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Official websites use. Share sensitive information only on official, secure websites. Corresponding authors: Y. Iris Chen , Ph. Chronic use of cocaine is associated with lasting alterations in brain metabolism, circuitry and receptor properties. Functional connectivity analysis showed increased correlations in the SA rats upon acute cocaine challenge, especially in the S1, mPFC, and thalamus. Since D3 receptors are postulated to increase following chronic cocaine administration we also examined the response to 0. Cocaine SA animals showed a decreased overall CBV response to this drug, except in the globus pallidus. The hypothalamus showed a negative CBV change in response to cocaine challenge similar to that noted with the D3 agonist and showed a smaller response in the cocaine-SA animals than the controls. Given the good coupling of cerebral hemodynamics with dopamine dynamics previously observed with phMRI, these data suggest that increased persistence of dopamine in prefrontal cortex may be responsible for some of the behavioral alterations observed subsequent to chronic cocaine use. Chronic use of cocaine can lead to enduring alterations in brain circuitry including both limbic elements such as the nucleus accumbens NAc and medial prefrontal cortex mPFC as well as alterations in motor circuitry Schmidt et al. This chronic use can also lead to alterations in cerebral blood flow and metabolism Volkow et al. Prior evidence in primates as well as rodents shows that chronic cocaine can lead to decreases in dopamine DA D2 receptor binding Volkow et al. There is also evidence for upregulation of D3 receptors following chronic cocaine intake in rodents Neisewander et al. Magnetic resonance imaging can provide maps of brain activity across the whole brain associated with stimulation of drugs such as cocaine Chen et al. The response of a given brain region to a drug such as cocaine or amphetamine is associated with both positive and negative hemodynamic changes reflected in either BOLD, cerebral blood flow CBF or cerebral blood volume CBV measures. This points out one of the fundamental strengths of the MRI experiments that not only does one get a map, but also a time course, and this time course, in the case of drugs such as cocaine or amphetamine, can be associated with the time course of DA in the brain Chen et al. In this manuscript we examined the response to both a cocaine challenge as well as a challenge to a D3-preferring agonist 7-hydroxy-NN-di-r-propylaminotetralin 7-OHDPAT in animals trained to self-administer SA cocaine and saline-yoked controls. In particular we wished to determine what alterations might be observed in the mPFC — limbic circuitry including the nucleus accumbens and pedunculopontine tegmental nucleus PPTg. We recently showed that the latter region is strongly involved in the limbic circuitry associated with cocaine reinstatement Schmidt et al. We further postulated that we would be able to see alterations in the D3 receptor circuitry as a consequence of cocaine self-administration. Animals were single-housed with food and water available ad libitum. All experimental procedures were performed during the light phase. Rats were allowed one week to acclimate to their home cages upon arrival. Louis, MO. An indwelling catheter CamCaths; Cambridge, UK was inserted into the right, external jugular vein and sutured securely in place. The catheter was connected to a mesh backmount, which was implanted subcutaneously above the shoulder blades. In order to prevent infection and to maintain patency, catheters were flushed daily with 0. When not in use, the catheters were sealed with plastic obturators. After surgery, rats were allowed seven days to recover before behavioral testing commenced. Initially, rats were placed in operant chambers daily and allowed to lever press for intravenous cocaine 0. Each session began with the i. Rats were allowed to self-administer a maximum of 30 injections per minute operant session. After stable responding was achieved, animals were switched to a fixed-ratio five FR5 schedule of reinforcement. The maximum number of injections was again limited to 30 per daily self-administration session under the FR5 schedule. For both the FR1 and FR5 schedules, a 20 second time-out period followed each cocaine infusion, during which time active lever responses were tabulated but had no scheduled consequences. In this experiment, rats were randomly assigned to one of two groups: cocaine-experimental or saline-yoked. Each rat trained to respond for contingent cocaine infusions cocaine-experimental was paired with a yoked subject that received infusions of saline. Responses on the inactive lever were not reinforced for the experimental cocaine rat. Lever pressing for the saline-yoked rats had no scheduled consequences, but these animals received the same number and temporal pattern of infusions as self-administered by the paired cocaine-experimental rat. After 21 days of operant training, rats experienced 28 days of forced drug abstinence spent in home cages , a length of time equivalent to the combined extinction and reinstatement phases of the behavioral studies from the same cohort of animals that were not scanned described in Schmidt et al. Schmidt et al. Following this period of forced drug abstinence, rats underwent imaging. The animals were ventilated to maintain pCO2 in a normal physiological range mmHg during the imaging session. Scanning took place under halothane anesthesia 1. The tail vein was catheterized for both contrast agent and drug administration. Arterial blood gas sampling and blood pressure were measured by catheterization of the femoral artery. Blood gases were taken periodically before and during imaging while blood pressure was measured continuously throughout the session. Animals were scanned in a 9. Iron oxide contrast agent was injected through a tail vein to sensitize the images to CBV as described previously Chen et al. Then continuous imaging was performed to attain a post-MION baseline time points before cocaine administration. The cocaine challenge injection was administered through a tail vein as a bolus 0. Temporal resolution was 10s per time point. We administered 0. At this time point cocaine effects have recovered to baseline for CBV and the lifetime for cocaine in the rat brain is about 20 min Du et al. In macaques and Sprague-Dawley rats, our PET data shows that tracer level doses of cocaine are back to baseline in about 40 min, quite similar to what has been reported in humans Telang et al. Our microdialysis studies in rats show that extracellular fluid ECF DA levels return to baseline in less than 40 min when using 0. Chen et al. Therefore the 60 min interval we chose was to allow for clearance of cocaine and DA, but to minimize the time spent under anesthesia. For the 7-OHDPAT the rationale for the dose was to use a dose that evokes strong behavioral effects and also evokes strong alterations in cerebral blood volume, but still shows selectivity for D3 over D2 receptors. All images were registered onto the same standard brain template for subsequent averaging across animals using an automatic routine developed by Dr. JB Mandeville. Registration between the functional image set and the standard template was performed by adjusting 12 registration variables 3 translations, 3 rotation angles, 3 skew non-rigid angles and 3 inflations on the 3 major planes. The imaging data were analyzed by conversion of changes in signal intensity to CBV values. The CBV time courses from the ROIs were fit to gamma variate functions using a general linear model and statistical maps were corrected for the total numbers of voxels fit for in the image in the brain only. Maps were constructed for both the self-administering animals as well as the saline-yoked controls of the following: significant changes in CBV, peak CBV values, the full width half maximum FWHM of the gamma variate function, and the contrast between all these functions in the self-administering as well as saline animals. Seed-based functional connectivity analysis was carried out on the set of CBV study with acute cocaine challenge. CBV temporal profiles from selected seeding areas were used as basis functions temporally detrained for correlation analysis through the whole brain on a pixel-by-pixel basis AFNI 3dDeconvolve. Functional connectivity associated with cocaine challenge was obatined using the contextual dependent approach to deconvolve functional connectivity from the basal resting period. We examined the response to cocaine stimulus 0. In both groups, cocaine induces a biphasic signal change with an early negative CBV response followed by a larger positive response. Such a map is shown for the cocaine-SA animals and saline-yoked animals in Fig. Overall, the pattern of response to the cocaine challenge is reasonably similar between the cocaine SA and saline-yoked controls as shown in the maps in Fig. However, there were significant differences in a number of brain regions. The group data are reported in Table 1. Comparisons between the cocaine SA and saline-yoked animals for the brain regions showing significant differences in the two groups are shown in Figs. Interestingly, in the hypothalamus cocaine induces a monotonic negative CBV change Fig. In either case, there was a significant difference between the cocaine SA and saline-yoked controls with the cocaine SA animals having the smaller response for cocaine SA vs. The hypothalamic signal may represent D3 receptor mediated signal change as suggested by our recent data with D3 receptors Choi et al. CBV responses to acute cocaine challenge 0. The upper panel shows brain areas with transient CBV decreases fit to the green line , the 2 nd panel shows brain areas with CBV increases fit to the red line. Time courses are from the whole CPu. Cocaine was administered at 0. Time courses are taken from ROI the blue filled areas in the top panel bilaterally only one side is shown in blue for clarity. Maps are shown for significant changes in CBV in both the cocaine-SA animals and saline-yoked controls. Time courses are taken from ROI the blue filled areas in the top panel. CBV response to acute cocaine challenge in M1 motor cortex. Maps are shown for regions showing significant differences between the cocaine-SA animals and controls in CBV amplitude. CBV response to acute cocaine challenge in the hypothalamus. Note that in this brain regions the changes in CBV induced by cocaine challenge are negative compared to the positive CBV changes observed in the brain regions shown in the prior figures. These data analyses were performed using different seed regions and the response during the 16 min during which CBV is elevated following cocaine injection after correction for the effects of the baseline see Methods for full description of the analysis. These data revealed that at 28 days of abstinence the cocaine group demonstrated increased functional connectivity from almost all seed regions to other brain regions. The effects were particularly strong in numerous cortical areas — especially in S1 as well as mPFC, whether seeded from cortex or from thalamus. Shown in Fig. Quantitative results are shown in Fig Blue lines encircle the ROIs for the seeding areas. Cross correlation of functional connectivity upon acute cocaine challenge. Values represent correlation coefficients derived from connectivity analysis made as described in the Methods. We were also interested in probing D3 receptor function as there are suggestions of increased D3 receptor binding in rats abstinent from cocaine for time periods comparable to those of the rats we studied here Neisewander et al. Therefore, at the end of the cocaine imaging session sixty min following cocaine injection , we injected a D3 preferring agonist 7-OHDPAT at 0. There is a delayed CBV increase in the globus pallidus in saline-yoked animals, indicating downstream activity of the dopaminergic striato-pallidal neurons. The delayed positive CBV response was greater in the cocaine-SA rats, compared to the saline-yoked rats. These results indicate a pattern of alterations in limbic and motor circuitry in animals trained to self-administer cocaine. Our data show alterations in brain regions not previously described, such as hypothalamus or little described such as the PPTg. Our data also show altered time courses for the CBV changes elicited by cocaine in various brain regions that have not previously been described such as hypothalamus. We found that there is a pronounced increase in the response to cocaine, as measured using the amplitude of changes in CBV, in primary motor cortex M1 and in motor regions of the CPu. Smaller increases were noted in the PPTg. These changes are accompanied by alterations in functional connectivity in the cocaine SA animals. The alterations show large increases in the functional connectivity overall, with the largest increases occurring to and from cortical areas. These increases are not inconsistent with sensorimotor sensitization noted with cocaine self-administration. Given the ability of cocaine to greatly increase locomotor activity in rodents as well as to produce locomotor sensitization after chronic exposure Marin et al. Given that we only examined rats with saline-yoked controls rather than cocaine-yoked controls i. Locomotor sensitization does occur, however, with non-contingent administration of cocaine Marin et al. There is a large body of evidence indicating dysregulation of the prefrontal cortex and its glutamatergic connections to the NAc as a consequence of substance abuse Thomas et al. It is unclear, however, what form such alterations might take in vivo. There are two possible explanations for this. This mechanism was tested in both wild-type mice and mice with knockouts of catechol-O-methyltransferase COMT where it was found that cocaine induced an increased overflow time for DA without increasing the peak DA amplitude Yavich et al. These prior studies show that the induced CBV changes following cocaine or amphetamine challenge can be used as a readout for changes in DA concentration. Genetic polymorphisms of COMT that lead to higher or lower activity and thereby lead to increased or decreased DA metabolism produce correspondingly increased or decreased fMRI response in reward tasks in frontal cortex Dreher et al. Human studies show decreased functional connectivity in cocaine abusers compared to controls in either the resting state or in selective tasks using fMRI or following cocaine administration Li et al. Our data show increased functional connectivity in rats. There a several possible interpretations of these differences. First, in humans, there are disparities in total cocaine administered and time of administration compared to our well controlled group. Second, the humans are awake in the scanner and this may lead to profound differences in the connectivities. We recently showed that infusion of the AMPA antagonist CNQX directly into the PPTg attenuated the ability of a priming injection of cocaine to reinstate drug seeking in animals trained with the same self-administration protocol as those used in this study Schmidt et al. This would accord with increased glutamatergic tone in the PPT that is reflected in increased CBV in response to cocaine and with the increased response we see in mPFC. Interestingly, in the first minute after cocaine infusion there is a transient decrease in CBV that has recently been reported by Luo et al. Luo et al. Our maps of this early dip show that it is quite close to maps one sees with D2 agonists Chen et al. Since D2 presynaptic receptors as well as D3 receptors have a much higher affinity for DA than do post-synaptic D2 or D1 receptors Cooper et al. A previous study found a large decrease in the amplitude of the BOLD response to a cocaine challenge in rats that had been given repeated i. Those data were collected in awake rats without control of CO 2. Administration of cocaine can lead to hyperventilation Sharkey et al. Our data show, however, that there are not huge differences in the amplitude of the response to cocaine in self-administering and saline-yoked controls, but rather more subtle regional differences in peak response and FWHM. The effects of cocaine on dopamine receptors have been previously examined using in vivo positron emission tomography scans in rodents and primates including monkeys and humans. These studies show a consistent pattern of decreased D2 binding potential in both animals self-administering cocaine Volkow et al. Not as much work has gone into studying the effects of chronic cocaine administration on D3 receptors. One study of cocaine SA found that days after abstinence that there was no change in D3 binding as measured using autoradiography, but at 30 days of abstinence following cocaine there was an increase in D3 receptor binding Neisewander et al. Oddly in that paper they used a challenge dose of cocaine 24 hrs before the D3 autoradiography. Other data showed that a single dose of cocaine was enough to increase D3 receptor expression Le Foll et al. It should be noted that the phMRI data is producing a readout on the functional status of the receptors as opposed to autoradiography which looks at a static picture of receptors available for binding. Our data could be explained in two ways. Since we challenged the animals with cocaine 60 min before the D3 agonist it is possible that the decrease in D3R is larger in the cocaine SA animals than in controls. The other possibility is that there is diminished D3 tone overall in the cocaine SA animals, although this explanation would not agree with the D3 findings in either Neisewander et al. Future molecular studies examining the functional status of these receptors should serve to distinguish between these two possibilities. Although the primary response to cocaine in both the cocaine SA animal as well as the saline-yoked controls is mostly positive — there are brain regions in which a negative CBV response is found such as the septum or hypothalamus. The response of the hypothalamus to cocaine challenge produced a negative CBV change in both the cocaine SA animals as well as the saline-yoked controls. The time course for this change was quite distinct from that produced in the areas of the brain where mostly positive CBV changes were noted compare Figs. Therefore, these data suggest that measurement of cocaine-induced signal changes in hypothalamus may produce a readout on the status of D3 receptors, although this concept requires further proof. In summary, cocaine produces enduring changes in brain circuitry consistent with both motor sensitization increase response to cocaine challenge in M1 cortex and motor striatum as well as limbic alterations altered dynamics in medial prefrontal cortex and decreased response to D3R stimulation in the nucleus accumbens. These data suggest the great potential that in vivo neuroimaging may play in discovering alterations in dopaminergic circuitry in brains subject to chronic intake of psychostimulants. As a library, NLM provides access to scientific literature. Eur J Neurosci. Published in final edited form as: Eur J Neurosci. Find articles by Y Iris Chen. Find articles by Katie Famous. Find articles by Haibo Xu. Ji-Kyung Choi 1 Athinoula A. Find articles by Ji-Kyung Choi. Joseph B Mandeville 1 Athinoula A. Find articles by Joseph B Mandeville. Find articles by Heath D Schmidt. Find articles by R Christopher Pierce. Bruce G Jenkins 1 Athinoula A. Find articles by Bruce G Jenkins. PMC Copyright notice. The publisher's version of this article is available at Eur J Neurosci. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

Mandeville where can I buy cocaine