidence of physiological uncoupling between neuronal and cerebrovascular events highlights the need for methods to simultaneously measure these three properties. We report a multimodality optical approach that integrates dual-wavelength laser speckle imaging (measures changes in blood flow, blood volume and hemoglobin oxygenation), digital-frequency-ramping optical coherence tomography (images quantitative 3D vascular network) and Rhod2 fluorescence (images intracellular calcium for measure of neuronal activity) at high spatiotemporal resolutions (30μm, 10Hz) and over a large field of view (3 × 5mm2). We apply it to assess cocaine’s effects in rat cortical brain and show an immediate decrease (3.5 ± 0.9min, phase 1) in the oxygen content of hemoglobin and the cerebral blood flow followed by an overshoot (7.1 ± 0.2min, phase 2) lasting over 20min whereas Ca2+ increased immediately (peaked at t=4.1 ± 0.4min) and remained elevated. This enabled us to identify a delay (2.9 ± 0.5min) between peak neuronal and vascular responses in phase 2. The ability of this multimodality optical approach for simultaneous imaging at high spatiotemporal resolutions permits us to distinguish the vascular versus cellular changes of the brain, thus complimenting other neuroimaging modalities for brain functional studies (e. g., PET, fMRI).

Ischemic stroke triggers a massive, although transient, glutamate efflux and excessive activation of NMDA receptors (NMDARs), possibly leading to neuronal death. However, multiple clinical trials with NMDA antagonists failed to improve, or even worsened, stroke outcome. Recent findings of a persistent post-stroke decline in NMDAR density, which plays a pivotal role in plasticity and memory formation, suggest that NMDAR stimulation, rather than inhibition, may prove beneficial in the subacute period after stroke. Aim This study aims to examine the effect of the NMDAR partial agonist d-cycloserine (DCS) on long-term structural, functional and behavioral outcomes in rats subjected to transient middle cerebral artery occlusion, an animal model of ischemic stroke. Materials & methods Rats (n = 36) that were subjected to 90 min of middle cerebral artery occlusion were given a single injection of DCS (10 mg/kg) or vehicle (phosphate-buffered saline) 24 h after occlusion and followed up for 30 days. MRI (structural and functional) was used to measure infarction, atrophy and cortical activation due to electrical forepaw stimulation. Memory function was assessed on days 7, 21 and 30 postocclusion using the novel object recognition test. A total of 20 nonischemic controls were included for comparison. Results DCS treatment resulted in significant improvement of somatosensory and cognitive function relative to vehicle treatment. By day 30, cognitive performance of the DCS-treated animals was indistinguishable from nonischemic controls, while vehicle-treated animals demonstrated a stable memory deficit. DCS had no significant effect on infarction or atrophy. Conclusion These results support a beneficial role for NMDAR stimulation during the recovery period after stroke, most likely due to enhanced neuroplasticity rather than neuroprotection.

Most studies of cocaine's effects on brain activity in laboratory animals are preformed under anesthesia, which could potentially affect the physiological responses to cocaine. Here we assessed the effects of two commonly used anesthetics (α-chloralose and isofluorane) on the effects of acute cocaine (1 mg/kg iv) on cerebral-blood-flow (CBF), cerebral-blood-volume (CBV), and tissue-hemoglobin-oxygenation (S t O 2 ) using optical techniques and cocaine's pharmacokinetics and binding in the rat brain using PET and [ 11 C]cocaine. We showed that acute cocaine at a dose abused by cocaine abusers decreased CBF, CBV and S t O 2 in rats anesthetized with isoflurane, whereas it increased these parameters in rats anesthetized with α-chloralose. Importantly, in isoflurane-anesthetized animals cocaine-induced changes in CBF and S t O 2 were coupled whereas for α-chloralose these measures were uncoupled. Moreover, the clearance of [ 11 ]cocaine from brain was faster for isoflurance (peak-half-clearance 15.8±2.8 min) than for α-chloralose (27.5±0.6 min) and the ratio of the specific to non-specific binding of [ 11 C]cocaine in brain was higher for isoflurane (3.37 ± 0.32) than for α-chloralose anesthetized rats (2.24 ± 0.4). For both anesthetics cocaine induced changes in CBF followed the fast uptake of [ 11 C]cocaine in brain (peaking at ~ 2.5-4 minutes) but only for isoflurane did the duration of the CBV and S t O 2 changes correspond to the rate of [ 11 C]cocaine's clearance from the brain. These results demonstrate that anesthetics influence cocaine's hemodynamic and metabolic changes in brain and its binding and pharmacokinetics, which highlights the need to better understand the interactions between anesthetics and pharmacological challenges in brain functional imaging studies. Keywordscocaine and anesthesia; pharmacodynamic; pharmacokinetics of cocaine; brain imaging; cerebral blood flow; cerebral blood volume and hemoglobin oxygenation of tissue

BACKGROUND Lidocaine can alleviate acute as well as chronic neuropathic pain at very low plasma concentrations in humans and laboratory animals. The mechanism(s) underlying lidocaine’s analgesic effect when administered systemically is poorly understood but clearly not related to interruption of peripheral nerve conduction. Other targets for lidocaine’s analgesic action(s) have been suggested, including sodium channels and other receptor sites in the central rather than peripheral nervous system. To our knowledge, the effect of lidocaine on the brain’s functional response to pain has never been investigated. Here, we therefore characterized the effect of systemic lidocaine on the brain’s response to innocuous and acute noxious stimulation in the rat using functional magnetic resonance imaging (fMRI). METHODS Alpha-chloralose anesthetized rats underwent fMRI to quantify brain activation patterns in response to innocuous and noxious forepaw stimulation before and after IV administration of lidocaine. RESULTS Innocuous forepaw stimulation elicited brain activation only in the contralateral primary somatosensory (S1) cortex. Acute noxious forepaw stimulation induced activation in additional brain areas associated with pain perception, including the secondary somatosensory cortex (S2), thalamus, insula and limbic regions. Lidocaine administered at IV doses of either 1 mg/kg, 4 mg/kg or 10 mg/kg did not abolish or diminish brain activation in response to innocuous or noxious stimulation. In fact, IV doses of 4 mg/kg and 10 mg/kg lidocaine enhanced S1 and S2 responses to acute nociceptive stimulation, increasing the activated cortical volume by 50%–60%. CONCLUSION The analgesic action of systemic lidocaine in acute pain is not reflected in a straightforward interruption of pain-induced fMRI brain activation as has been observed with opioids. The enhancement of cortical fMRI responses to acute pain by lidocaine observed here has also been reported for cocaine. We recently showed that both lidocaine and cocaine increased intra-cellular calcium concentrations in cortex, suggesting that this pharmacological effect could account for the enhanced sensitivity to somatosensory stimulation. As our model only measured physiological acute pain, it will be important to also test the response of these same pathways to lidocaine in a model of neuropathic pain to further investigate lidocaine’s analgesic mechanism of action.

A digital frequency ramping method (DFRM) is proposed to improve the signal-to-noise ratio (SNR) of Doppler flow imaging in Fourier-domain optical coherence tomography (FDOCT). To examine the efficacy of DFRM for enhancing flow detection, computer simulation and tissue phantom study were conducted for phase noise reduction and flow quantification. In addition, the utility of this technique was validated in our in vivo clinical bladder imaging with endoscopic FDOCT. The Doppler flow images reconstructed by DFRM were compared with the counterparts by traditional Doppler FDOCT. The results demonstrate that DFRM enables real-time Doppler FDOCT imaging at significantly enhanced sensitivity without hardware modification, thus rendering it uniquely suitable for endoscopic subsurface blood flow imaging and diagnosis.

A dual-imaging modality is demonstrated for high-resolution quantitative imaging of local cerebral blood flow in the rat cortex by combining simultaneous spectral-domain Doppler optical coherence tomography (SDOCT) and full-field laser speckle contrast imaging (LSCI). Preliminary studies in tissue flow phantom and cocaine-induced cerebral blood flow changes indicated that by correlating coregistered cortical arterial blood flow, the relative measurement of flow changes by LSCI could be accurately calibrated by the absolute flow imaging provided by SDOCT (least square fit, r(2) approximately 0.96). Quantitative LSCI of cerebral blood flow is crucial to the quantitative analyses of the spatiotemporal hemodynamics of functional brain activations and thus improved understanding of neural process.