Characterization of effects of mean arterial blood pressure induced by cocaine and cocaine methiodide on BOLD signals in rat brain

Abstract

A total of 45 male Sprague-Dawley rats were employed to determine whether cocaine or cocaine methiodide (CM) administration can induce a significant increase in mean arterial blood pressure (MABP) in rats, and whether such an increase in MABP can produce a global increase in blood oxygenation level-dependent (BOLD) contrast in the rat brain detectable by functional magnetic resonance imaging (fMRI). Cocaine methiodide is a quaternary derivative of cocaine that shares the same cardiovascular effects of cocaine, but does not penetrate the blood-brain barrier ( Since the development of functional MRI (fMRI) in the early 1990s, this noninvasive neuroimaging modality has rapidly gained a prominent position in systems-level neuroscience research to map cognitive brain functions. Recent studies have applied fMRI methodologies to localize acute pharmacological effects and detect changes in regional brain activity of abused substances in humans (1-3) and animals (4 -6). However, there is concern as to whether fMRI methods used to map cognitive function can be simply and directly extended to neuropharmacological studies.There are several issues to be addressed. First, it is not clear how peripheral and cardiovascular changes induced by drug administration affect blood oxygenation level-dependent (BOLD) contrast in the brain. Since the most commonly used fMRI method relies on BOLD contrast, which is a result of oversupply of local cerebral blood oxygen during increased neuronal activity, it is conceivable that acute drug-induced respiratory changes, as well as mean arterial blood pressure (MABP) and heart rate (HR) increases, could cause global cerebral blood flow changes and result in BOLD signal changes. For example, we demonstrated previously (6) that heroin administration affects respiratory inhibition and causes a global decrease in the BOLD signal, although such a global decrease in BOLD contrast can be eliminated using the proper artificial respiratory rate with normal pressures of blood gases. It is not clear how MABP and HR changes affect detection of the BOLD signal in the brain.Second, the pharmacological administration of drugs such as cocaine can induce not only neuronal activity but also cerebral vascular constriction. In a pioneering pharmacological fMRI study, Breiter et al. (1) detected changes in the nucleus accumbens after acute cocaine administration, implicating changes in the brain networks associated with induced euphoria and craving. Data from Kaufman et al. (7), using MR angiography (MRA), suggest that cocaine administration can cause cerebral vasoconstriction in the human brain. These studies indicate that cocaine administration induces not only neuronal activity, but also a cerebrovascular response and a decrease in blood flow. It is necessary to characterize such confounding factors when interpreting BOLD signal changes in pharmacological fMRI research.Third, when applying pharmacological fMRI methods to the study of neuronal activity, the question of how druginduced peripheral and cerebral vasc...

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

“…Whether temporal correlations observed between the time series from different brain regions truly reflect correlation between neural activity rather than correlation between drug-induced changes in cerebral blood flow remains difficult to be certain. However, it has been shown that the shape of the hemodynamic response that is used to estimate effects in fMRI studies is not altered by drugs known to have vascular effects (Gollub et al, 1998;Luo et al, 2003;Murphy et al, 2006). Furthermore, even if the effects of delta-9-THC and/or CBD on global cerebral blood flow were to have influenced the results of the connectivity analysis, such effects would not have been localized to specific brain regions as observed here.…”

Effects of hypoxia, hyperoxia, and hypercapnia on baseline and stimulus-evoked BOLD, CBF, and CMRO2 in spontaneously breathing animals

“…Of note, in an fMRI study performed at 4.7 T, Spenger et al (2000) also report highly variable activations outside the somatosensory pathway (with no changes in MABP and HR) during forepaw stimulation in rats under α-chloralose anesthesia previously optimized to eliminate pain response to electrical stimulation. Second, isoflurane also depresses cerebrovascular reactivity to CO 2 relative to awake conditions (Sicard et al, 2003) which may explain the stronger hypercapnic challenges required to derive M. In animal studies, 5% and 10% CO 2 challenges are commonly used with other anesthetics (Luo et al, 2003;Wu et al, 2002), and the former is frequently used in human studies (Davis et al, 1998;Hoge et al, 1999). Third, isoflurane is a cerebrovasodilator which increases basal CBF (Hendrich et al, 2001;Matta et al, 1999), thus potentially reducing the head room for forepaw stimulation-or hypercapnia-evoked CBF and/or BOLD increases.…”

“…Another implication is in pharmacological fMRI. Following drug administration, for example, the baseline physiological state of the brain could be different regionally or globally due to drug-induced changes in respiration rate, blood pressure and/or volume, and vascular tone (Luo et al, 2003). These alterations, which are independent of the drug-induced changes in neural activity, could markedly affect the relative stimulus-evoked fMRI signals.…”

Cocaine Increases the Intracellular Calcium Concentration in Brain Independently of Its Cerebrovascular Effects

“…For example, using 0.7% halothane, 1 mg/kg cocaine was found to elicit widespread increases in regional CBV using contrast and functional MRI (fMRI) (Marota et al, 2000). In another study, urethane was used as an anesthetic, and cocaine was found to cause widespread and dosedepended early decreases and later increases in the blood oxygenation level-dependent (BOLD) fMRI signal with intravenous cocaine challenges in the rat brain (Luo et al, 2003). Recently, isoflurane-anesthetized rats were used, and intravenous cocaine (1 mg/kg) was found to elicit a negative BOLD fMRI signal on the cortical surface (Schmidt et al, 2006), which is especially relevant for our study because our optical probe only records changes in the cortical surface (1-2 mm) (Du et al, 2005).…”